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WO2024100531A1 - Méthode de traitement de troubles épileptiques - Google Patents

Méthode de traitement de troubles épileptiques Download PDF

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Publication number
WO2024100531A1
WO2024100531A1 PCT/IB2023/061196 IB2023061196W WO2024100531A1 WO 2024100531 A1 WO2024100531 A1 WO 2024100531A1 IB 2023061196 W IB2023061196 W IB 2023061196W WO 2024100531 A1 WO2024100531 A1 WO 2024100531A1
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WIPO (PCT)
Prior art keywords
subject
compound
pharmaceutically acceptable
administered
acceptable salt
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
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PCT/IB2023/061196
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English (en)
Inventor
Mahnaz ASGHARNEJAD
Wei Yin
Naga Venkatesha Murthy Pathi Jagannatham
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Takeda Pharmaceutical Co Ltd
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Takeda Pharmaceutical Co Ltd
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Publication of WO2024100531A1 publication Critical patent/WO2024100531A1/fr
Anticipated expiration legal-status Critical
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    • 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
    • A61P25/08—Antiepileptics; Anticonvulsants
    • 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
    • A61K31/4523—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems
    • A61K31/4545—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems containing a six-membered ring with nitrogen as a ring hetero atom, e.g. pipamperone, anabasine
    • 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
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2022—Organic macromolecular compounds
    • A61K9/205—Polysaccharides, e.g. alginate, gums; Cyclodextrin
    • A61K9/2054—Cellulose; Cellulose derivatives, e.g. hydroxypropyl methylcellulose

Definitions

  • the present invention relates to compounds and methods of treating seizure disorders in a subject in need thereof.
  • CH24H cholesterol 24-hydroxylase
  • CYP461 cytochrome P450 46 Al
  • 24HC has rapid efflux from neurons into the extracellular space and moves through the blood brain barrier into systemic circulation for hepatic elimination.
  • high levels of CH24H activity can increase 24HC levels in the extracellular space where it can act as a positive allosteric modulator of N-methyl-D-aspartate (NMD A) receptor activity in neurons.
  • NMD A N-methyl-D-aspartate
  • 24HC may also stimulate CH24H expression in astrocytes, which would deplete the cholesterol in lipid rafts required for glutamate uptake and decrease astrocytic cholesterol export to neurons. Decreased glutamate uptake could markedly increase extracellular glutamate leading to excitotoxicity in neurons.
  • High levels of 24HC can increased tonic neuronal hyperactivity resulting increased activity of NMD A receptor, depolarization, and excitotoxicity.
  • 24HC-mediated neuronal hyperactivity could contribute to developmental and epileptic encephalopathies (collectively, DEE) and other neurodegenerations such as those observed in patients diagnosed with 15Q duplication syndrome (Dup 15q) and cyclin-dependent kinase-like 5 deficiency disorder (CDD).
  • DEE and related neurodegenerations may be characterized by multiple seizure types, and developmental delay or regression, and affect approximately 100,000-200,000 people in the USA.
  • DEE includes a number of orphan syndromes, including Lennox-Gastaut syndrome (LGS), with an estimated prevalence of 1-5 individual(s) per 10,000 worldwide; and Dravet syndrome (DS), with an estimated prevalence of 1 individual per 15,700 people in the USA.
  • LGS Lennox-Gastaut syndrome
  • DS Dravet syndrome
  • Many DEE patients experience daily seizures resulting in a lower quality of life and significant morbidity. The seizures of most patients are refractory to current anti- seizure treatments and therefore there is a significant need for an effective therapy.
  • Increased NMDA receptor activation may produce excitotoxicity in other neurodegenerations, such as Huntington’s disease and Parkinson’s disease. Epileptiform seizure activity is present in about half of Alzheimer’s disease patients and is associated with faster cognitive decline.
  • postmortem CH24H levels are significantly higher in glia cells from Alzheimer’s disease patient’s brains than from cognitive controls.
  • plasma 24HC is significantly decreased in Alzheimer’s disease patients compared to 24HC levels from cognitive controls. This indicates that 24HC may accumulate in brains of Alzheimer’s disease patients and could cause induce NMD A- mediated epileptiform seizure activity and excitotoxicity mediated neuron death, contributing to Alzheimer’s disease etiology.
  • 24HC may decrease cholesterol synthesis in glia cells. Decreased cholesterol synthesis and increased cholesterol hydroxylation in astrocytes would decrease cholesterol transport to neurons, which would deplete their cholesterol rich lipid rafts, resulting in reduced signal transduction and cognitive deficits.
  • Compound 1 selectively binds to CH24H inhibiting enzyme activity.
  • Compound 1 may have significant therapeutic potential for treating disorders caused by 24HC-mediated neuronal hyperactivity, such as DEE and other neurodegenerations.
  • the present invention provides methods of treating seizure disorders comprising administering to a subject in need thereof, Compound 1 or a pharmaceutically acceptable salt thereof, wherein the subject experiences a reduction in seizure frequency.
  • One aspect of the present invention provides a method of treating a seizure disorder in a subject in need thereof, comprising administering to the subject a dose of from about 75 mg to about 650 mg of Compound 1 (Compound 1), or a dose equivalent of a pharmaceutically acceptable salt thereof, at least once per day over a treatment period wherein
  • the subject is diagnosed with cyclin-dependent kinase-like 5 deficiency disorder (CDD), Dravet syndrome (DS), or Lennox-Gastaut syndrome (LGS), and (b) the subject experiences a reduction in all seizure frequency of about 10% or more, wherein the reduction in seizure frequency lasts for at least 52 weeks during the treatment period.
  • CDD cyclin-dependent kinase-like 5 deficiency disorder
  • DS Dravet syndrome
  • LGS Lennox-Gastaut syndrome
  • the subject is diagnosed with CDD, and the subject experiences a reduction in all seizure frequency of about 20% or more, wherein the reduction in seizure frequency lasts for at least 52 weeks during the treatment period.
  • the subject experiences a reduction in all seizure frequency of about 30% or more for at least 72 weeks during the treatment period.
  • the subject is diagnosed with CDD, and the subject experiences a reduction in motor seizure frequency of about 40% or more, wherein the reduction in seizure frequency lasts for at least 52 weeks during the treatment period.
  • the subject experiences a reduction in motor seizure frequency of about 50% or more for at least 72 weeks during the treatment period. In other examples, the subject experiences a reduction in motor seizure frequency of about 55% or more for at least 100 weeks during the treatment period.
  • motor seizure frequency is the subject's seizure frequency for drop seizures; tonic-clonic, tonic, bilateral clonic, atonic, myoclonic-atonic, myoclonic-tonic-clonic, and focal seizures with bilateral hyperkinetic motor features.
  • the subject is diagnosed with DS, and the subject experiences a reduction in all seizure frequency of about 20% or more, wherein the reduction in seizure frequency lasts for at least 52 weeks during the treatment period.
  • the subject experiences a reduction in all seizure frequency of about 40% or more for at least 72 weeks during the treatment period.
  • the subject experiences a reduction in all seizure frequency of about 45% or more for at least 72 weeks during the treatment period.
  • the subject is diagnosed with DS, and the subject experiences a reduction in convulsive seizure frequency of about 20% or more, wherein the reduction in seizure frequency lasts for at least 52 weeks during the treatment period.
  • the subject experiences a reduction in convulsive seizure frequency of about 30% or more for at least 72 weeks during the treatment period.
  • the subject experiences a reduction in convulsive seizure frequency of about 40% or more for at least 100 weeks during the treatment period.
  • the subject is diagnosed with LGS, and the subject experiences a reduction in all seizure frequency of about 15% or more, wherein the reduction in seizure frequency lasts for at least 52 weeks during the treatment period.
  • the subject experiences a reduction in all seizure frequency of about 20% or more for at least 72 weeks during the treatment period.
  • the subject experiences a reduction in all seizure frequency of about 25% or more for at least 72 weeks during the treatment period.
  • the subject is diagnosed with LGS, and the subject experiences a reduction in drop seizure frequency of about 10% or more, wherein the reduction in seizure frequency lasts for at least 52 weeks during the treatment period.
  • the subject is diagnosed with LGS, and the subject experiences a reduction in convulsive seizure frequency of about 10% or more, wherein the reduction in seizure frequency lasts for at least 52 weeks during the treatment period.
  • Another aspect of the invention provides a method of treating a seizure disorder in a subject in need thereof, comprising administering to the subject a dose of from about 75 mg to about 650 mg of Compound 1 (Compound 1), or a dose equivalent of a pharmaceutically acceptable salt thereof, at least once per day, wherein
  • the subject is diagnosed with CDD, DS, or LGS, and
  • the subject is diagnosed with CDD, and the subject experiences a reduction in all seizure frequency of about 40% or more beginning at least 23 weeks after treatment onset. For example, wherein the subject experiences a reduction in all seizure frequency of about 45% or more beginning at least 23 weeks after treatment onset. In other examples, the subject experiences a reduction in all seizure frequency of about 45% or more beginning at least 61 weeks after treatment onset.
  • the subject is diagnosed with CDD, and the subject experiences a reduction in motor seizure frequency of about 50% or more beginning at least 23 weeks after treatment onset. And, in some examples, the subject experiences a reduction in motor seizure frequency of about 55% or more beginning at least 25 weeks after treatment onset. In other instances, the subject experiences a reduction in motor seizure frequency of about 60% or more beginning at least 61 weeks after treatment onset. And, in some instances, motor seizure frequency is the subject's seizure frequency for drop seizures; tonic- clonic, tonic, bilateral clonic, atonic, myoclonic-atonic, myoclonic-tonic-clonic, and focal seizures with bilateral hyperkinetic motor features.
  • the subject is diagnosed with DS, and the subject experiences a reduction in all seizure frequency of about 20% or more beginning at least 23 weeks after treatment onset. In some examples, the subject experiences a reduction in all seizure frequency of about 30% or more beginning at least 36 weeks after treatment onset. [0019] In some implementations, the subject is diagnosed with DS, and the subject experiences a reduction in convulsive seizure frequency of about 20% or more beginning at least 23 weeks after treatment onset. In some examples, the subject experiences a reduction in convulsive seizure frequency of about 40% or more beginning at least 60 weeks after treatment onset.
  • the subject is diagnosed with LGS, and the subject experiences a reduction in all seizure frequency of about 10% or more beginning at least 23 weeks after treatment onset.
  • the subject is diagnosed with LGS, and the subject experiences a reduction in drop seizure frequency of about 10% or more beginning at least 23 weeks after treatment onset. In other examples, the subject experiences a reduction in drop seizure frequency of about 15% or more beginning at least 61 weeks after treatment onset. [0022] In some implementations, the subject is diagnosed with LGS, and the subject experiences a reduction in convulsive seizure frequency of about 10% or more beginning at least 23 weeks after treatment onset. For instance, the subject experiences a reduction in convulsive seizure frequency of about 30% or more beginning at least 25 weeks after treatment onset.
  • the subject experiences a reduction in convulsive seizure frequency of about 40% or more beginning at least 61 weeks after treatment onset.
  • the subject is from about 2 years to about 17 years of age.
  • the subject is administered Compound 1 or a dose equivalent of a pharmaceutically acceptable salt thereof at a weight-adjusted dosage amount.
  • the subject is administered from about 75 mg to about 325 mg of Compound 1 or a dose equivalent of a pharmaceutically acceptable salt thereof at least once per day (e.g., QD, BID, TID, or QID).
  • the subject is administered from about 75 mg to about 325 mg of Compound 1 or a dose equivalent of a pharmaceutically acceptable salt thereof twice per day.
  • the subject is administered from about 75 mg to about 85 mg, from about 95 mg to about 105 mg, from about 115 mg to about 125 mg, from about 135 mg to about 145 mg, from about 155 mg to about 165 mg, from about 175 mg to about 185 mg, from about 195 mg to about 205 mg, from about 215 mg to about 225 mg, from about 235 mg to about 245 mg, from about 255 mg to about 265 mg, from about 275 mg to about 285 mg or from about 295 mg to about 305 mg of Compound 1 or a dose equivalent of a pharmaceutically acceptable salt thereof twice per day.
  • the subject is administered from about 105 mg to about 115 mg, from about 125 mg to about 130 mg, from about 155 mg to about 160 mg, or from about 175 mg to about 185 mg of Compound 1 or a dose equivalent of a pharmaceutically acceptable salt thereof twice per day.
  • the subject is administered about 80 mg, about 100 mg, about 110 mg, about 120 mg, about 130 mg, about 140 mg, about 160 mg, about 180 mg, about 200 mg, about 220 mg, about 240 mg, about 260 mg, about 280 mg, or about 300 mg of Compound 1 or a dose equivalent of a pharmaceutically acceptable salt thereof twice per day.
  • the subject is at least 18 years of age.
  • the subject is administered from about 95 mg to about 325 mg of Compound 1 or a dose equivalent of a pharmaceutically acceptable salt thereof at least once per day (e.g., QD, BID, TID, or QID).
  • a pharmaceutically acceptable salt thereof at least once per day (e.g., QD, BID, TID, or QID).
  • the subject is administered from about 95 mg to about 325 mg of Compound 1 or a dose equivalent of a pharmaceutically acceptable salt thereof twice per day.
  • the subject is administered from about 95 mg to about 105 mg, from about 195 mg to about 205 mg, or from about 295 mg to about 305 mg of Compound 1 or a dose equivalent of a pharmaceutically acceptable salt thereof twice per day.
  • the subject is administered from about 295 mg to about 305 mg of Compound 1 or a dose equivalent of a pharmaceutically acceptable salt thereof twice per day.
  • the subject is administered about 100 mg, about 200 mg, or about 300 mg of Compound 1 or a dose equivalent of a pharmaceutically acceptable salt thereof twice per day.
  • the subject is administered (e.g., concomitantly administered) at least one additional therapeutic agent.
  • the additional therapeutic agent is a barbiturate, a benzodiazepine derivative, a carboxamide derivative, a fatty acid derivative, a glucocorticoid, a herbal antiepileptic, a hydantoin derivative, an antiepileptic, a hypnotic/sedative, a succinimide derivative, or any combination thereof.
  • the additional therapeutic agent is phenobarbital, primidone, clobazam, clonazepam, clorazepate dipotassium, diazepam, lorazepam, midazolam, nitrazepam, carbamazepine, eslicarbazepine acetate, oxcarbazepine, rufmamide, valproate magnesium, valproate semisodium, valproate sodium, valproate sodium/valproic acid, valproic acid, vigabatrin, methylprednisolone, cannabis sativa, fosphenytoin, phenytoin, phenytoin sodium, brivaracetam, cannabidoil, cannabinoids, felbamate, lacosamide, lamotrigine, levetiracetam, stiripentol, sultiame, topiramate, zonisamide, potassium bromide, ethosux
  • Compound 1 or a pharmaceutically acceptable salt thereof is administered orally or administered through a gastrostomy tube or percutaneous endoscopic gastrostomy tube.
  • Compound 1 or a pharmaceutically acceptable salt thereof is administered orally.
  • Another aspect of the present invention provides a method of treating a seizure disorder in a subject in need thereof comprising administering to the subject a dose of from about 75 mg to about 650 mg of Compound 1 (Compound 1), or a dose equivalent of a pharmaceutically acceptable salt thereof, at least once per day, wherein
  • the subject is from about 2 years to about 17 years of age.
  • the subject is administered Compound 1 or a dose equivalent of a pharmaceutically acceptable salt thereof at a weight-adjusted dosage amount.
  • the subject is administered from about 75 mg to about 325 mg of Compound 1 or a dose equivalent of a pharmaceutically acceptable salt thereof at least once per day (e.g., QD, BID, TID, or QID). In some implementations, the subject is administered from about 75 mg to about 325 mg of Compound 1 or a dose equivalent of a pharmaceutically acceptable salt thereof twice per day.
  • a pharmaceutically acceptable salt thereof at least once per day (e.g., QD, BID, TID, or QID).
  • the subject is administered from about 75 mg to about 325 mg of Compound 1 or a dose equivalent of a pharmaceutically acceptable salt thereof twice per day.
  • the subject is administered from about 75 mg to about 85 mg, from about 95 mg to about 105 mg, from about 115 mg to about 125 mg, from about 135 mg to about 145 mg, from about 155 mg to about 165 mg, from about 175 mg to about 185 mg, from about 195 mg to about 205 mg, from about 215 mg to about 225 mg, from about 235 mg to about 245 mg, from about 255 mg to about 265 mg, from about 275 mg to about 285 mg or from about 295 mg to about 305 mg of Compound 1 or a dose equivalent of a pharmaceutically acceptable salt thereof twice per day.
  • the subject is administered from about 105 mg to about 115 mg, from about 125 mg to about 130 mg, from about 155 mg to about 160 mg, or from about 175 mg to about 185 mg of Compound 1 or a dose equivalent of a pharmaceutically acceptable salt thereof twice per day. And, in some implementations, the subject is administered about 80 mg, about 100 mg, about 110 mg, about 120 mg, about 130 mg, about 140 mg, about 160 mg, about 180 mg, about 200 mg, about 220 mg, about 240 mg, about 260 mg, about 280 mg, or about 300 mg of Compound 1 or a dose equivalent of a pharmaceutically acceptable salt thereof twice per day.
  • the subject is at least 18 years of age.
  • the subject is administered from about 95 mg to about 325 mg of Compound 1 or a dose equivalent of a pharmaceutically acceptable salt thereof at least once per day (e.g., QD, BID, TID, or QID). In other implementations, the subject is administered from about 95 mg to about 325 mg of Compound 1 or a dose equivalent of a pharmaceutically acceptable salt thereof twice per day. In some implementations, the subject is administered from about 95 mg to about 105 mg, from about 195 mg to about 205 mg, or from about 295 mg to about 305 mg of Compound 1 or a dose equivalent of a pharmaceutically acceptable salt thereof twice per day.
  • the subject is administered from about 295 mg to about 305 mg of Compound 1 or a dose equivalent of a pharmaceutically acceptable salt thereof twice per day. And, in some implementations, the subject is administered about 100 mg, about 200 mg, or about 300 mg of Compound 1 or a dose equivalent of a pharmaceutically acceptable salt thereof twice per day.
  • the subject experiences a reduction in all seizure frequency of about 45% or more beginning at least 23 weeks after treatment onset. In some implementations, the subject experiences a reduction in all seizure frequency of about 45% or more beginning at least 61 weeks after treatment onset. In other implementations, the subject experiences a reduction in motor seizure frequency of about 50% or more beginning at least 23 weeks after treatment onset. In some implementations, the subject experiences a reduction in motor seizure frequency of about 55% or more beginning at least 25 weeks after treatment onset. In some implementations, the subject experiences a reduction in motor seizure frequency of about 60% or more beginning at least 61 weeks after treatment onset.
  • motor seizure frequency is the subject's seizure frequency for drop seizures; tonic-clonic, tonic, bilateral clonic, atonic, myoclonic-atonic, myoclonic- tonic-clonic, and focal seizures with bilateral hyperkinetic motor features.
  • Another aspect of the present invention provides a method of treating a seizure disorder in a subject in need thereof comprising administering to the subject a dose of from about 75 mg to about 650 mg of Compound 1 (Compound 1), or a dose equivalent of a pharmaceutically acceptable salt thereof, at least once per day, wherein
  • the subject is from about 2 years to about 17 years of age.
  • the subject is administered Compound 1 or a dose equivalent of a pharmaceutically acceptable salt thereof at a weight-adjusted dosage amount.
  • the subject is administered from about 75 mg to about 325 mg of Compound 1 or a dose equivalent of a pharmaceutically acceptable salt thereof at least once per day (e.g., QD, BID, TID, or QID). In some implementations, the subject is administered from about 75 mg to about 325 mg of Compound 1 or a dose equivalent of a pharmaceutically acceptable salt thereof twice per day.
  • a pharmaceutically acceptable salt thereof at least once per day (e.g., QD, BID, TID, or QID).
  • the subject is administered from about 75 mg to about 325 mg of Compound 1 or a dose equivalent of a pharmaceutically acceptable salt thereof twice per day.
  • the subject is administered from about 75 mg to about 85 mg, from about 95 mg to about 105 mg, from about 115 mg to about 125 mg, from about 135 mg to about 145 mg, from about 155 mg to about 165 mg, from about 175 mg to about 185 mg, from about 195 mg to about 205 mg, from about 215 mg to about 225 mg, from about 235 mg to about 245 mg, from about 255 mg to about 265 mg, from about 275 mg to about 285 mg or from about 295 mg to about 305 mg of Compound 1 or a dose equivalent of a pharmaceutically acceptable salt thereof twice per day.
  • the subject is administered from about 105 mg to about 115 mg, from about 125 mg to about 130 mg, from about 155 mg to about 160 mg, or from about 175 mg to about 185 mg of Compound 1 or a dose equivalent of a pharmaceutically acceptable salt thereof twice per day. And, in some implementations, the subject is administered about 80 mg, about 100 mg, about 110 mg, about 120 mg, about 130 mg, about 140 mg, about 160 mg, about 180 mg, about 200 mg, about 220 mg, about 240 mg, about 260 mg, about 280 mg, or about 300 mg of Compound 1 or a dose equivalent of a pharmaceutically acceptable salt thereof twice per day.
  • the subject is at least 18 years of age.
  • the subject is administered from about 95 mg to about 325 mg of Compound 1 or a dose equivalent of a pharmaceutically acceptable salt thereof at least once per day (e.g., QD, BID, TID, or QID). In other implementations, the subject is administered from about 95 mg to about 325 mg of Compound 1 or a dose equivalent of a pharmaceutically acceptable salt thereof twice per day. In some implementations, the subject is administered from about 95 mg to about 105 mg, from about 195 mg to about 205 mg, or from about 295 mg to about 305 mg of Compound 1 or a dose equivalent of a pharmaceutically acceptable salt thereof twice per day.
  • the subject is administered from about 295 mg to about 305 mg of Compound 1 or a dose equivalent of a pharmaceutically acceptable salt thereof twice per day. And, in some implementations, the subject is administered about 100 mg, about 200 mg, or about 300 mg of Compound 1 or a dose equivalent of a pharmaceutically acceptable salt thereof twice per day.
  • the subject experiences a reduction in all seizure frequency of about 25% or more beginning at least 23 weeks after treatment onset. In some implementations, the subject experiences a reduction in all seizure frequency of about 50% or more beginning at least 61 weeks after treatment onset. In other implementations, the subject experiences a reduction in convulsive seizure frequency of about 25% or more beginning at least 23 weeks after treatment onset. In some implementations, the subject experiences a reduction in convulsive seizure frequency of about 30% or more beginning at least 25 weeks after treatment onset. And, in some implementations, the subject experiences a reduction in convulsive seizure frequency of about 40% or more beginning at least 61 weeks after treatment onset.
  • Another aspect of the present invention provides a method of treating a seizure disorder in a subject in need thereof comprising administering to the subject a dose of from about 75 mg to about 650 mg of Compound 1 (Compound 1), or a dose equivalent of a pharmaceutically acceptable salt thereof, at least once per day, wherein
  • the subject is from about 2 years to about 17 years of age.
  • the subject is administered Compound 1 or a dose equivalent of a pharmaceutically acceptable salt thereof at a weight-adjusted dosage amount.
  • the subject is administered from about 75 mg to about 325 mg of Compound 1 or a dose equivalent of a pharmaceutically acceptable salt thereof at least once per day (e.g., QD, BID, TID, or QID). In some implementations, the subject is administered from about 75 mg to about 325 mg of Compound 1 or a dose equivalent of a pharmaceutically acceptable salt thereof twice per day.
  • a pharmaceutically acceptable salt thereof at least once per day (e.g., QD, BID, TID, or QID).
  • the subject is administered from about 75 mg to about 325 mg of Compound 1 or a dose equivalent of a pharmaceutically acceptable salt thereof twice per day.
  • the subject is administered from about 75 mg to about 85 mg, from about 95 mg to about 105 mg, from about 115 mg to about 125 mg, from about 135 mg to about 145 mg, from about 155 mg to about 165 mg, from about 175 mg to about 185 mg, from about 195 mg to about 205 mg, from about 215 mg to about 225 mg, from about 235 mg to about 245 mg, from about 255 mg to about 265 mg, from about 275 mg to about 285 mg or from about 295 mg to about 305 mg of Compound 1 or a dose equivalent of a pharmaceutically acceptable salt thereof twice per day.
  • the subject is administered from about 105 mg to about 115 mg, from about 125 mg to about 130 mg, from about 155 mg to about 160 mg, or from about 175 mg to about 185 mg of Compound 1 or a dose equivalent of a pharmaceutically acceptable salt thereof twice per day. And, in some implementations, the subject is administered about 80 mg, about 100 mg, about 110 mg, about 120 mg, about 130 mg, about 140 mg, about 160 mg, about 180 mg, about 200 mg, about 220 mg, about 240 mg, about 260 mg, about 280 mg, or about 300 mg of Compound 1 or a dose equivalent of a pharmaceutically acceptable salt thereof twice per day.
  • the subject is at least 18 years of age.
  • the subject is administered from about 95 mg to about 325 mg of Compound 1 or a dose equivalent of a pharmaceutically acceptable salt thereof at least once per day (e.g., QD, BID, TID, or QID). In other implementations, the subject is administered from about 95 mg to about 325 mg of Compound 1 or a dose equivalent of a pharmaceutically acceptable salt thereof twice per day. In some implementations, the subject is administered from about 95 mg to about 105 mg, from about 195 mg to about 205 mg, or from about 295 mg to about 305 mg of Compound 1 or a dose equivalent of a pharmaceutically acceptable salt thereof twice per day.
  • the subject is administered from about 295 mg to about 305 mg of Compound 1 or a dose equivalent of a pharmaceutically acceptable salt thereof twice per day. And, in some implementations, the subject is administered about 100 mg, about 200 mg, or about 300 mg of Compound 1 or a dose equivalent of a pharmaceutically acceptable salt thereof twice per day.
  • the subject experiences a reduction in convulsive seizure frequency of about 10% or more beginning at least 23 weeks after treatment onset. In other implementations, the subject experiences a reduction in convulsive seizure frequency of about 30% or more beginning at least 25 weeks after treatment onset. And, in some implementations, the subject experiences a reduction in convulsive seizure frequency of about 40% or more beginning at least 61 weeks after treatment onset.
  • the subject is administered at least one additional therapeutic agent.
  • the additional therapeutic agent is a barbiturate, a benzodiazepine derivative, a carboxamide derivative, a fatty acid derivative, a glucocorticoid, a herbal antiepileptic, a hydantoin derivative, an antiepileptic, a hypnotic/sedative, a succinimide derivative, or any combination thereof.
  • the additional therapeutic agent is phenobarbital, primidone, clobazam, clonazepam, clorazepate dipotassium, diazepam, lorazepam, midazolam, nitrazepam, carbamazepine, eslicarbazepine acetate, oxcarbazepine, rufmamide, valproate magnesium, valproate semisodium, valproate sodium, valproate sodium/valproic acid, valproic acid, vigabatrin, methylprednisolone, cannabis sativa, fosphenytoin, phenytoin, phenytoin sodium, brivaracetam, cannabidoil, cannabinoids, felbamate, lacosamide, lamotrigine, levetiracetam, stiripentol, sultiame, topiramate, zonisamide, potassium bromide
  • Figure 1 is a flow-chart of the clinical study according to Example 3.
  • Figure 2A is a plot of median percent change from baseline in seizure frequency per 28 day treatment period in subjects diagnosed with DS according to Example 3.
  • Figure 2B is a plot of median percent change from baseline in seizure frequency per 28 day treatment period in subjects diagnosed with LGS according to Example 3.
  • Figure 2C is a plot of median percent change from baseline in all seizure frequency per 28 day treatment period in subjects diagnosed with DS or LGS according to Example 3.
  • Figure 3 is a plot of median percent change from baseline in all seizure frequency per 28 day treatment period in subjects diagnosed with CDD according to Example 3.
  • Figure 4 is a plot of median percent change from baseline in motor seizure frequency per 28 day treatment period in subjects with CDD according to Example 3.
  • the present invention provides a method of treating a method of treating a method of treating a seizure disorder (e.g., a rare epilepsy or DEE disorder) in a subject, wherein the subject experiences a reduction in seizure frequency.
  • a seizure disorder e.g., a rare epilepsy or DEE disorder
  • One aspect of the present invention provides a method of treating a seizure disorder comprising administering to a subject in need thereof a therapeutically effective amount of Compound 1 or a dose equivalent of a pharmaceutically acceptable salt thereof.
  • the term "about”, when referring to a numerical value or range of values, allows for a degree of variability in the value or range or values, for example, within 10%, or within 5% of a stated value or of a stated limit of a range.
  • Compound 1 means a compound having the structure
  • Compound 1 having the structure above, may also be referred to herein as "[2,4'-bipyridin]- 3 -yl(4-benzyl-4-hydroxypiperidin- 1 -y Ijmethanone " or " (4-benzyl-4-hydroxypiperidin- 1 - yl)(2,4'-bipyridin-3-yl)methanone".
  • a method of chemically synthesizing Compound 1 is described in U.S. Patent Application Publication No. 2020/0172509, the disclosure of which is incorporated herein by reference in its entirety.
  • the term "pharmaceutically acceptable” means approved or approvable by a regulatory agency of the Federal or a state government or the corresponding agency in countries other than the United States, or that is listed in the U.S. Pharmacopoeia or other generally recognized pharmacopoeia for use in animals, and more particularly, in humans.
  • the term "reduction in seizure frequency” refers to the percent change from baseline of the seizure frequency per 28 day treatment period.
  • the percent change from baseline is calculated according to the formula (1): wherein P is the percent change from baseline, FT is the seizure frequency per 28 day treatment period, and FB is the seizure frequency per 28 day period at baseline, i.e., prior to treatment onset.
  • seizure frequency refers to the total number of seizures experienced by a subject during a 28 consecutive day period (i.e., 28 consecutive days of a treatment period or a 28 consecutive day period prior to treatment onset giving the baseline) divided by the number of days (with no missing seizure during the relevant 28 day period) multiplied by 28.
  • motor seizures refers to drop, tonic-clonic, tonic, bilateral clonic, atonic, myoclonic-atonic, myoclonic-tonic-clonic, and/or focal seizures with bilateral hyperkinetic motor features.
  • convulsive seizures refers to generalized tonic-clonic, focal to bilateral tonic-clonic with impaired awareness, and simultaneous bilateral clonic (generalized clonic) seizures. In patients diagnosed with DS, hemi-clonic seizures are included as convulsive seizures.
  • the term "subject" to which administration is contemplated includes, but is not limited to, humans (e.g., 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 mammal.
  • the subject is a human.
  • 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 (or any symptom thereof), or retards or slows the progression of the disease, disorder or condition (“therapeutic treatment”), and also contemplates a prophylactic action that occurs before a subject begins to suffer from the specified disease, disorder or condition.
  • 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.
  • the present invention contemplates administration of the compounds of the present invention or a pharmaceutically acceptable salt or a pharmaceutically acceptable composition thereof, as a prophylactic before a subject begins to suffer from the specified disease, disorder or condition.
  • a prophylactically effective amount of a compound is an amount sufficient to prevent a disease, disorder or condition, or one or more symptoms associated with the disease, disorder or condition, or prevent its recurrence.
  • a prophylactically effective amount of a compound means an amount of a therapeutic agent, alone or in combination with other agents, which provides a prophylactic benefit in the prevention of the disease, disorder or condition.
  • the term “prophylactically effective amount” can encompass an amount that improves overall prophylaxis or enhances the prophylactic efficacy of another prophylactic agent.
  • treatment onset and “onset of treatment” are used interchangeably to refer to the day in which a treatment (e.g., administration of Compound 1 or a pharmaceutically acceptable salt thereof) begins.
  • a treatment e.g., administration of Compound 1 or a pharmaceutically acceptable salt thereof
  • the day of treatment onset is the day in which a chemotherapy is first administered.
  • treatment onset is the day in which Compound 1 or a pharmaceutically acceptable salt thereof is first administered.
  • the terms "initial” and “baseline” are used interchangeably herein and refer to seizure frequencies determined for a consecutive 28 day period prior to treatment onset.
  • the terms "cyclin-dependent kinase-like 5 deficiency disorder” and “CDD” are used interchangeably herein and refer to a developmental encephalopathy caused by pathogenic variants in the gene CDKL5. This unique disorder includes early infantile onset refractory epilepsy, hypotonia, developmental intellectual and motor disabilities, and cortical visual impairment.
  • DEE Developmental and epileptic encephalopathy
  • seizures As used herein, the terms “Developmental and epileptic encephalopathy” and “DEE” are used interchangeably herein and refer to a group of severe epilepsies that are characterized both by seizures, which are often drug-resistant, as well as encephalopathy, which is a term used to describe significant developmental delay or even loss of developmental skills.
  • Dravet syndrome and "DS” are used interchangeably herein and refer to an epilepsy syndrome, previously called severe myoclonic epilepsy of infancy (SMEI), that begins in infancy or early childhood and can include a spectrum of symptoms ranging from mild to severe.
  • SMEI severe myoclonic epilepsy of infancy
  • Children with Dravet syndrome initially show focal (confined to one area) or generalized (throughout the brain) convulsive seizures that start before 15 months of age (often before age one). These initial seizures are often prolonged and involve half of the body, with subsequent seizures that may switch to the other side of the body. These initial seizures are frequently provoked by seizures or exposure to increased temperatures or temperature changes, such as getting out of a bath. Other seizure types emerge after 12 months of age and can be quite varied.
  • Status epilepticus - a state of continuous seizure requiring emergency medical care - may occur frequently in these children, particularly in the first five years of life.
  • Lennox-Gastaut syndrome and “LGS” are used interchangeably herein and refer to a severe form of epilepsy that typically becomes apparent during infancy or early childhood. Affected children experience several different types of seizures most commonly atonic, tonic and atypical absence seizures.
  • the term "dose equivalent" means a bioequivalent dose.
  • the dose equivalent of a pharmaceutically acceptable salt of Compound 1 for a 50 mg dose of Compound 1 is the amount of the pharmaceutically acceptable salt (by weight) needed to provide a bioequivalent dose to the 50 mg dose of the free base of Compound 1.
  • the present invention provides a compound useful for treating seizures.
  • One aspect of the present invention provides Compound 1 (Compound 1).
  • Another aspect of the present invention provides a pharmaceutically acceptable salt of
  • the pharmaceutically acceptable salt of Compound 1 is nontoxic, and may be inorganic or organic acid addition salts and base addition salts.
  • such salts include: (1) acid addition salts, formed with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like; or formed with organic acids such as acetic acid, propionic acid, hexanoic acid, cyclopentanepropionic acid, glycolic acid, pyruvic acid, lactic acid, malonic acid, succinic acid, malic acid, maleic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, 3 -(4- hy dr oxybenzoyl) benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, 1,2-ethane-disulfonic acid, 2-hydroxy ethanesul
  • Salts further include, by way of example only, sodium, potassium, calcium, magnesium, ammonium, tetraalkylammonium, and the like; and when the compound contains a basic functionality, salts of non-toxic organic or inorganic acids, such as hydrochloride, hydrobromide, tartrate, mesylate, acetate, maleate, oxalate and the like.
  • non-toxic organic or inorganic acids such as hydrochloride, hydrobromide, tartrate, mesylate, acetate, maleate, oxalate and the like.
  • the compounds described herein can be formulated into pharmaceutical compositions that further comprise a pharmaceutically acceptable carrier, diluent, adjuvant or vehicle.
  • the present invention provides a pharmaceutical composition comprising a compound of the invention described above, and a pharmaceutically acceptable carrier, diluent, adjuvant or vehicle.
  • the present invention is a pharmaceutical composition comprising an effective amount of a compound of the present invention or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier, diluent, adjuvant or vehicle.
  • the present invention provides a pharmaceutical composition comprising a compound of the invention described above, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier, excipient, or diluent.
  • Pharmaceutically acceptable carriers include, for example, pharmaceutical diluents, excipients or carriers suitably selected with respect to the intended form of administration, and consistent with conventional pharmaceutical practices.
  • the invention provides a composition comprising a compound of this invention or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier, excipient, or diluent.
  • Pharmaceutical compositions of this invention comprise a therapeutically effective amount of Compound 1, or a pharmaceutically acceptable salt thereof.
  • a pharmaceutically acceptable derivative includes, but is not limited to, pharmaceutically acceptable prodrugs, salts, esters, salts of such esters, or any other adduct or derivative that upon administration to a patient in need is capable of providing, directly or indirectly, a compound as otherwise described herein, or a metabolite or residue thereof.
  • the term "pharmaceutically acceptable salt” refers to those salts that are, within the scope of sound medical judgement, suitable for use in contact with the tissues of humans and lower animals without undue toxicity, irritation, allergic response and the like.
  • Pharmaceutically acceptable salts are well known in the art. For example, S. M. Berge et al., describe pharmaceutically acceptable salts in detail in J. Pharmaceutical Sciences, 1977, 66, 1-19, incorporated herein by reference.
  • 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 include 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.
  • inorganic acids such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid and perchloric acid
  • 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.
  • salts include adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphorate, camphorsulfonate, citrate, cyclopentanepropionate, digluconate, dodecyl sulfate, ethane sulfonate, 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, pec
  • Salts derived from appropriate bases include alkali metal, alkaline earth metal, ammonium and N + (Ci-4alkyl)4 salts.
  • This invention also envisions the quaternization of any basic nitrogen-containing groups of the compounds disclosed herein. Water or oilsoluble or dispersible products may be obtained by such quaternization.
  • Representative alkali or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium, 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.
  • a pharmaceutically acceptable carrier may contain inert ingredients that do not unduly inhibit the biological activity of the compounds.
  • the pharmaceutically acceptable carriers should be biocompatible, e.g., non-toxic, non-inflammatory, non-immunogenic or devoid of other undesired reactions or side-effects upon the administration to a subject. Standard pharmaceutical formulation techniques can be employed.
  • the pharmaceutically acceptable carrier, adjuvant, or vehicle includes any and all solvents, diluents, or other liquid vehicle, dispersion or suspension aids, surface active agents, isotonic agents, thickening or emulsifying agents, preservatives, solid binders, lubricants and the like, as suited to the particular dosage form desired.
  • Remington's Pharmaceutical Sciences, Sixteenth Edition, E. W. Martin (Mack Publishing Co., Easton, Pa., 1980) discloses various carriers used in formulating pharmaceutically acceptable compositions and known techniques for the preparation thereof.
  • any conventional carrier medium is incompatible with the compounds described herein, such as by producing any undesirable biological effect or otherwise interacting in a deleterious manner with any other component(s) of the pharmaceutically acceptable composition
  • the use of such conventional carrier medium is contemplated to be within the scope of this invention.
  • side effects encompasses unwanted and adverse effects of a therapy (e.g., a prophylactic or therapeutic agent). Side effects are always unwanted, but unwanted effects are not necessarily adverse. An adverse effect from a therapy (e.g., prophylactic or therapeutic agent) might be harmful, uncomfortable, or risky.
  • Side effects include, but are not limited to, fever, chills, lethargy, gastrointestinal toxicities (including gastric and intestinal ulcerations and erosions), nausea, vomiting, neurotoxicities, nephrotoxicities, renal toxicities (including such conditions as papillary necrosis and chronic interstitial nephritis), hepatic toxicities (including elevated serum liver enzyme levels), myelotoxicities (including leukopenia, myelosuppression, thrombocytopenia and anemia), dry mouth, metallic taste, prolongation of gestation, weakness, somnolence, pain (including muscle pain, bone pain and headache), hair loss, asthenia, dizziness, extra-pyramidal symptoms, akathisia, cardiovascular disturbances and sexual dysfunction.
  • gastrointestinal toxicities including gastric and intestinal ulcerations and erosions
  • nausea vomiting
  • neurotoxicities including nephrotoxicities, renal toxicities (including such conditions as papillary necrosis and chronic interstitial nephritis)
  • hepatic toxicities including elevated
  • Some examples of materials that can serve as pharmaceutically acceptable carriers include, but are not limited to, ion exchangers, alumina, aluminum stearate, lecithin, serum proteins (such as human serum albumin), buffer substances (such as twin 80, phosphates, glycine, sorbic acid, or potassium sorbate), partial glyceride mixtures of saturated vegetable fatty acids, water, salts or electrolytes (such as protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, or zinc salts), colloidal silica, magnesium trisilicate, polyvinyl pyrrolidone, polyacrylates, waxes, polyethylene- polyoxypropylene-block polymers, methylcellulose, hydroxypropyl methylcellulose, wool fat, sugars such as lactose, glucose and sucrose; starches such as corn starch and potato starch; cellulose and its derivatives such as sodium carboxymethyl cellulose, ethyl cellulose and cellulose
  • compositions of the present invention may be administered orally, parenterally, by inhalation spray, topically, rectally, nasally, buccally, vaginally or via an implanted reservoir.
  • parenteral includes subcutaneous, intravenous, intramuscular, intra-articular, intra-synovial, intrasternal, intrathecal, intraocular, intrahepatic, intralesional and intracranial injection or infusion techniques.
  • the compositions are administered orally, intraperitoneally or intravenously.
  • Sterile injectable forms of the compositions of this invention may be aqueous or oleaginous suspension.
  • the sterile injectable preparation also may be a sterile injectable solution or suspension in a non-toxic parenterally-acceptable diluent or solvent, for example as a solution in 1,3-butanediol.
  • a non-toxic parenterally-acceptable diluent or solvent for example as a solution in 1,3-butanediol.
  • acceptable vehicles and solvents that may be employed are water, Ringer's solution and isotonic sodium chloride solution.
  • sterile, fixed oils are conventionally employed as a solvent or suspending medium.
  • any bland fixed oil may be employed including synthetic mono- or di-glycerides.
  • Fatty acids such as oleic acid and its glyceride derivatives
  • injectables are useful in the preparation of injectables, as are natural pharmaceutically acceptable oils, such as olive oil or castor oil, especially in their polyoxyethylated versions.
  • oils such as olive oil or castor oil, especially in their polyoxyethylated versions.
  • These oil solutions or suspensions also may contain a long-chain alcohol diluent or dispersant, such as carboxymethyl cellulose or similar dispersing agents that are commonly used in the formulation of pharmaceutically acceptable dosage forms including emulsions and suspensions.
  • Other commonly used surfactants such as Tweens, Spans and other emulsifying agents or bioavailability enhancers that are commonly used in the manufacture of pharmaceutically acceptable solid, liquid, or other dosage forms may also be used for the purposes of formulation.
  • compositions of this invention may be orally administered in any orally acceptable dosage form including, but not limited to, capsules, tablets, aqueous suspensions or solutions.
  • carriers commonly used include lactose and com starch.
  • Lubricating agents such as magnesium stearate, are also typically added.
  • useful diluents include lactose and dried cornstarch.
  • aqueous suspensions are required for oral use, the active ingredient is combined with emulsifying and suspending agents. If desired, certain sweetening, flavoring or coloring agents also may be added.
  • compositions of this invention may be administered in the form of suppositories for rectal or vaginal administration.
  • suppositories for rectal or vaginal administration.
  • These can be prepared by mixing the agent with a suitable non-irritating excipient that is solid at room temperature but liquid at rectal temperature and therefore will melt in the rectum or vaginal cavity to release the drug.
  • suitable non-irritating excipient include cocoa butter, polyethylene glycol or a suppository wax that is solid at ambient temperature but liquid at body temperature and therefore melt in the rectum or vaginal cavity and release the active compound.
  • compositions of this invention also may be administered topically, especially when the target of treatment includes areas or organs readily accessible by topical application, including diseases of the eye, skin, or lower intestinal tract. Suitable topical formulations are readily prepared for each of these areas or organs.
  • Topical application for the lower intestinal tract can be effected in a rectal suppository formulation (see above) or in a suitable enema formulation. Topically-transdermal patches also may be used.
  • the pharmaceutically acceptable compositions may be formulated in a suitable ointment containing the active component suspended or dissolved in one or more carriers.
  • Carriers for topical administration of the compounds of this invention include, but are not limited to, mineral oil, liquid petrolatum, white petrolatum, propylene glycol, polyoxyethylene, polyoxypropylene compound, emulsifying wax and water.
  • the pharmaceutically acceptable compositions can be formulated in a suitable lotion or cream containing the active components suspended or dissolved in one or more pharmaceutically acceptable carriers.
  • Suitable carriers include, but are not limited to, mineral oil, sorbitan monostearate, polysorbate 60, cetyl esters wax, cetearyl alcohol, 2-octyldodecanol, benzyl alcohol and water.
  • the pharmaceutically acceptable compositions may be formulated, e.g., as micronized suspensions in isotonic, pH adjusted sterile saline or other aqueous solution, or, preferably, as solutions in isotonic, pH adjusted sterile saline or other aqueous solution, either with or without a preservative such as benzylalkonium chloride.
  • the pharmaceutically acceptable compositions may be formulated in an ointment such as petrolatum.
  • the pharmaceutically acceptable compositions of this invention also may be administered by nasal aerosol or inhalation.
  • compositions are prepared according to techniques well-known in the art of pharmaceutical formulation and may be prepared as solutions in saline, employing benzyl alcohol or other suitable preservatives, absorption promoters to enhance bioavailability, fluorocarbons, and/or other conventional solubilizing or dispersing agents.
  • Liquid dosage forms for oral administration include, but are not limited to, pharmaceutically acceptable emulsions, microemulsions, solutions, suspensions, syrups and elixirs.
  • the liquid dosage forms may contain inert diluents commonly used in the art such as, for example, water or other solvents, solubilizing agents and emulsifiers such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3 -butylene glycol, dimethylformamide, oils (in particular, cottonseed, groundnut, corn, germ, olive, castor, and sesame oils), glycerol, tetrahydrofiirfuryl alcohol, polyethylene glycols and fatty acid esters of sorbitan, and mixtures thereof.
  • inert diluents such as, for example, water or other solvents, solub
  • Injectable preparations for example, sterile injectable aqueous or oleaginous suspensions, may be formulated according to the known art using suitable dispersing or wetting agents and suspending agents.
  • the sterile injectable preparation also may be a sterile injectable solution, suspension or emulsion in a nontoxic parenterally acceptable diluent or solvent, for example, as a solution in 1,3 -butanediol.
  • the acceptable vehicles and solvents that may be employed are water, Ringer's solution, U.S.P. and isotonic sodium chloride solution.
  • sterile, fixed oils are conventionally employed as a solvent or suspending medium.
  • any bland fixed oil can be employed including synthetic mono- or diglycerides.
  • fatty acids such as oleic acid may be used in the preparation of injectables.
  • the injectable formulations can be sterilized, for example, by filtration through a bacterial-retaining filter, or by incorporating sterilizing agents in the form of sterile solid compositions that can be dissolved or dispersed in sterile water or other sterile injectable medium prior to use.
  • a compound of the present invention In order to prolong the effect of a compound of the present invention, it is often desirable to slow the absorption of the compound from subcutaneous or intramuscular injection. This may be accomplished by the use of a liquid suspension of crystalline or amorphous material with poor water solubility. The rate of absorption of the compound then depends upon its rate of dissolution that, in turn, may depend upon crystal size and crystalline form. Alternatively, delayed absorption of a parenterally administered compound form is accomplished by dissolving or suspending the compound in an oil vehicle. Injectable depot forms are made by forming microencapsule matrices of the compound in biodegradable polymers such as polylactide-polyglycolide.
  • the rate of compound release can be controlled.
  • biodegradable polymers include poly(orthoesters) and poly(anhydrides).
  • Depot injectable formulations also are prepared by entrapping the compound in liposomes or microemulsions that are compatible with body tissues.
  • Solid dosage forms for oral administration include capsules, tablets, pills, powders, and granules.
  • the active compound is mixed with at least one inert, pharmaceutically acceptable excipient or carrier such as sodium citrate or dicalcium phosphate and/or a) fillers or extenders such as starches, lactose, sucrose, glucose, mannitol, and silicic acid, b) binders such as carboxymethylcellulose, alginates, gelatin, polyvinylpyrrolidinone, sucrose, and acacia, c) humectants such as glycerol, d) disintegrating agents such as agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicates, and sodium carbonate, e) solution retarding agents such as paraffin, f) absorption accelerators such as quaternary ammonium compounds, g) wetting agents such as, for example, cetyl alcohol and gly
  • Solid compositions of a similar type also may be employed as fillers in soft and hard- filled gelatin capsules using such excipients as lactose or milk sugar as well as high molecular weight polyethylene glycols and the like.
  • the solid dosage forms of tablets, dragees, capsules, pills, and granules can be prepared with coatings and shells such as enteric coatings and other coatings well known in the pharmaceutical formulating art.
  • Solid dosage forms optionally may contain opacifying agents.
  • These solid dosage forms also can be of a composition such that they release the active ingredient(s) only, or preferentially, in a certain part of the intestinal tract, optionally, in a delayed manner. Examples of embedding compositions that can be used include polymeric substances and waxes.
  • Solid compositions of a similar type also may be employed as fillers in soft and hard-filled gelatin capsules using such excipients as lactose or milk sugar as well as high molecular weight polethylene glycols and the like.
  • the active compounds also can be in micro-encapsulated form with one or more excipients as noted above.
  • the solid dosage forms of tablets, dragees, capsules, pills, and granules can be prepared with coatings and shells such as enteric coatings, release controlling coatings and other coatings well known in the pharmaceutical formulating art.
  • the active compound may be admixed with at least one inert diluent such as sucrose, lactose or starch.
  • Such dosage forms also may comprise, as is normal practice, additional substances other than inert diluents, e.g., tableting lubricants and other tableting aids such a magnesium stearate and microcrystalline cellulose.
  • the dosage forms also may comprise buffering agents. They may optionally contain opacifying agents and also can be of a composition such that they release the active ingredient(s) only, or preferentially, in a certain part of the intestinal tract, optionally, in a delayed manner.
  • buffering agents include polymeric substances and waxes.
  • Dosage forms for topical or transdermal administration of a compound of this invention include ointments, pastes, creams, lotions, gels, powders, solutions, sprays, inhalants or patches.
  • the active component is admixed under sterile conditions with a pharmaceutically acceptable carrier and any needed preservatives or buffers as may be required.
  • Ophthalmic formulation, ear drops, and eye drops also are contemplated as being within the scope of this invention.
  • the present invention contemplates the use of transdermal patches, which have the added advantage of providing controlled delivery of a compound to the body.
  • Such dosage forms can be made by dissolving or dispensing the compound in the proper medium.
  • Absorption enhancers also can be used to increase the flux of the compound across the skin. The rate can be controlled by either providing a rate controlling membrane or by dispersing the compound in a polymer matrix or gel.
  • the compounds of the invention preferably are formulated in dosage unit form for ease of administration and uniformity of dosage.
  • dosage unit form refers to a physically discrete unit of agent appropriate for the patient to be treated. It will be understood, however, that the total daily usage of the compounds and compositions of the present invention will be decided by the attending physician within the scope of sound medical judgment.
  • the specific effective dose level for any particular patient or organism will depend upon a variety of factors including the disorder being treated and the severity of the disorder; the activity of the specific compound employed; the specific composition employed; the age, body weight, general health, sex and diet of the patient; the time of administration, route of administration, and rate of excretion of the specific compound employed; the duration of the treatment; drugs used in combination or coincidental with the specific compound employed, and like factors well known in the medical arts.
  • Compounds and/or compositions of the invention can be delivered in a controlled release system.
  • a pump can be used to facilitate controlled release of the compounds and/or compositions of the invention (see Langer, supra; Sefton, CRC Crit. Ref. Biomed. Eng. 14:201 (1987); Buchwald et al., Surgery 88:507 (1980); Saudek et al., N. Engl. J. Med. 321 :574 (1989)).
  • compositions of the invention can comprise polymeric materials to provide sustained, intermediate, pulsatile, or alternate release (see MEDICAL APPLICATIONS OF CONTROLLED RELEASE, Langer and Wise (eds.), CRC Pres., Boca Raton, Fla. (1974); CONTROLLED DRUG BIO AVAILABILITY, DRUG PRODUCT DESIGN AND PERFORMANCE, Smolen and Ball (eds ), Wiley, New York (1984); Ranger and Peppas, J. Macromol. Sci. Rev. Macromol. Chem. 23:61 (1983); see also Levy et al., Science 228: 190 (1985); During et al., Ann. Neurol.
  • compositions should be formulated so that a dosage of between 0.01 - 100 mg/kg body weight/day of the inhibitor can be administered to a patient receiving these compositions.
  • the invention provides a pharmaceutical composition for treating a seizure disorder in a subject, wherein the pharmaceutical composition comprises Compound 1 (Compound 1), or a pharmaceutically acceptable salt thereof.
  • the present invention provides a method of treating a seizure disorder in a subject in need thereof, comprising administering to the subject a dose of from about 75 mg to about 650 mg of Compound 1 (Compound 1), or a dose equivalent of a pharmaceutically acceptable salt thereof, at least once per day over a treatment period wherein
  • the subject is diagnosed with cyclin-dependent kinase-like 5 deficiency disorder (CDD), Dravet syndrome (DS), or Lennox-Gastaut syndrome (LGS), and
  • CDD cyclin-dependent kinase-like 5 deficiency disorder
  • DS Dravet syndrome
  • LGS Lennox-Gastaut syndrome
  • the subject experiences a reduction in all seizure frequency of about 10% or more, wherein the reduction in seizure frequency lasts for at least about 12 weeks during the treatment period (i.e., the period in which Compound 1 or a pharmaceutically acceptable salt thereof is administered to the subject).
  • the treatment period has a duration that is at least as long as the period during which the reduction in seizure frequency is observed. In some implementations, the treatment period is at least about 12 weeks, at least about 24 weeks, at least about 36 weeks, at least about 48 weeks, at least about 60 weeks, or at least about 72 weeks.
  • the reduction in all seizure frequency lasts for at least about 12 weeks (e.g., at least about 13 weeks or from about 13 to about 108 weeks, at least about 24 weeks (e.g., from about 25 weeks to about 108 weeks), at least about 36 weeks (e.g., from about 37 to about 108 weeks), at least about 48 weeks (e.g., from about 49 to about 108 weeks), at least about 52 weeks (e.g., from about 53 to about 108 weeks), at least about 60 weeks (e.g., from about 61 to about 108 weeks), at least about 72 weeks (e.g., from about 73 to about 108 weeks), at least about 84 weeks (e.g., from about 85 to about 108 weeks), at least about 96 weeks (e.g., from about 97 to about 108 weeks), or at least about 108 weeks.
  • 12 weeks e.g., at least about 13 weeks or from about 13 to about 108 weeks, at least about 24 weeks (e.g., from about 25 weeks to about
  • the reduction in all seizure frequency lasts for at least about 52 weeks.
  • the subject is diagnosed with CDD, and the subject experiences a reduction in all seizure frequency of about 40% or more, wherein the reduction in seizure frequency lasts for at least about 12 weeks (e.g., from about 13 to about 108 weeks, at least about 24 weeks (e.g., from about 25 weeks to about 108 weeks), at least about 36 weeks (e.g., from about 37 to about 108 weeks), at least about 48 weeks (e.g., from about 49 to about 108 weeks), at least about 52 weeks (e.g., from about 53 to about 108 weeks), at least about 60 weeks (e.g., from about 61 to about 108 weeks), at least about 72 weeks (e.g., from about 73 to about 108 weeks), at least about 84 weeks (e.g., from about 85 to about 108 weeks), at least about 96 weeks (e.g., from about 97 to about 108 weeks),
  • the subject is diagnosed with CDD, and the subject experiences a reduction in motor seizure frequency of about 40% or more, wherein the reduction in seizure frequency lasts for at least about 12 weeks (e.g., from about 13 to about 108 weeks, at least about 24 weeks (e.g., from about 25 weeks to about 108 weeks), at least about 36 weeks (e.g., from about 37 to about 108 weeks), at least about 48 weeks (e.g., from about 49 to about 108 weeks), at least about 52 weeks (e.g., from about 53 to about 108 weeks), at least about 60 weeks (e.g., from about 61 to about 108 weeks), at least about 72 weeks (e.g., from about 73 to about 108 weeks), at least about 84 weeks (e.g., from about 85 to about 108 weeks), at least about 96 weeks (e.g., from about 97 to about 108 weeks), or at least about 108 weeks) during the treatment period.
  • the reduction in seizure frequency lasts for at least about 12
  • the subject experiences a reduction in motor seizure frequency of about 50% or more for at least 72 weeks during the treatment period. In other examples, the subject experiences a reduction in motor seizure frequency of about 55% or more for at least 100 weeks during the treatment period.
  • motor seizure frequency is the subject's seizure frequency for drop seizures; tonic-clonic, tonic, bilateral clonic, atonic, myoclonic-atonic, myoclonic-tonic-clonic, and focal seizures with bilateral hyperkinetic motor features.
  • the subject is diagnosed with DS, and the subject experiences a reduction in all seizure frequency of about 20% or more, wherein the reduction in seizure frequency lasts for at least about 12 weeks (e.g., from about 13 to about 108 weeks, at least about 24 weeks (e.g., from about 25 weeks to about 108 weeks), at least about 36 weeks (e.g., from about 37 to about 108 weeks), at least about 48 weeks (e.g., from about 49 to about 108 weeks), at least about 52 weeks (e.g., from about 53 to about 108 weeks), at least about 60 weeks (e.g., from about 61 to about 108 weeks), at least about 72 weeks (e.g., from about 73 to about 108 weeks), at least about 84 weeks (e.g., from about 85 to about 108 weeks), at least about 96 weeks (e.g., from about 97 to about 108 weeks), or at least about 108 weeks) during the treatment period.
  • the subject is diagnosed with DS, and the subject experiences a reduction in convulsive seizure frequency of about 20% or more, wherein the reduction in seizure frequency lasts for at least about 12 weeks (e.g., from about 13 to about 108 weeks, at least about 24 weeks (e.g., from about 25 weeks to about 108 weeks), at least about 36 weeks (e.g., from about 37 to about 108 weeks), at least about 48 weeks (e.g., from about 49 to about 108 weeks), at least about 52 weeks (e.g., from about 53 to about 108 weeks), at least about 60 weeks (e.g., from about 61 to about 108 weeks), at least about 72 weeks (e.g., from about 73 to about 108 weeks), at least about 84 weeks (e.g., from about 85 to about 108 weeks), at least about 96 weeks (e.g., from about 97 to about 108 weeks), or at least about 108 weeks) during the treatment period.
  • the reduction in seizure frequency lasts for at
  • the subject experiences a reduction in convulsive seizure frequency of about 30% or more for at least 72 weeks during the treatment period.
  • the subject experiences a reduction in convulsive seizure frequency of about 40% or more for at least 100 weeks during the treatment period.
  • the subject is diagnosed with LGS, and the subject experiences a reduction in all seizure frequency of about 20% or more, wherein the reduction in seizure frequency lasts for at least about 12 weeks (e.g., from about 13 to about 108 weeks, at least about 24 weeks (e.g., from about 25 weeks to about 108 weeks), at least about 36 weeks (e.g., from about 37 to about 108 weeks), at least about 48 weeks (e.g., from about 49 to about 108 weeks), at least about 52 weeks (e.g., from about 53 to about 108 weeks), at least about 60 weeks (e.g., from about 61 to about 108 weeks), at least about 72 weeks (e.g., from about 73 to about 108 weeks), at least about 84 weeks (e.g., from about 85 to about 108 weeks), at least about 96 weeks (e.g., from about 97 to about 108 weeks), or at least about 108 weeks) during the treatment period.
  • the subject is diagnosed with LGS, and the subject experiences a reduction in drop seizure frequency of about 10% or more, wherein the reduction in seizure frequency lasts for at least about 12 weeks (e.g., from about 13 to about 108 weeks, at least about 24 weeks (e.g., from about 25 weeks to about 108 weeks), at least about 36 weeks (e.g., from about 37 to about 108 weeks), at least about 48 weeks (e.g., from about 49 to about 108 weeks), at least about 52 weeks (e.g., from about 53 to about 108 weeks), at least about 60 weeks (e.g., from about 61 to about 108 weeks), at least about 72 weeks (e.g., from about 73 to about 108 weeks), at least about 84 weeks (e.g., from about 85 to about 108 weeks), at least about 96 weeks (e.g., from about 97 to about 108 weeks), or at least about 108 weeks) during the treatment period.
  • the reduction in seizure frequency lasts for at least about 12
  • the subject is diagnosed with LGS, and the subject experiences a reduction in convulsive seizure frequency of about 10% or more, wherein the reduction in seizure frequency lasts for at least 52 weeks during the treatment period.
  • the subject is from about 2 years to about 17 years of age.
  • the subject is administered Compound 1 or a dose equivalent of a pharmaceutically acceptable salt thereof at a weight-adjusted dosage amount.
  • the subject is administered from about 75 mg to about 325 mg of Compound 1 or a dose equivalent of a pharmaceutically acceptable salt thereof at least once per day (e.g., QD, BID, TID, or QID).
  • the subject is administered from about 75 mg to about 325 mg of Compound 1 or a dose equivalent of a pharmaceutically acceptable salt thereof twice per day.
  • the subject is administered from about 75 mg to about 85 mg, from about 95 mg to about 105 mg, from about 115 mg to about 125 mg, from about 135 mg to about 145 mg, from about 155 mg to about 165 mg, from about 175 mg to about 185 mg, from about 195 mg to about 205 mg, from about 215 mg to about 225 mg, from about 235 mg to about 245 mg, from about 255 mg to about 265 mg, from about 275 mg to about 285 mg or from about 295 mg to about 305 mg of Compound 1 or a dose equivalent of a pharmaceutically acceptable salt thereof twice per day.
  • the subject is administered from about 105 mg to about 115 mg, from about 125 mg to about 130 mg, from about 155 mg to about 160 mg, or from about 175 mg to about 185 mg of Compound 1 or a dose equivalent of a pharmaceutically acceptable salt thereof twice per day.
  • the subject is administered about 80 mg, about 100 mg, about 110 mg, about 120 mg, about 130 mg, about 140 mg, about 160 mg, about 180 mg, about 200 mg, about 220 mg, about 240 mg, about 260 mg, about 280 mg, or about 300 mg of Compound 1 or a dose equivalent of a pharmaceutically acceptable salt thereof twice per day.
  • the subject has a weight of from about 10 kg to about 14 kg, and the subject is administered about 30 mg to about 50 mg, about 70 mg to about 90 mg, or about 100 to about 120 mg of Compound 1 or a dose equivalent of a pharmaceutically acceptable salt thereof at least once per day (e.g., QD, BID, TID, or QID).
  • the subject has a weight of from about 10 kg to about 14 kg, and the subject is administered about 30 mg to about 50 mg, about 70 mg to about 90 mg, or about 100 to about 120 mg of Compound 1 or a dose equivalent of a pharmaceutically acceptable salt thereof twice per day.
  • the subject has a weight of from about 15 kg to about 19 kg, and the subject is administered about 50 mg to about 70 mg, about 90 mg to about 110 mg, or about 120 mg to about 140 mg of Compound 1 or a dose equivalent of a pharmaceutically acceptable salt thereof at least once per day (e.g., QD, BID, TID, or QID).
  • the subject has a weight of from about 15 kg to about 19 kg, and the subject is administered about 50 mg to about 70 mg, about 90 mg to about 110 mg, or about 120 mg to about 140 mg of Compound 1 or a dose equivalent of a pharmaceutically acceptable salt thereof twice per day.
  • the subject has a weight of from about 20 kg to about 24 kg, and the subject is administered about 50 mg to about 70 mg, about 110 mg to about 130 mg, or about 150 mg to about 170 mg of Compound 1 or a dose equivalent of a pharmaceutically acceptable salt thereof at least once per day (e.g., QD, BID, TID, or QID).
  • the subject has a weight of from about 20 kg to about 24 kg, and the subject is administered about 50 mg to about 70 mg, about 110 mg to about 130 mg, or about 150 mg to about 170 mg of Compound 1 or a dose equivalent of a pharmaceutically acceptable salt thereof twice per day.
  • the subject has a weight of from about 25 kg to about 29 kg, and the subject is administered about 50 mg to about 70 mg, about 110 mg to about 130 mg, or about 170 mg to about 190 mg of Compound 1 or a dose equivalent of a pharmaceutically acceptable salt thereof at least once per day (e.g., QD, BID, TID, or QID).
  • the subject has a weight of from about 25 kg to about 29 kg, and the subject is administered about 50 mg to about 70 mg, about 110 mg to about 130 mg, or about 170 mg to about 190 mg of Compound 1 or a dose equivalent of a pharmaceutically acceptable salt thereof twice per day.
  • the subject has a weight of from about 30 kg to about 34 kg, and the subject is administered about 70 mg to about 90 mg, about 130 mg to about 150 mg, or about 190 mg to about 210 mg of Compound 1 or a dose equivalent of a pharmaceutically acceptable salt thereof at least once per day (e.g., QD, BID, TID, or QID).
  • the subject has a weight of from about 30 kg to about 34 kg, and the subject is administered about 70 mg to about 90 mg, about 130 mg to about 150 mg, or about 190 mg to about 210 mg of Compound 1 or a dose equivalent of a pharmaceutically acceptable salt thereof twice per day.
  • the subject has a weight of from about 35 kg to about 39 kg, and the subject is administered about 70 mg to about 90 mg, about 130 mg to about 150 mg, or about 210 mg to about 230 mg of Compound 1 or a dose equivalent of a pharmaceutically acceptable salt thereof at least once per day (e.g., QD, BID, TID, or QID).
  • the subject has a weight of from about 35 kg to about 39 kg, and the subject is administered about 70 mg to about 90 mg, about 130 mg to about 150 mg, or about 210 mg to about 230 mg of Compound 1 or a dose equivalent of a pharmaceutically acceptable salt thereof twice per day.
  • the subject has a weight of from about 40 kg to about 44 kg, and the subject is administered about 70 mg to about 90 mg, about 150 mg to about 170 mg, or about 230 mg to about 250 mg of Compound 1 or a dose equivalent of a pharmaceutically acceptable salt thereof at least once per day (e.g., QD, BID, TID, or QID).
  • the subject has a weight of from about 40 kg to about 44 kg, and the subject is administered about 70 mg to about 90 mg, about 150 mg to about 170 mg, or about 230 mg to about 250 mg of Compound 1 or a dose equivalent of a pharmaceutically acceptable salt thereof twice per day.
  • the subject has a weight of from about 45 kg to about 49 kg, and the subject is administered about 90 mg to about 110 mg, about 170 mg to about 190 mg, or about 230 mg to about 250 mg of Compound 1 or a dose equivalent of a pharmaceutically acceptable salt thereof at least once per day (e.g., QD, BID, TID, or QID).
  • the subject has a weight of from about 45 kg to about 49 kg, and the subject is administered about 90 mg to about 110 mg, about 170 mg to about 190 mg, or about 230 mg to about 250 mg of Compound 1 or a dose equivalent of a pharmaceutically acceptable salt thereof at least twice per day.
  • the subject has a weight of from about 50 kg to about 54 kg, and the subject is administered about 90 mg to about 110 mg, about 170 mg to about 190 mg, or about 250 mg to about 270 mg of Compound 1 or a dose equivalent of a pharmaceutically acceptable salt thereof at least once per day (e.g., QD, BID, TID, or QID).
  • the subject has a weight of from about 50 kg to about 54 kg, and the subject is administered about 90 mg to about 110 mg, about 170 mg to about 190 mg, or about 250 mg to about 270 mg of Compound 1 or a dose equivalent of a pharmaceutically acceptable salt thereof twice per day.
  • the subject has a weight of from about 55 kg to about 59 kg, and the subject is administered about 90 mg to about 110 mg, about 170 mg to about 190 mg, or about 270 mg to about 290 mg of Compound 1 or a dose equivalent of a pharmaceutically acceptable salt thereof at least once per day (e.g., QD, BID, TID, or QID).
  • the subject has a weight of from about 55 kg to about 59 kg, and the subject is administered about 90 mg to about 110 mg, about 170 mg to about 190 mg, or about 270 mg to about 290 mg of Compound 1 or a dose equivalent of a pharmaceutically acceptable salt thereof twice per day.
  • the subject has a weight of greater than 60 kg, and the subject is administered about 90 mg to about 110 mg, about 190 mg to about 210 mg, or about 290 mg to about 310 mg of Compound 1 or a dose equivalent of a pharmaceutically acceptable salt thereof at least once per day (e.g., QD, BID, TID, or QID).
  • the subject has a weight of greater than 60 kg, and the subject is administered about 90 mg to about 110 mg, about 190 mg to about 210 mg, or about 290 mg to about 310 mg of Compound 1 or a dose equivalent of a pharmaceutically acceptable salt thereof twice per day.
  • the subject has a weight of from about 10 kg to about 14 kg, and the subject is administered about 60 mg to about 70 mg or about 100 mg to about 120 mg of Compound 1 or a dose equivalent of a pharmaceutically acceptable salt thereof at least once per day (e.g., QD, BID, TID, or QID).
  • the subject has a weight of from about 10 kg to about 14 kg, and the subject is administered about 60 mg to about 70 mg or about 100 mg to about 120 mg of Compound 1 or a dose equivalent of a pharmaceutically acceptable salt thereof twice per day.
  • the subject has a weight of from about 15 kg to about 19 kg, and the subject is administered about 90 mg to about 110 mg or about 120 mg to about 140 mg of Compound 1 or a dose equivalent of a pharmaceutically acceptable salt thereof at least once per day (e.g., QD, BID, TID, or QID).
  • the subject has a weight of from about 15 kg to about 19 kg, and the subject is administered about 90 mg to about 110 mg or about 120 mg to about 140 mg of Compound 1 or a dose equivalent of a pharmaceutically acceptable salt thereof twice per day.
  • the subject has a weight of from about 20 kg to about 24 kg, and the subject is administered about 110 mg to about 130 mg or about 150 mg to about 170 mg of Compound 1 or a dose equivalent of a pharmaceutically acceptable salt thereof at least once per day (e.g., QD, BID, TID, or QID).
  • the subject has a weight of from about 20 kg to about 24 kg, and the subject is administered about 110 mg to about 130 mg or about 150 mg to about 170 mg of Compound 1 or a dose equivalent of a pharmaceutically acceptable salt thereof twice per day.
  • the subject has a weight of from about 25 kg to about 29 kg, and the subject is administered about 110 mg to about 130 mg or about 170 mg to about 190 mg of Compound 1 or a dose equivalent of a pharmaceutically acceptable salt thereof at least once per day (e.g., QD, BID, TTD, or QID).
  • the subject has a weight of from about 25 kg to about 29 kg, and the subject is administered about 110 mg to about 130 mg or about 170 mg to about 190 mg of Compound 1 or a dose equivalent of a pharmaceutically acceptable salt thereof twice per day.
  • the subject has a weight of from about 30 kg to about 34 kg, and the subject is administered about 130 mg to about 150 mg or about 190 mg to about 210 mg of Compound 1 or a dose equivalent of a pharmaceutically acceptable salt thereof at least once per day (e.g., QD, BID, TTD, or QID).
  • the subject has a weight of from about 30 kg to about 34 kg, and the subject is administered about 130 mg to about 150 mg or about 190 mg to about 210 mg of Compound 1 or a dose equivalent of a pharmaceutically acceptable salt thereof twice per day.
  • the subject has a weight of from about 35 kg to about 39 kg, and the subject is administered about 130 mg to about 150 mg or about 210 mg to about 230 mg of Compound 1 or a dose equivalent of a pharmaceutically acceptable salt thereof at least once per day (e.g., QD, BID, TTD, or QID).
  • the subject has a weight of from about 35 kg to about 39 kg, and the subject is administered about 130 mg to about 150 mg or about 210 mg to about 230 mg of Compound 1 or a dose equivalent of a pharmaceutically acceptable salt thereof twice per day.
  • the subject has a weight of from about 40 kg to about 44 kg, and the subject is administered about 150 mg to about 170 mg or about 230 mg to about 250 mg of Compound 1 or a dose equivalent of a pharmaceutically acceptable salt thereof at least once per day (e.g., QD, BID, TTD, or QID).
  • the subject has a weight of from about 40 kg to about 44 kg, and the subject is administered about 150 mg to about 170 mg or about 230 mg to about 250 mg of Compound 1 or a dose equivalent of a pharmaceutically acceptable salt thereof twice per day.
  • the subject has a weight of from about 45 kg to about 49 kg, and the subject is administered about 170 mg to about 190 mg or about 230 mg to about 250 mg of Compound 1 or a dose equivalent of a pharmaceutically acceptable salt thereof at least once per day (e.g., QD, BID, TTD, or QID).
  • the subject has a weight of from about 45 kg to about 49 kg, and the subject is administered about 170 mg to about 190 mg or about 230 mg to about 250 mg of Compound 1 or a dose equivalent of a pharmaceutically acceptable salt thereof twice per day.
  • the subject has a weight of from about 50 kg to about 54 kg, and the subject is administered about 170 mg to about 190 mg or about 250 mg to about 270 mg of Compound 1 or a dose equivalent of a pharmaceutically acceptable salt thereof at least once per day (e.g., QD, BID, TTD, or QID).
  • the subject has a weight of from about 50 kg to about 54 kg, and the subject is administered about 170 mg to about 190 mg or about 250 mg to about 270 mg of Compound 1 or a dose equivalent of a pharmaceutically acceptable salt thereof twice per day.
  • the subject has a weight of from about 55 kg to about 59 kg, and the subject is administered about 170 mg to about 190 mg or about 270 mg to about 290 mg of Compound 1 or a dose equivalent of a pharmaceutically acceptable salt thereof at least once per day (e.g., QD, BID, TTD, or QID).
  • the subject has a weight of from about 55 kg to about 59 kg, and the subject is administered about 170 mg to about 190 mg or about 270 mg to about 290 mg of Compound 1 or a dose equivalent of a pharmaceutically acceptable salt thereof twice per day.
  • the subject has a weight of greater than 60 kg, and the subject is administered about 190 mg to about 210 mg or about 290 mg to about 310 mg of Compound 1 or a dose equivalent of a pharmaceutically acceptable salt thereof at least once per day (e.g., QD, BID, TID, or QID).
  • the subject has a weight of greater than 60 kg, and the subject is administered about 190 mg to about 210 mg or about 290 mg to about 310 mg of Compound 1 or a dose equivalent of a pharmaceutically acceptable salt thereof twice per day.
  • the subject is at least 18 years of age.
  • the subject is administered from about 95 mg to about 325 mg of Compound 1 or a dose equivalent of a pharmaceutically acceptable salt thereof at least once per day (e.g., QD, BID, TID, or QID).
  • the subject is administered from about 95 mg to about 325 mg of Compound 1 or a dose equivalent of a pharmaceutically acceptable salt thereof twice per day.
  • the subject is administered from about 95 mg to about 105 mg, from about 195 mg to about 205 mg, or from about 295 mg to about 305 mg of Compound 1 or a dose equivalent of a pharmaceutically acceptable salt thereof twice per day.
  • the subject is administered from about 295 mg to about 305 mg of Compound 1 or a dose equivalent of a pharmaceutically acceptable salt thereof twice per day.
  • the subject is administered about 100 mg, about 200 mg, or about 300 mg of Compound 1 or a dose equivalent of a pharmaceutically acceptable salt thereof twice per day.
  • the subject is administered (e.g., concomitantly administered) at least one additional therapeutic agent with Compound 1 or a pharmaceutically acceptable salt thereof.
  • the additional therapeutic agent is a barbiturate, a benzodiazepine derivative, a carboxamide derivative, a fatty acid derivative, a glucocorticoid, a herbal antiepileptic, a hydantoin derivative, an antiepileptic, a hypnotic/sedative, a succinimide derivative, or any combination thereof.
  • the additional therapeutic agent is phenobarbital, primidone, clobazam, clonazepam, clorazepate dipotassium, diazepam, lorazepam, midazolam, nitrazepam, carbamazepine, eslicarbazepine acetate, oxcarbazepine, rufinamide, valproate magnesium, valproate semisodium, valproate sodium, valproate sodium/valproic acid, valproic acid, vigabatrin, methylprednisolone, cannabis sativa, fosphenytoin, phenytoin, phenytoin sodium, brivaracetam, cannabidoil, cannabinoids, felbamate, lacosamide, lamotrigine, levetiracetam, stiripentol, sultiame, topiramate, zonisamide, potassium bromide, ethosux
  • Compound 1 or a pharmaceutically acceptable salt thereof is administered orally or administered through a gastrostomy tube or percutaneous endoscopic gastrostomy tube.
  • Compound 1 or a pharmaceutically acceptable salt thereof is administered orally.
  • Another aspect of the invention provides a method of treating a seizure disorder in a subject in need thereof, comprising administering to the subject a dose of from about 75 mg to about 650 mg of Compound 1 (Compound 1), or a dose equivalent of a pharmaceutically acceptable salt thereof, at least once per day, wherein
  • the subject is diagnosed with CDD, DS, or LGS, and
  • the method further comprises administering Compound 1 or a pharmaceutically acceptable salt thereof for a treatment of period of at least about 12 weeks.
  • the treatment period has a duration of at least about 24 weeks.
  • the treatment period has a duration of at least about 36 weeks.
  • the treatment period has a duration of at least about 48 weeks.
  • the treatment period has a duration of at least about 60 weeks.
  • the treatment period has a duration of at least about 72 weeks.
  • the subject is diagnosed with CDD, and the subject experiences a reduction in all seizure frequency of about 40% or more beginning at least 23 weeks after treatment onset. For example, wherein the subject experiences a reduction in all seizure frequency of about 45% or more beginning at least 23 weeks after treatment onset. In other examples, the subject experiences a reduction in all seizure frequency of about 45% or more beginning at least 61 weeks after treatment onset.
  • the subject experiences a reduction in motor seizure frequency of about 50% or more beginning at least 23 weeks after treatment onset. And, in some examples, the subject experiences a reduction in motor seizure frequency of about 55% or more beginning at least 25 weeks after treatment onset. In other instances, the subject experiences a reduction in motor seizure frequency of about 60% or more beginning at least 61 weeks after treatment onset. And, in some instances and examples, motor seizure frequency is the subject's seizure frequency for drop seizures; tonic-clonic, tonic, bilateral clonic, atonic, myoclonic-atonic, myoclonic-tonic-clonic, and focal seizures with bilateral hyperkinetic motor features.
  • the subject is diagnosed with DS, and the subject experiences a reduction in all seizure frequency of about 20% or more beginning at least 23 weeks after treatment onset. In some examples, the subject experiences a reduction in all seizure frequency of about 30% or more beginning at least 36 weeks after treatment onset. In other examples, the subject experiences a reduction in convulsive seizure frequency of about 20% or more beginning at least 23 weeks after treatment onset. In some examples, the subject experiences a reduction in convulsive seizure frequency of about 40% or more beginning at least 60 weeks after treatment onset.
  • the subject is diagnosed with LGS, and the subject experiences a reduction in all seizure frequency of about 10% or more beginning at least 23 weeks after treatment onset.
  • the subject experiences a reduction in drop seizure frequency of about 10% or more beginning at least 23 weeks after treatment onset.
  • the subject experiences a reduction in drop seizure frequency of about 15% or more beginning at least 61 weeks after treatment onset.
  • the subject experiences a reduction in convulsive seizure frequency of about 10% or more beginning at least 23 weeks after treatment onset.
  • the subject experiences a reduction in convulsive seizure frequency of about 30% or more beginning at least 25 weeks after treatment onset.
  • the subject experiences a reduction in convulsive seizure frequency of about 40% or more beginning at least 61 weeks after treatment onset.
  • the subject is from about 2 years to about 17 years of age.
  • the subject is administered Compound 1 or a dose equivalent of a pharmaceutically acceptable salt thereof at a weight-adjusted dosage amount.
  • the subject is administered from about 75 mg to about 325 mg of Compound 1 or a dose equivalent of a pharmaceutically acceptable salt thereof at least once per day (e.g., QD, BID, TID, or QID).
  • the subject is administered from about 75 mg to about 325 mg of Compound 1 or a dose equivalent of a pharmaceutically acceptable salt thereof twice per day.
  • the subject is administered from about 75 mg to about 85 mg, from about 95 mg to about 105 mg, from about 115 mg to about 125 mg, from about 135 mg to about 145 mg, from about 155 mg to about 165 mg, from about 175 mg to about 185 mg, from about 195 mg to about 205 mg, from about 215 mg to about 225 mg, from about 235 mg to about 245 mg, from about 255 mg to about 265 mg, from about 275 mg to about 285 mg or from about 295 mg to about 305 mg of Compound 1 or a dose equivalent of a pharmaceutically acceptable salt thereof twice per day.
  • the subject is administered from about 105 mg to about 115 mg, from about 125 mg to about 130 mg, from about 155 mg to about 160 mg, or from about 175 mg to about 185 mg of Compound 1 or a dose equivalent of a pharmaceutically acceptable salt thereof twice per day.
  • the subject is administered about 80 mg, about 100 mg, about 110 mg, about 120 mg, about 130 mg, about 140 mg, about 160 mg, about 180 mg, about 200 mg, about 220 mg, about 240 mg, about 260 mg, about 280 mg, or about 300 mg of Compound 1 or a dose equivalent of a pharmaceutically acceptable salt thereof twice per day.
  • the subject has a weight of from about 10 kg to about 14 kg, and the subject is administered about 30 mg to about 50 mg, about 70 mg to about 90 mg, or about 100 to about 120 mg of Compound 1 or a dose equivalent of a pharmaceutically acceptable salt thereof at least once per day (e.g., QD, BID, TID, or QID).
  • the subject has a weight of from about 10 kg to about 14 kg, and the subject is administered about 30 mg to about 50 mg, about 70 mg to about 90 mg, or about 100 to about 120 mg of Compound 1 or a dose equivalent of a pharmaceutically acceptable salt thereof twice per day.
  • the subject has a weight of from about 15 kg to about 19 kg, and the subject is administered about 50 mg to about 70 mg, about 90 mg to about 110 mg, or about 120 mg to about 140 mg of Compound 1 or a dose equivalent of a pharmaceutically acceptable salt thereof at least once per day (e.g., QD, BID, TID, or QID).
  • the subject has a weight of from about 15 kg to about 19 kg, and the subject is administered about 50 mg to about 70 mg, about 90 mg to about 110 mg, or about 120 mg to about 140 mg of Compound 1 or a dose equivalent of a pharmaceutically acceptable salt thereof twice per day.
  • the subject has a weight of from about 20 kg to about 24 kg, and the subject is administered about 50 mg to about 70 mg, about 110 mg to about 130 mg, or about 150 mg to about 170 mg of Compound 1 or a dose equivalent of a pharmaceutically acceptable salt thereof at least once per day (e.g., QD, BID, TID, or QID).
  • the subject has a weight of from about 20 kg to about 24 kg, and the subject is administered about 50 mg to about 70 mg, about 110 mg to about 130 mg, or about 150 mg to about 170 mg of Compound 1 or a dose equivalent of a pharmaceutically acceptable salt thereof twice per day.
  • the subject has a weight of from about 25 kg to about 29 kg, and the subject is administered about 50 mg to about 70 mg, about 110 mg to about 130 mg, or about 170 mg to about 190 mg of Compound 1 or a dose equivalent of a pharmaceutically acceptable salt thereof at least once per day (e.g., QD, BID, TID, or QID).
  • the subject has a weight of from about 25 kg to about 29 kg, and the subject is administered about 50 mg to about 70 mg, about 110 mg to about 130 mg, or about 170 mg to about 190 mg of Compound 1 or a dose equivalent of a pharmaceutically acceptable salt thereof twice per day.
  • the subject has a weight of from about 30 kg to about 34 kg, and the subject is administered about 70 mg to about 90 mg, about 130 mg to about 150 mg, or about 190 mg to about 210 mg of Compound 1 or a dose equivalent of a pharmaceutically acceptable salt thereof at least once per day (e.g., QD, BID, TID, or QID).
  • the subject has a weight of from about 30 kg to about 34 kg, and the subject is administered about 70 mg to about 90 mg, about 130 mg to about 150 mg, or about 190 mg to about 210 mg of Compound 1 or a dose equivalent of a pharmaceutically acceptable salt thereof twice per day.
  • the subject has a weight of from about 35 kg to about 39 kg, and the subject is administered about 70 mg to about 90 mg, about 130 mg to about 150 mg, or about 210 mg to about 230 mg of Compound 1 or a dose equivalent of a pharmaceutically acceptable salt thereof at least once per day (e.g., QD, BID, TID, or QID).
  • the subject has a weight of from about 35 kg to about 39 kg, and the subject is administered about 70 mg to about 90 mg, about 130 mg to about 150 mg, or about 210 mg to about 230 mg of Compound 1 or a dose equivalent of a pharmaceutically acceptable salt thereof twice per day.
  • the subject has a weight of from about 40 kg to about 44 kg, and the subject is administered about 70 mg to about 90 mg, about 150 mg to about 170 mg, or about 230 mg to about 250 mg of Compound 1 or a dose equivalent of a pharmaceutically acceptable salt thereof at least once per day (e.g., QD, BID, TID, or QID).
  • the subject has a weight of from about 40 kg to about 44 kg, and the subject is administered about 70 mg to about 90 mg, about 150 mg to about 170 mg, or about 230 mg to about 250 mg of Compound 1 or a dose equivalent of a pharmaceutically acceptable salt thereof twice per day.
  • the subject has a weight of from about 45 kg to about 49 kg, and the subject is administered about 90 mg to about 110 mg, about 170 mg to about 190 mg, or about 230 mg to about 250 mg of Compound 1 or a dose equivalent of a pharmaceutically acceptable salt thereof at least once per day (e.g., QD, BID, TID, or QID).
  • the subject has a weight of from about 45 kg to about 49 kg, and the subject is administered about 90 mg to about 110 mg, about 170 mg to about 190 mg, or about 230 mg to about 250 mg of Compound 1 or a dose equivalent of a pharmaceutically acceptable salt thereof at least twice per day.
  • the subject has a weight of from about 50 kg to about 54 kg, and the subject is administered about 90 mg to about 110 mg, about 170 mg to about 190 mg, or about 250 mg to about 270 mg of Compound 1 or a dose equivalent of a pharmaceutically acceptable salt thereof at least once per day (e.g., QD, BID, TID, or QID).
  • the subject has a weight of from about 50 kg to about 54 kg, and the subject is administered about 90 mg to about 110 mg, about 170 mg to about 190 mg, or about 250 mg to about 270 mg of Compound 1 or a dose equivalent of a pharmaceutically acceptable salt thereof twice per day.
  • the subject has a weight of from about 55 kg to about 59 kg, and the subject is administered about 90 mg to about 110 mg, about 170 mg to about 190 mg, or about 270 mg to about 290 mg of Compound 1 or a dose equivalent of a pharmaceutically acceptable salt thereof at least once per day (e.g., QD, BID, TID, or QID).
  • the subject has a weight of from about 55 kg to about 59 kg, and the subject is administered about 90 mg to about 110 mg, about 170 mg to about 190 mg, or about 270 mg to about 290 mg of Compound 1 or a dose equivalent of a pharmaceutically acceptable salt thereof twice per day.
  • the subject has a weight of greater than 60 kg, and the subject is administered about 90 mg to about 110 mg, about 190 mg to about 210 mg, or about 290 mg to about 310 mg of Compound 1 or a dose equivalent of a pharmaceutically acceptable salt thereof at least once per day (e.g., QD, BID, TID, or QID).
  • the subject has a weight of greater than 60 kg, and the subject is administered about 90 mg to about 110 mg, about 190 mg to about 210 mg, or about 290 mg to about 310 mg of Compound 1 or a dose equivalent of a pharmaceutically acceptable salt thereof twice per day.
  • the subject has a weight of from about 10 kg to about 14 kg, and the subject is administered about 60 mg to about 70 mg or about 100 mg to about 120 mg of Compound 1 or a dose equivalent of a pharmaceutically acceptable salt thereof at least once per day (e.g., QD, BID, TID, or QID).
  • the subject has a weight of from about 10 kg to about 14 kg, and the subject is administered about 60 mg to about 70 mg or about 100 mg to about 120 mg of Compound 1 or a dose equivalent of a pharmaceutically acceptable salt thereof twice per day.
  • the subject has a weight of from about 15 kg to about 19 kg, and the subject is administered about 90 mg to about 110 mg or about 120 mg to about 140 mg of Compound 1 or a dose equivalent of a pharmaceutically acceptable salt thereof at least once per day (e.g., QD, BID, TID, or QID).
  • the subject has a weight of from about 15 kg to about 19 kg, and the subject is administered about 90 mg to about 110 mg or about 120 mg to about 140 mg of Compound 1 or a dose equivalent of a pharmaceutically acceptable salt thereof twice per day.
  • the subject has a weight of from about 20 kg to about 24 kg, and the subject is administered about 110 mg to about 130 mg or about 150 mg to about 170 mg of Compound 1 or a dose equivalent of a pharmaceutically acceptable salt thereof at least once per day (e.g., QD, BID, TID, or QID).
  • the subject has a weight of from about 20 kg to about 24 kg, and the subject is administered about 110 mg to about 130 mg or about 150 mg to about 170 mg of Compound 1 or a dose equivalent of a pharmaceutically acceptable salt thereof twice per day.
  • the subject has a weight of from about 25 kg to about 29 kg, and the subject is administered about 110 mg to about 130 mg or about 170 mg to about 190 mg of Compound 1 or a dose equivalent of a pharmaceutically acceptable salt thereof at least once per day (e.g., QD, BID, TTD, or QID).
  • the subject has a weight of from about 25 kg to about 29 kg, and the subject is administered about 110 mg to about 130 mg or about 170 mg to about 190 mg of Compound 1 or a dose equivalent of a pharmaceutically acceptable salt thereof twice per day.
  • the subject has a weight of from about 30 kg to about 34 kg, and the subject is administered about 130 mg to about 150 mg or about 190 mg to about 210 mg of Compound 1 or a dose equivalent of a pharmaceutically acceptable salt thereof at least once per day (e.g., QD, BID, TTD, or QID).
  • the subject has a weight of from about 30 kg to about 34 kg, and the subject is administered about 130 mg to about 150 mg or about 190 mg to about 210 mg of Compound 1 or a dose equivalent of a pharmaceutically acceptable salt thereof twice per day.
  • the subject has a weight of from about 35 kg to about 39 kg, and the subject is administered about 130 mg to about 150 mg or about 210 mg to about 230 mg of Compound 1 or a dose equivalent of a pharmaceutically acceptable salt thereof at least once per day (e.g., QD, BID, TTD, or QID).
  • the subject has a weight of from about 35 kg to about 39 kg, and the subject is administered about 130 mg to about 150 mg or about 210 mg to about 230 mg of Compound 1 or a dose equivalent of a pharmaceutically acceptable salt thereof twice per day.
  • the subject has a weight of from about 40 kg to about 44 kg, and the subject is administered about 150 mg to about 170 mg or about 230 mg to about 250 mg of Compound 1 or a dose equivalent of a pharmaceutically acceptable salt thereof at least once per day (e.g., QD, BID, TTD, or QID).
  • the subject has a weight of from about 40 kg to about 44 kg, and the subject is administered about 150 mg to about 170 mg or about 230 mg to about 250 mg of Compound 1 or a dose equivalent of a pharmaceutically acceptable salt thereof twice per day.
  • the subject has a weight of from about 45 kg to about 49 kg, and the subject is administered about 170 mg to about 190 mg or about 230 mg to about 250 mg of Compound 1 or a dose equivalent of a pharmaceutically acceptable salt thereof at least once per day (e.g., QD, BID, TTD, or QID).
  • the subject has a weight of from about 45 kg to about 49 kg, and the subject is administered about 170 mg to about 190 mg or about 230 mg to about 250 mg of Compound 1 or a dose equivalent of a pharmaceutically acceptable salt thereof twice per day.
  • the subject has a weight of from about 50 kg to about 54 kg, and the subject is administered about 170 mg to about 190 mg or about 250 mg to about 270 mg of Compound 1 or a dose equivalent of a pharmaceutically acceptable salt thereof at least once per day (e.g., QD, BID, TTD, or QID).
  • the subject has a weight of from about 50 kg to about 54 kg, and the subject is administered about 170 mg to about 190 mg or about 250 mg to about 270 mg of Compound 1 or a dose equivalent of a pharmaceutically acceptable salt thereof twice per day.
  • the subject has a weight of from about 55 kg to about 59 kg, and the subject is administered about 170 mg to about 190 mg or about 270 mg to about 290 mg of Compound 1 or a dose equivalent of a pharmaceutically acceptable salt thereof at least once per day (e.g., QD, BID, TTD, or QID).
  • the subject has a weight of from about 55 kg to about 59 kg, and the subject is administered about 170 mg to about 190 mg or about 270 mg to about 290 mg of Compound 1 or a dose equivalent of a pharmaceutically acceptable salt thereof twice per day.
  • the subject has a weight of greater than 60 kg, and the subject is administered about 190 mg to about 210 mg or about 290 mg to about 310 mg of Compound 1 or a dose equivalent of a pharmaceutically acceptable salt thereof at least once per day (e.g., QD, BID, TID, or QID).
  • the subject has a weight of greater than 60 kg, and the subject is administered about 190 mg to about 210 mg or about 290 mg to about 310 mg of Compound 1 or a dose equivalent of a pharmaceutically acceptable salt thereof twice per day.
  • the subject is at least 18 years of age.
  • the subject is administered from about 95 mg to about 325 mg of Compound 1 or a dose equivalent of a pharmaceutically acceptable salt thereof at least once per day (e.g., QD, BID, TID, or QID).
  • a pharmaceutically acceptable salt thereof at least once per day (e.g., QD, BID, TID, or QID).
  • the subject is administered from about 95 mg to about 325 mg of Compound 1 or a dose equivalent of a pharmaceutically acceptable salt thereof twice per day.
  • the subject is administered from about 95 mg to about 105 mg, from about 195 mg to about 205 mg, or from about 295 mg to about 305 mg of Compound 1 or a dose equivalent of a pharmaceutically acceptable salt thereof twice per day.
  • the subject is administered from about 295 mg to about 305 mg of Compound 1 or a dose equivalent of a pharmaceutically acceptable salt thereof twice per day.
  • the subject is administered about 100 mg, about 200 mg, or about 300 mg of Compound 1 or a dose equivalent of a pharmaceutically acceptable salt thereof twice per day.
  • the subject is administered (e.g., concomitantly administered) at least one additional therapeutic agent.
  • the additional therapeutic agent is a barbiturate, a benzodiazepine derivative, a carboxamide derivative, a fatty acid derivative, a glucocorticoid, a herbal antiepileptic, a hydantoin derivative, an antiepileptic, a hypnotic/sedative, a succinimide derivative, or any combination thereof.
  • the additional therapeutic agent is phenobarbital, primidone, clobazam, clonazepam, clorazepate dipotassium, diazepam, lorazepam, midazolam, nitrazepam, carbamazepine, eslicarbazepine acetate, oxcarbazepine, rufmamide, valproate magnesium, valproate semisodium, valproate sodium, valproate sodium/valproic acid, valproic acid, vigabatrin, methylprednisolone, cannabis sativa, fosphenytoin, phenytoin, phenytoin sodium, brivaracetam, cannabidoil, cannabinoids, felbamate, lacosamide, lamotrigine, levetiracetam, stiripentol, sultiame, topiramate, zonisamide, potassium bromide, ethosux
  • Compound 1 or a pharmaceutically acceptable salt thereof is administered orally or administered through a gastrostomy tube or percutaneous endoscopic gastrostomy tube.
  • Compound 1 or a pharmaceutically acceptable salt thereof is administered orally.
  • the subject is a human. In other implementations, the human is an adult or child.
  • the subject is from about 2 years to about 17 years of age. In some implementations, the subject is from about 2 years to about 10 years of age. And, in other implementations, the subject is from about 11 years to about 17 years of age.
  • the subject is administered Compound 1 or a dose equivalent of a pharmaceutically acceptable salt thereof at a weight-adjusted dosage amount.
  • the subject is administered from about 75 mg to about 325 mg of Compound 1 or a dose equivalent of a pharmaceutically acceptable salt thereof at least once per day (e.g., QD, BID, TID, or QID).
  • the subject is administered from about 75 mg to about 325 mg of Compound 1 or a dose equivalent of a pharmaceutically acceptable salt thereof twice per day.
  • the subject is administered from about 75 mg to about 85 mg, from about 95 mg to about 105 mg, from about 115 mg to about 125 mg, from about 135 mg to about 145 mg, from about 155 mg to about 165 mg, from about 175 mg to about 185 mg, from about 195 mg to about 205 mg, from about 215 mg to about 225 mg, from about 235 mg to about 245 mg, from about 255 mg to about 265 mg, from about 275 mg to about 285 mg or from about 295 mg to about 305 mg of Compound 1 or a dose equivalent of a pharmaceutically acceptable salt thereof twice per day.
  • the subject is administered from about 105 mg to about 115 mg, from about 125 mg to about 130 mg, from about 155 mg to about 160 mg, or from about 175 mg to about 185 mg of Compound 1 or a dose equivalent of a pharmaceutically acceptable salt thereof twice per day. And, in some implementations, the subject is administered about 80 mg, about 100 mg, about 110 mg, about 120 mg, about 130 mg, about 140 mg, about 160 mg, about 180 mg, about 200 mg, about 220 mg, about 240 mg, about 260 mg, about 280 mg, or about 300 mg of Compound 1 or a dose equivalent of a pharmaceutically acceptable salt thereof twice per day.
  • the subject has a weight of from about 10 kg to about 14 kg, and the subject is administered about 30 mg to about 50 mg, about 70 mg to about 90 mg, or about 100 to about 120 mg of Compound 1 or a dose equivalent of a pharmaceutically acceptable salt thereof at least once per day (e.g., QD, BID, TID, or QID).
  • the subject has a weight of from about 10 kg to about 14 kg, and the subject is administered about 30 mg to about 50 mg, about 70 mg to about 90 mg, or about 100 to about 120 mg of Compound 1 or a dose equivalent of a pharmaceutically acceptable salt thereof twice per day.
  • the subject has a weight of from about 15 kg to about 19 kg, and the subject is administered about 50 mg to about 70 mg, about 90 mg to about 110 mg, or about 120 mg to about 140 mg of Compound 1 or a dose equivalent of a pharmaceutically acceptable salt thereof at least once per day (e.g., QD, BID, TID, or QID).
  • the subject has a weight of from about 15 kg to about 19 kg, and the subject is administered about 50 mg to about 70 mg, about 90 mg to about 110 mg, or about 120 mg to about 140 mg of Compound 1 or a dose equivalent of a pharmaceutically acceptable salt thereof twice per day.
  • the subject has a weight of from about 20 kg to about 24 kg, and the subject is administered about 50 mg to about 70 mg, about 110 mg to about 130 mg, or about 150 mg to about 170 mg of Compound 1 or a dose equivalent of a pharmaceutically acceptable salt thereof at least once per day (e.g., QD, BID, TID, or QID).
  • the subject has a weight of from about 20 kg to about 24 kg, and the subject is administered about 50 mg to about 70 mg, about 110 mg to about 130 mg, or about 150 mg to about 170 mg of Compound 1 or a dose equivalent of a pharmaceutically acceptable salt thereof twice per day.
  • the subject has a weight of from about 25 kg to about 29 kg, and the subject is administered about 50 mg to about 70 mg, about 110 mg to about 130 mg, or about 170 mg to about 190 mg of Compound 1 or a dose equivalent of a pharmaceutically acceptable salt thereof at least once per day (e.g., QD, BID, TID, or QID).
  • the subject has a weight of from about 25 kg to about 29 kg, and the subject is administered about 50 mg to about 70 mg, about 110 mg to about 130 mg, or about 170 mg to about 190 mg of Compound 1 or a dose equivalent of a pharmaceutically acceptable salt thereof twice per day.
  • the subject has a weight of from about 30 kg to about 34 kg, and the subject is administered about 70 mg to about 90 mg, about 130 mg to about 150 mg, or about 190 mg to about 210 mg of Compound 1 or a dose equivalent of a pharmaceutically acceptable salt thereof at least once per day (e.g., QD, BID, TID, or QID).
  • the subject has a weight of from about 30 kg to about 34 kg, and the subject is administered about 70 mg to about 90 mg, about 130 mg to about 150 mg, or about 190 mg to about 210 mg of Compound 1 or a dose equivalent of a pharmaceutically acceptable salt thereof twice per day.
  • the subject has a weight of from about 35 kg to about 39 kg, and the subject is administered about 70 mg to about 90 mg, about 130 mg to about 150 mg, or about 210 mg to about 230 mg of Compound 1 or a dose equivalent of a pharmaceutically acceptable salt thereof at least once per day (e.g., QD, BID, TID, or QID).
  • the subject has a weight of from about 35 kg to about 39 kg, and the subject is administered about 70 mg to about 90 mg, about 130 mg to about 150 mg, or about 210 mg to about 230 mg of Compound 1 or a dose equivalent of a pharmaceutically acceptable salt thereof twice per day.
  • the subject has a weight of from about 40 kg to about 44 kg, and the subject is administered about 70 mg to about 90 mg, about 150 mg to about 170 mg, or about 230 mg to about 250 mg of Compound 1 or a dose equivalent of a pharmaceutically acceptable salt thereof at least once per day (e.g., QD, BID, TID, or QID).
  • the subject has a weight of from about 40 kg to about 44 kg, and the subject is administered about 70 mg to about 90 mg, about 150 mg to about 170 mg, or about 230 mg to about 250 mg of Compound 1 or a dose equivalent of a pharmaceutically acceptable salt thereof twice per day.
  • the subject has a weight of from about 45 kg to about 49 kg, and the subject is administered about 90 mg to about 110 mg, about 170 mg to about 190 mg, or about 230 mg to about 250 mg of Compound 1 or a dose equivalent of a pharmaceutically acceptable salt thereof at least once per day (e.g., QD, BID, TID, or QID).
  • the subject has a weight of from about 45 kg to about 49 kg, and the subject is administered about 90 mg to about 110 mg, about 170 mg to about 190 mg, or about 230 mg to about 250 mg of Compound 1 or a dose equivalent of a pharmaceutically acceptable salt thereof at least twice per day.
  • the subject has a weight of from about 50 kg to about 54 kg, and the subject is administered about 90 mg to about 110 mg, about 170 mg to about 190 mg, or about 250 mg to about 270 mg of Compound 1 or a dose equivalent of a pharmaceutically acceptable salt thereof at least once per day (e.g., QD, BID, TID, or QID).
  • the subject has a weight of from about 50 kg to about 54 kg, and the subject is administered about 90 mg to about 110 mg, about 170 mg to about 190 mg, or about 250 mg to about 270 mg of Compound 1 or a dose equivalent of a pharmaceutically acceptable salt thereof twice per day.
  • the subject has a weight of from about 55 kg to about 59 kg, and the subject is administered about 90 mg to about 110 mg, about 170 mg to about 190 mg, or about 270 mg to about 290 mg of Compound 1 or a dose equivalent of a pharmaceutically acceptable salt thereof at least once per day (e.g., QD, BID, TID, or QID).
  • the subject has a weight of from about 55 kg to about 59 kg, and the subject is administered about 90 mg to about 110 mg, about 170 mg to about 190 mg, or about 270 mg to about 290 mg of Compound 1 or a dose equivalent of a pharmaceutically acceptable salt thereof twice per day.
  • the subject has a weight of greater than 60 kg, and the subject is administered about 90 mg to about 110 mg, about 190 mg to about 210 mg, or about 290 mg to about 310 mg of Compound 1 or a dose equivalent of a pharmaceutically acceptable salt thereof at least once per day (e.g., QD, BID, TID, or QID).
  • the subject has a weight of greater than 60 kg, and the subject is administered about 90 mg to about 110 mg, about 190 mg to about 210 mg, or about 290 mg to about 310 mg of Compound 1 or a dose equivalent of a pharmaceutically acceptable salt thereof twice per day.
  • the subject has a weight of from about 10 kg to about 14 kg, and the subject is administered about 60 mg to about 70 mg or about 100 mg to about 120 mg of Compound 1 or a dose equivalent of a pharmaceutically acceptable salt thereof at least once per day (e.g., QD, BID, TID, or QID).
  • the subject has a weight of from about 10 kg to about 14 kg, and the subject is administered about 60 mg to about 70 mg or about 100 mg to about 120 mg of Compound 1 or a dose equivalent of a pharmaceutically acceptable salt thereof twice per day.
  • the subject has a weight of from about 15 kg to about 19 kg, and the subject is administered about 90 mg to about 110 mg or about 120 mg to about 140 mg of Compound 1 or a dose equivalent of a pharmaceutically acceptable salt thereof at least once per day (e.g., QD, BID, TID, or QID).
  • the subject has a weight of from about 15 kg to about 19 kg, and the subject is administered about 90 mg to about 110 mg or about 120 mg to about 140 mg of Compound 1 or a dose equivalent of a pharmaceutically acceptable salt thereof twice per day.
  • the subject has a weight of from about 20 kg to about 24 kg, and the subject is administered about 110 mg to about 130 mg or about 150 mg to about 170 mg of Compound 1 or a dose equivalent of a pharmaceutically acceptable salt thereof at least once per day (e.g., QD, BID, TID, or QID).
  • the subject has a weight of from about 20 kg to about 24 kg, and the subject is administered about 110 mg to about 130 mg or about 150 mg to about 170 mg of Compound 1 or a dose equivalent of a pharmaceutically acceptable salt thereof twice per day.
  • the subject has a weight of from about 25 kg to about 29 kg, and the subject is administered about 110 mg to about 130 mg or about 170 mg to about 190 mg of Compound 1 or a dose equivalent of a pharmaceutically acceptable salt thereof at least once per day (e.g., QD, BID, TID, or QID).
  • the subject has a weight of from about 25 kg to about 29 kg, and the subject is administered about 110 mg to about 130 mg or about 170 mg to about 190 mg of Compound 1 or a dose equivalent of a pharmaceutically acceptable salt thereof twice per day.
  • the subject has a weight of from about 30 kg to about 34 kg, and the subject is administered about 130 mg to about 150 mg or about 190 mg to about 210 mg of Compound 1 or a dose equivalent of a pharmaceutically acceptable salt thereof at least once per day (e.g., QD, BID, TID, or QID).
  • the subject has a weight of from about 30 kg to about 34 kg, and the subject is administered about 130 mg to about 150 mg or about 190 mg to about 210 mg of Compound 1 or a dose equivalent of a pharmaceutically acceptable salt thereof twice per day.
  • the subject has a weight of from about 35 kg to about 39 kg, and the subject is administered about 130 mg to about 150 mg or about 210 mg to about 230 mg of Compound 1 or a dose equivalent of a pharmaceutically acceptable salt thereof at least once per day (e.g., QD, BID, TTD, or QID).
  • the subject has a weight of from about 35 kg to about 39 kg, and the subject is administered about 130 mg to about 150 mg or about 210 mg to about 230 mg of Compound 1 or a dose equivalent of a pharmaceutically acceptable salt thereof twice per day.
  • the subject has a weight of from about 40 kg to about 44 kg, and the subject is administered about 150 mg to about 170 mg or about 230 mg to about 250 mg of Compound 1 or a dose equivalent of a pharmaceutically acceptable salt thereof at least once per day (e.g., QD, BID, TTD, or QID).
  • the subject has a weight of from about 40 kg to about 44 kg, and the subject is administered about 150 mg to about 170 mg or about 230 mg to about 250 mg of Compound 1 or a dose equivalent of a pharmaceutically acceptable salt thereof twice per day.
  • the subject has a weight of from about 45 kg to about 49 kg, and the subject is administered about 170 mg to about 190 mg or about 230 mg to about 250 mg of Compound 1 or a dose equivalent of a pharmaceutically acceptable salt thereof at least once per day (e.g., QD, BID, TTD, or QID).
  • the subject has a weight of from about 45 kg to about 49 kg, and the subject is administered about 170 mg to about 190 mg or about 230 mg to about 250 mg of Compound 1 or a dose equivalent of a pharmaceutically acceptable salt thereof twice per day.
  • the subject has a weight of from about 50 kg to about 54 kg, and the subject is administered about 170 mg to about 190 mg or about 250 mg to about 270 mg of Compound 1 or a dose equivalent of a pharmaceutically acceptable salt thereof at least once per day (e.g., QD, BID, TTD, or QID).
  • the subject has a weight of from about 50 kg to about 54 kg, and the subject is administered about 170 mg to about 190 mg or about 250 mg to about 270 mg of Compound 1 or a dose equivalent of a pharmaceutically acceptable salt thereof twice per day.
  • the subject has a weight of from about 55 kg to about 59 kg, and the subject is administered about 170 mg to about 190 mg or about 270 mg to about 290 mg of Compound 1 or a dose equivalent of a pharmaceutically acceptable salt thereof at least once per day (e.g., QD, BID, TTD, or QID).
  • the subject has a weight of from about 55 kg to about 59 kg, and the subject is administered about 170 mg to about 190 mg or about 270 mg to about 290 mg of Compound 1 or a dose equivalent of a pharmaceutically acceptable salt thereof twice per day.
  • the subject has a weight of greater than 60 kg, and the subject is administered about 190 mg to about 210 mg or about 290 mg to about 310 mg of Compound 1 or a dose equivalent of a pharmaceutically acceptable salt thereof at least once per day (e.g., QD, BID, TID, or QID).
  • the subject has a weight of greater than 60 kg, and the subject is administered about 190 mg to about 210 mg or about 290 mg to about 310 mg of Compound 1 or a dose equivalent of a pharmaceutically acceptable salt thereof twice per day.
  • the subject is at least 18 years of age. In some implementations the subject is at least 25 years of age. In other implementations, the subject is at least 35 years of age. In some implementations, the subject is at least 45 years of age. And, in some implementations, the subject is at least 55 years of age.
  • the subject is administered from about 95 mg to about 325 mg of Compound 1 or a dose equivalent of a pharmaceutically acceptable salt thereof at least once per day (e.g., QD, BID, TID, or QID). In other implementations, the subject is administered from about 95 mg to about 325 mg of Compound 1 or a dose equivalent of a pharmaceutically acceptable salt thereof twice per day. In some implementations, the subject is administered from about 95 mg to about 105 mg, from about 195 mg to about 205 mg, or from about 295 mg to about 305 mg of Compound 1 or a dose equivalent of a pharmaceutically acceptable salt thereof twice per day.
  • the subject is administered from about 295 mg to about 305 mg of Compound 1 or a dose equivalent of a pharmaceutically acceptable salt thereof twice per day. And, in some implementations, the subject is administered about 100 mg, about 200 mg, or about 300 mg of Compound 1 or a dose equivalent of a pharmaceutically acceptable salt thereof twice per day.
  • the subject is administered (e.g., concomitantly administered) at least one additional therapeutic agent with Compound 1 or a pharmaceutically acceptable salt thereof.
  • the additional therapeutic agent is a barbiturate, a benzodiazepine derivative, a carboxamide derivative, a fatty acid derivative, a glucocorticoid, a herbal antiepileptic, a hydantoin derivative, an antiepileptic, a hypnotic/sedative, a succinimide derivative, or any combination thereof.
  • the additional therapeutic agent is phenobarbital, primidone, clobazam, clonazepam, clorazepate dipotassium, diazepam, lorazepam, midazolam, nitrazepam, carbamazepine, eslicarbazepine acetate, oxcarbazepine, rufinamide, valproate magnesium, valproate semisodium, valproate sodium, valproate sodium/valproic acid, valproic acid, vigabatrin, methylprednisolone, cannabis sativa, fosphenytoin, phenytoin, phenytoin sodium, brivaracetam, cannabidoil, cannabinoids, felbamate, lacosamide, lamotrigine, levetiracetam, stiripentol, sultiame, topiramate, zonisamide, potassium bromide, ethosux
  • Compound 1 or a pharmaceutically acceptable salt thereof is administered orally or administered through a gastrostomy tube or percutaneous endoscopic gastrostomy tube.
  • Compound 1 or a pharmaceutically acceptable salt thereof is administered orally.
  • the present invention provides a method of treating a seizure disorder in a subject in need thereof comprising administering to the subject a dose of from about 75 mg to about 650 mg of Compound 1 (Compound 1), or a dose equivalent of a pharmaceutically acceptable salt thereof, at least once per day, wherein
  • the method further comprises administering Compound 1 or a pharmaceutically acceptable salt thereof for a treatment period of at least about 12 weeks, at least about 24 weeks, or at least about 36 weeks.
  • the subject is from about 2 years to about 17 years of age.
  • the subject is administered Compound 1 or a dose equivalent of a pharmaceutically acceptable salt thereof at a weight-adjusted dosage amount.
  • the subject is administered from about 75 mg to about 325 mg of Compound 1 or a dose equivalent of a pharmaceutically acceptable salt thereof at least once per day (e.g., QD, BID, TID, or QID). In some implementations, the subject is administered from about 75 mg to about 325 mg of Compound 1 or a dose equivalent of a pharmaceutically acceptable salt thereof twice per day.
  • a pharmaceutically acceptable salt thereof at least once per day (e.g., QD, BID, TID, or QID).
  • the subject is administered from about 75 mg to about 325 mg of Compound 1 or a dose equivalent of a pharmaceutically acceptable salt thereof twice per day.
  • the subject is administered from about 75 mg to about 85 mg, from about 95 mg to about 105 mg, from about 115 mg to about 125 mg, from about 135 mg to about 145 mg, from about 155 mg to about 165 mg, from about 175 mg to about 185 mg, from about 195 mg to about 205 mg, from about 215 mg to about 225 mg, from about 235 mg to about 245 mg, from about 255 mg to about 265 mg, from about 275 mg to about 285 mg or from about 295 mg to about 305 mg of Compound 1 or a dose equivalent of a pharmaceutically acceptable salt thereof twice per day.
  • the subject is administered from about 105 mg to about 115 mg, from about 125 mg to about 130 mg, from about 155 mg to about 160 mg, or from about 175 mg to about 185 mg of Compound 1 or a dose equivalent of a pharmaceutically acceptable salt thereof twice per day. And, in some implementations, the subject is administered about 80 mg, about 100 mg, about 110 mg, about 120 mg, about 130 mg, about 140 mg, about 160 mg, about 180 mg, about 200 mg, about 220 mg, about 240 mg, about 260 mg, about 280 mg, or about 300 mg of Compound 1 or a dose equivalent of a pharmaceutically acceptable salt thereof twice per day.
  • the subject has a weight of from about 10 kg to about 14 kg, and the subject is administered about 30 mg to about 50 mg, about 70 mg to about 90 mg, or about 100 to about 120 mg of Compound 1 or a dose equivalent of a pharmaceutically acceptable salt thereof at least once per day (e.g., QD, BID, TID, or QID).
  • the subject has a weight of from about 10 kg to about 14 kg, and the subject is administered about 30 mg to about 50 mg, about 70 mg to about 90 mg, or about 100 to about 120 mg of Compound 1 or a dose equivalent of a pharmaceutically acceptable salt thereof twice per day.
  • the subject has a weight of from about 15 kg to about 19 kg, and the subject is administered about 50 mg to about 70 mg, about 90 mg to about 110 mg, or about 120 mg to about 140 mg of Compound 1 or a dose equivalent of a pharmaceutically acceptable salt thereof at least once per day (e.g., QD, BID, TID, or QID).
  • the subject has a weight of from about 15 kg to about 19 kg, and the subject is administered about 50 mg to about 70 mg, about 90 mg to about 110 mg, or about 120 mg to about 140 mg of Compound 1 or a dose equivalent of a pharmaceutically acceptable salt thereof twice per day.
  • the subject has a weight of from about 20 kg to about 24 kg, and the subject is administered about 50 mg to about 70 mg, about 110 mg to about 130 mg, or about 150 mg to about 170 mg of Compound 1 or a dose equivalent of a pharmaceutically acceptable salt thereof at least once per day (e.g., QD, BID, TID, or QID).
  • the subject has a weight of from about 20 kg to about 24 kg, and the subject is administered about 50 mg to about 70 mg, about 110 mg to about 130 mg, or about 150 mg to about 170 mg of Compound 1 or a dose equivalent of a pharmaceutically acceptable salt thereof twice per day.
  • the subject has a weight of from about 25 kg to about 29 kg, and the subject is administered about 50 mg to about 70 mg, about 110 mg to about 130 mg, or about 170 mg to about 190 mg of Compound 1 or a dose equivalent of a pharmaceutically acceptable salt thereof at least once per day (e.g., QD, BID, TID, or QID).
  • the subject has a weight of from about 25 kg to about 29 kg, and the subject is administered about 50 mg to about 70 mg, about 110 mg to about 130 mg, or about 170 mg to about 190 mg of Compound 1 or a dose equivalent of a pharmaceutically acceptable salt thereof twice per day.
  • the subject has a weight of from about 30 kg to about 34 kg, and the subject is administered about 70 mg to about 90 mg, about 130 mg to about 150 mg, or about 190 mg to about 210 mg of Compound 1 or a dose equivalent of a pharmaceutically acceptable salt thereof at least once per day (e.g., QD, BID, TID, or QID).
  • the subject has a weight of from about 30 kg to about 34 kg, and the subject is administered about 70 mg to about 90 mg, about 130 mg to about 150 mg, or about 190 mg to about 210 mg of Compound 1 or a dose equivalent of a pharmaceutically acceptable salt thereof twice per day.
  • the subject has a weight of from about 35 kg to about 39 kg, and the subject is administered about 70 mg to about 90 mg, about 130 mg to about 150 mg, or about 210 mg to about 230 mg of Compound 1 or a dose equivalent of a pharmaceutically acceptable salt thereof at least once per day (e.g., QD, BID, TID, or QID).
  • the subject has a weight of from about 35 kg to about 39 kg, and the subject is administered about 70 mg to about 90 mg, about 130 mg to about 150 mg, or about 210 mg to about 230 mg of Compound 1 or a dose equivalent of a pharmaceutically acceptable salt thereof twice per day.
  • the subject has a weight of from about 40 kg to about 44 kg, and the subject is administered about 70 mg to about 90 mg, about 150 mg to about 170 mg, or about 230 mg to about 250 mg of Compound 1 or a dose equivalent of a pharmaceutically acceptable salt thereof at least once per day (e.g., QD, BID, TID, or QID).
  • the subject has a weight of from about 40 kg to about 44 kg, and the subject is administered about 70 mg to about 90 mg, about 150 mg to about 170 mg, or about 230 mg to about 250 mg of Compound 1 or a dose equivalent of a pharmaceutically acceptable salt thereof twice per day.
  • the subject has a weight of from about 45 kg to about 49 kg, and the subject is administered about 90 mg to about 110 mg, about 170 mg to about 190 mg, or about 230 mg to about 250 mg of Compound 1 or a dose equivalent of a pharmaceutically acceptable salt thereof at least once per day (e.g., QD, BID, TID, or QID).
  • the subject has a weight of from about 45 kg to about 49 kg, and the subject is administered about 90 mg to about 110 mg, about 170 mg to about 190 mg, or about 230 mg to about 250 mg of Compound 1 or a dose equivalent of a pharmaceutically acceptable salt thereof at least twice per day.
  • the subject has a weight of from about 50 kg to about 54 kg, and the subject is administered about 90 mg to about 110 mg, about 170 mg to about 190 mg, or about 250 mg to about 270 mg of Compound 1 or a dose equivalent of a pharmaceutically acceptable salt thereof at least once per day (e.g., QD, BID, TID, or QID).
  • the subject has a weight of from about 50 kg to about 54 kg, and the subject is administered about 90 mg to about 110 mg, about 170 mg to about 190 mg, or about 250 mg to about 270 mg of Compound 1 or a dose equivalent of a pharmaceutically acceptable salt thereof twice per day.
  • the subject has a weight of from about 55 kg to about 59 kg, and the subject is administered about 90 mg to about 110 mg, about 170 mg to about 190 mg, or about 270 mg to about 290 mg of Compound 1 or a dose equivalent of a pharmaceutically acceptable salt thereof at least once per day (e.g., QD, BID, TID, or QID).
  • the subject has a weight of from about 55 kg to about 59 kg, and the subject is administered about 90 mg to about 110 mg, about 170 mg to about 190 mg, or about 270 mg to about 290 mg of Compound 1 or a dose equivalent of a pharmaceutically acceptable salt thereof twice per day.
  • the subject has a weight of greater than 60 kg, and the subject is administered about 90 mg to about 110 mg, about 190 mg to about 210 mg, or about 290 mg to about 310 mg of Compound 1 or a dose equivalent of a pharmaceutically acceptable salt thereof at least once per day (e.g., QD, BID, TID, or QID).
  • the subject has a weight of greater than 60 kg, and the subject is administered about 90 mg to about 110 mg, about 190 mg to about 210 mg, or about 290 mg to about 310 mg of Compound 1 or a dose equivalent of a pharmaceutically acceptable salt thereof twice per day.
  • the subject has a weight of from about 10 kg to about 14 kg, and the subject is administered about 60 mg to about 70 mg or about 100 mg to about 120 mg of Compound 1 or a dose equivalent of a pharmaceutically acceptable salt thereof at least once per day (e.g., QD, BID, TID, or QID).
  • the subject has a weight of from about 10 kg to about 14 kg, and the subject is administered about 60 mg to about 70 mg or about 100 mg to about 120 mg of Compound 1 or a dose equivalent of a pharmaceutically acceptable salt thereof twice per day.
  • the subject has a weight of from about 15 kg to about 19 kg, and the subject is administered about 90 mg to about 110 mg or about 120 mg to about 140 mg of Compound 1 or a dose equivalent of a pharmaceutically acceptable salt thereof at least once per day (e.g., QD, BID, TID, or QID).
  • the subject has a weight of from about 15 kg to about 19 kg, and the subject is administered about 90 mg to about 110 mg or about 120 mg to about 140 mg of Compound 1 or a dose equivalent of a pharmaceutically acceptable salt thereof twice per day.
  • the subject has a weight of from about 20 kg to about 24 kg, and the subject is administered about 110 mg to about 130 mg or about 150 mg to about 170 mg of Compound 1 or a dose equivalent of a pharmaceutically acceptable salt thereof at least once per day (e.g., QD, BID, TID, or QID).
  • the subject has a weight of from about 20 kg to about 24 kg, and the subject is administered about 110 mg to about 130 mg or about 150 mg to about 170 mg of Compound 1 or a dose equivalent of a pharmaceutically acceptable salt thereof twice per day.
  • the subject has a weight of from about 25 kg to about 29 kg, and the subject is administered about 110 mg to about 130 mg or about 170 mg to about 190 mg of Compound 1 or a dose equivalent of a pharmaceutically acceptable salt thereof at least once per day (e.g., QD, BID, TID, or QID).
  • the subject has a weight of from about 25 kg to about 29 kg, and the subject is administered about 110 mg to about 130 mg or about 170 mg to about 190 mg of Compound 1 or a dose equivalent of a pharmaceutically acceptable salt thereof twice per day.
  • the subject has a weight of from about 30 kg to about 34 kg, and the subject is administered about 130 mg to about 150 mg or about 190 mg to about 210 mg of Compound 1 or a dose equivalent of a pharmaceutically acceptable salt thereof at least once per day (e.g., QD, BID, TID, or QID).
  • the subject has a weight of from about 30 kg to about 34 kg, and the subject is administered about 130 mg to about 150 mg or about 190 mg to about 210 mg of Compound 1 or a dose equivalent of a pharmaceutically acceptable salt thereof twice per day.
  • the subject has a weight of from about 35 kg to about 39 kg, and the subject is administered about 130 mg to about 150 mg or about 210 mg to about 230 mg of Compound 1 or a dose equivalent of a pharmaceutically acceptable salt thereof at least once per day (e.g., QD, BID, TTD, or QID).
  • the subject has a weight of from about 35 kg to about 39 kg, and the subject is administered about 130 mg to about 150 mg or about 210 mg to about 230 mg of Compound 1 or a dose equivalent of a pharmaceutically acceptable salt thereof twice per day.
  • the subject has a weight of from about 40 kg to about 44 kg, and the subject is administered about 150 mg to about 170 mg or about 230 mg to about 250 mg of Compound 1 or a dose equivalent of a pharmaceutically acceptable salt thereof at least once per day (e.g., QD, BID, TTD, or QID).
  • the subject has a weight of from about 40 kg to about 44 kg, and the subject is administered about 150 mg to about 170 mg or about 230 mg to about 250 mg of Compound 1 or a dose equivalent of a pharmaceutically acceptable salt thereof twice per day.
  • the subject has a weight of from about 45 kg to about 49 kg, and the subject is administered about 170 mg to about 190 mg or about 230 mg to about 250 mg of Compound 1 or a dose equivalent of a pharmaceutically acceptable salt thereof at least once per day (e.g., QD, BID, TTD, or QID).
  • the subject has a weight of from about 45 kg to about 49 kg, and the subject is administered about 170 mg to about 190 mg or about 230 mg to about 250 mg of Compound 1 or a dose equivalent of a pharmaceutically acceptable salt thereof twice per day.
  • the subject has a weight of from about 50 kg to about 54 kg, and the subject is administered about 170 mg to about 190 mg or about 250 mg to about 270 mg of Compound 1 or a dose equivalent of a pharmaceutically acceptable salt thereof at least once per day (e.g., QD, BID, TTD, or QID).
  • the subject has a weight of from about 50 kg to about 54 kg, and the subject is administered about 170 mg to about 190 mg or about 250 mg to about 270 mg of Compound 1 or a dose equivalent of a pharmaceutically acceptable salt thereof twice per day.
  • the subject has a weight of from about 55 kg to about 59 kg, and the subject is administered about 170 mg to about 190 mg or about 270 mg to about 290 mg of Compound 1 or a dose equivalent of a pharmaceutically acceptable salt thereof at least once per day (e.g., QD, BID, TTD, or QID).
  • the subject has a weight of from about 55 kg to about 59 kg, and the subject is administered about 170 mg to about 190 mg or about 270 mg to about 290 mg of Compound 1 or a dose equivalent of a pharmaceutically acceptable salt thereof twice per day.
  • the subject has a weight of greater than 60 kg, and the subject is administered about 190 mg to about 210 mg or about 290 mg to about 310 mg of Compound 1 or a dose equivalent of a pharmaceutically acceptable salt thereof at least once per day (e.g., QD, BID, TID, or QID).
  • the subject has a weight of greater than 60 kg, and the subject is administered about 190 mg to about 210 mg or about 290 mg to about 310 mg of Compound 1 or a dose equivalent of a pharmaceutically acceptable salt thereof twice per day.
  • the subject is at least 18 years of age. In some implementations, the subject is administered from about 95 mg to about 325 mg of Compound 1 or a dose equivalent of a pharmaceutically acceptable salt thereof at least once per day (e.g., QD, BID, TID, or QID). In other implementations, the subject is administered from about 95 mg to about 325 mg of Compound 1 or a dose equivalent of a pharmaceutically acceptable salt thereof twice per day. In some implementations, the subject is administered from about 95 mg to about 105 mg, from about 195 mg to about 205 mg, or from about 295 mg to about 305 mg of Compound 1 or a dose equivalent of a pharmaceutically acceptable salt thereof twice per day.
  • the subject is administered from about 295 mg to about 305 mg of Compound 1 or a dose equivalent of a pharmaceutically acceptable salt thereof twice per day. And, in some implementations, the subject is administered about 100 mg, about 200 mg, or about 300 mg of Compound 1 or a dose equivalent of a pharmaceutically acceptable salt thereof twice per day.
  • the subject experiences a reduction in all seizure frequency of about 45% or more beginning at least 23 weeks after treatment onset. In some implementations, the subject experiences a reduction in all seizure frequency of about 45% or more beginning at least 61 weeks after treatment onset. In other implementations, the subject experiences a reduction in motor seizure frequency of about 50% or more beginning at least 23 weeks after treatment onset. In some implementations, the subject experiences a reduction in motor seizure frequency of about 55% or more beginning at least 25 weeks after treatment onset. In some implementations, the subject experiences a reduction in motor seizure frequency of about 60% or more beginning at least 61 weeks after treatment onset.
  • motor seizure frequency is the subject's seizure frequency for drop seizures; tonic-clonic, tonic, bilateral clonic, atonic, myoclonic-atonic, myoclonic-tonic-clonic, and focal seizures with bilateral hyperkinetic motor features.
  • the subject is administered (e.g., concomitantly administered) at least one additional therapeutic agent with Compound 1 or a pharmaceutically acceptable salt thereof.
  • the additional therapeutic agent is a barbiturate, a benzodiazepine derivative, a carboxamide derivative, a fatty acid derivative, a glucocorticoid, a herbal antiepileptic, a hydantoin derivative, an antiepileptic, a hypnotic/sedative, a succinimide derivative, or any combination thereof.
  • the additional therapeutic agent is phenobarbital, primidone, clobazam, clonazepam, clorazepate dipotassium, diazepam, lorazepam, midazolam, nitrazepam, carbamazepine, eslicarbazepine acetate, oxcarbazepine, rufinamide, valproate magnesium, valproate semisodium, valproate sodium, valproate sodium/valproic acid, valproic acid, vigabatrin, methylprednisolone, cannabis sativa, fosphenytoin, phenytoin, phenytoin sodium, brivaracetam, cannabidoil, cannabinoids, felbamate, lacosamide, lamotrigine, levetiracetam, stiripentol, sultiame, topiramate, zonisamide, potassium bromide, ethosux
  • Compound 1 or a pharmaceutically acceptable salt thereof is administered orally or administered through a gastrostomy tube or percutaneous endoscopic gastrostomy tube.
  • Compound 1 or a pharmaceutically acceptable salt thereof is administered orally.
  • the present invention provides a method of treating a seizure disorder in a subject in need thereof comprising administering to the subject a dose of from about 75 mg to about 650 mg of Compound 1 (Compound 1), or a dose equivalent of a pharmaceutically acceptable salt thereof, at least once per day, wherein
  • the method further comprises administering Compound 1 or a pharmaceutically acceptable salt thereof for a treatment period of at least about 12 weeks, at least about 24 weeks, or at least about 36 weeks.
  • the subject is from about 2 years to about 17 years of age.
  • the subject is administered Compound 1 or a dose equivalent of a pharmaceutically acceptable salt thereof at a weight-adjusted dosage amount.
  • the subject is administered from about 75 mg to about 325 mg of Compound 1 or a dose equivalent of a pharmaceutically acceptable salt thereof at least once per day (e.g., QD, BID, TID, or QID). In some implementations, the subject is administered from about 75 mg to about 325 mg of Compound 1 or a dose equivalent of a pharmaceutically acceptable salt thereof twice per day.
  • a pharmaceutically acceptable salt thereof at least once per day (e.g., QD, BID, TID, or QID).
  • the subject is administered from about 75 mg to about 325 mg of Compound 1 or a dose equivalent of a pharmaceutically acceptable salt thereof twice per day.
  • the subject is administered from about 75 mg to about 85 mg, from about 95 mg to about 105 mg, from about 115 mg to about 125 mg, from about 135 mg to about 145 mg, from about 155 mg to about 165 mg, from about 175 mg to about 185 mg, from about 195 mg to about 205 mg, from about 215 mg to about 225 mg, from about 235 mg to about 245 mg, from about 255 mg to about 265 mg, from about 275 mg to about 285 mg or from about 295 mg to about 305 mg of Compound 1 or a dose equivalent of a pharmaceutically acceptable salt thereof twice per day.
  • the subject is administered from about 105 mg to about 115 mg, from about 125 mg to about 130 mg, from about 155 mg to about 160 mg, or from about 175 mg to about 185 mg of Compound 1 or a dose equivalent of a pharmaceutically acceptable salt thereof twice per day. And, in some implementations, the subject is administered about 80 mg, about 100 mg, about 110 mg, about 120 mg, about 130 mg, about 140 mg, about 160 mg, about 180 mg, about 200 mg, about 220 mg, about 240 mg, about 260 mg, about 280 mg, or about 300 mg of Compound 1 or a dose equivalent of a pharmaceutically acceptable salt thereof twice per day.
  • the subject has a weight of from about 10 kg to about 14 kg, and the subject is administered about 30 mg to about 50 mg, about 70 mg to about 90 mg, or about 100 to about 120 mg of Compound 1 or a dose equivalent of a pharmaceutically acceptable salt thereof at least once per day (e.g., QD, BID, TID, or QID).
  • the subject has a weight of from about 10 kg to about 14 kg, and the subject is administered about 30 mg to about 50 mg, about 70 mg to about 90 mg, or about 100 to about 120 mg of Compound 1 or a dose equivalent of a pharmaceutically acceptable salt thereof twice per day.
  • the subject has a weight of from about 15 kg to about 19 kg, and the subject is administered about 50 mg to about 70 mg, about 90 mg to about 110 mg, or about 120 mg to about 140 mg of Compound 1 or a dose equivalent of a pharmaceutically acceptable salt thereof at least once per day (e.g., QD, BID, TID, or QID).
  • the subject has a weight of from about 15 kg to about 19 kg, and the subject is administered about 50 mg to about 70 mg, about 90 mg to about 110 mg, or about 120 mg to about 140 mg of Compound 1 or a dose equivalent of a pharmaceutically acceptable salt thereof twice per day.
  • the subject has a weight of from about 20 kg to about 24 kg, and the subject is administered about 50 mg to about 70 mg, about 110 mg to about 130 mg, or about 150 mg to about 170 mg of Compound 1 or a dose equivalent of a pharmaceutically acceptable salt thereof at least once per day (e.g., QD, BID, TID, or QID).
  • the subject has a weight of from about 20 kg to about 24 kg, and the subject is administered about 50 mg to about 70 mg, about 110 mg to about 130 mg, or about 150 mg to about 170 mg of Compound 1 or a dose equivalent of a pharmaceutically acceptable salt thereof twice per day.
  • the subject has a weight of from about 25 kg to about 29 kg, and the subject is administered about 50 mg to about 70 mg, about 110 mg to about 130 mg, or about 170 mg to about 190 mg of Compound 1 or a dose equivalent of a pharmaceutically acceptable salt thereof at least once per day (e.g., QD, BID, TID, or QID).
  • the subject has a weight of from about 25 kg to about 29 kg, and the subject is administered about 50 mg to about 70 mg, about 110 mg to about 130 mg, or about 170 mg to about 190 mg of Compound 1 or a dose equivalent of a pharmaceutically acceptable salt thereof twice per day.
  • the subject has a weight of from about 30 kg to about 34 kg, and the subject is administered about 70 mg to about 90 mg, about 130 mg to about 150 mg, or about 190 mg to about 210 mg of Compound 1 or a dose equivalent of a pharmaceutically acceptable salt thereof at least once per day (e.g., QD, BID, TID, or QID).
  • the subject has a weight of from about 30 kg to about 34 kg, and the subject is administered about 70 mg to about 90 mg, about 130 mg to about 150 mg, or about 190 mg to about 210 mg of Compound 1 or a dose equivalent of a pharmaceutically acceptable salt thereof twice per day.
  • the subject has a weight of from about 35 kg to about 39 kg, and the subject is administered about 70 mg to about 90 mg, about 130 mg to about 150 mg, or about 210 mg to about 230 mg of Compound 1 or a dose equivalent of a pharmaceutically acceptable salt thereof at least once per day (e.g., QD, BID, TID, or QID).
  • the subject has a weight of from about 35 kg to about 39 kg, and the subject is administered about 70 mg to about 90 mg, about 130 mg to about 150 mg, or about 210 mg to about 230 mg of Compound 1 or a dose equivalent of a pharmaceutically acceptable salt thereof twice per day.
  • the subject has a weight of from about 40 kg to about 44 kg, and the subject is administered about 70 mg to about 90 mg, about 150 mg to about 170 mg, or about 230 mg to about 250 mg of Compound 1 or a dose equivalent of a pharmaceutically acceptable salt thereof at least once per day (e.g., QD, BID, TID, or QID).
  • the subject has a weight of from about 40 kg to about 44 kg, and the subject is administered about 70 mg to about 90 mg, about 150 mg to about 170 mg, or about 230 mg to about 250 mg of Compound 1 or a dose equivalent of a pharmaceutically acceptable salt thereof twice per day.
  • the subject has a weight of from about 45 kg to about 49 kg, and the subject is administered about 90 mg to about 110 mg, about 170 mg to about 190 mg, or about 230 mg to about 250 mg of Compound 1 or a dose equivalent of a pharmaceutically acceptable salt thereof at least once per day (e.g., QD, BID, TID, or QID).
  • the subject has a weight of from about 45 kg to about 49 kg, and the subject is administered about 90 mg to about 110 mg, about 170 mg to about 190 mg, or about 230 mg to about 250 mg of Compound 1 or a dose equivalent of a pharmaceutically acceptable salt thereof at least twice per day.
  • the subject has a weight of from about 50 kg to about 54 kg, and the subject is administered about 90 mg to about 110 mg, about 170 mg to about 190 mg, or about 250 mg to about 270 mg of Compound 1 or a dose equivalent of a pharmaceutically acceptable salt thereof at least once per day (e.g., QD, BID, TID, or QID).
  • the subject has a weight of from about 50 kg to about 54 kg, and the subject is administered about 90 mg to about 110 mg, about 170 mg to about 190 mg, or about 250 mg to about 270 mg of Compound 1 or a dose equivalent of a pharmaceutically acceptable salt thereof twice per day.
  • the subject has a weight of from about 55 kg to about 59 kg, and the subject is administered about 90 mg to about 110 mg, about 170 mg to about 190 mg, or about 270 mg to about 290 mg of Compound 1 or a dose equivalent of a pharmaceutically acceptable salt thereof at least once per day (e.g., QD, BID, TID, or QID).
  • the subject has a weight of from about 55 kg to about 59 kg, and the subject is administered about 90 mg to about 110 mg, about 170 mg to about 190 mg, or about 270 mg to about 290 mg of Compound 1 or a dose equivalent of a pharmaceutically acceptable salt thereof twice per day.
  • the subject has a weight of greater than 60 kg, and the subject is administered about 90 mg to about 110 mg, about 190 mg to about 210 mg, or about 290 mg to about 310 mg of Compound 1 or a dose equivalent of a pharmaceutically acceptable salt thereof at least once per day (e.g., QD, BID, TID, or QID).
  • the subject has a weight of greater than 60 kg, and the subject is administered about 90 mg to about 110 mg, about 190 mg to about 210 mg, or about 290 mg to about 310 mg of Compound 1 or a dose equivalent of a pharmaceutically acceptable salt thereof twice per day.
  • the subject has a weight of from about 10 kg to about 14 kg, and the subject is administered about 60 mg to about 70 mg or about 100 mg to about 120 mg of Compound 1 or a dose equivalent of a pharmaceutically acceptable salt thereof at least once per day (e.g., QD, BID, TID, or QID).
  • the subject has a weight of from about 10 kg to about 14 kg, and the subject is administered about 60 mg to about 70 mg or about 100 mg to about 120 mg of Compound 1 or a dose equivalent of a pharmaceutically acceptable salt thereof twice per day.
  • the subject has a weight of from about 15 kg to about 19 kg, and the subject is administered about 90 mg to about 110 mg or about 120 mg to about 140 mg of Compound 1 or a dose equivalent of a pharmaceutically acceptable salt thereof at least once per day (e.g., QD, BID, TID, or QID).
  • the subject has a weight of from about 15 kg to about 19 kg, and the subject is administered about 90 mg to about 110 mg or about 120 mg to about 140 mg of Compound 1 or a dose equivalent of a pharmaceutically acceptable salt thereof twice per day.
  • the subject has a weight of from about 20 kg to about 24 kg, and the subject is administered about 110 mg to about 130 mg or about 150 mg to about 170 mg of Compound 1 or a dose equivalent of a pharmaceutically acceptable salt thereof at least once per day (e.g., QD, BID, TID, or QID).
  • the subject has a weight of from about 20 kg to about 24 kg, and the subject is administered about 110 mg to about 130 mg or about 150 mg to about 170 mg of Compound 1 or a dose equivalent of a pharmaceutically acceptable salt thereof twice per day.
  • the subject has a weight of from about 25 kg to about 29 kg, and the subject is administered about 110 mg to about 130 mg or about 170 mg to about 190 mg of Compound 1 or a dose equivalent of a pharmaceutically acceptable salt thereof at least once per day (e.g., QD, BID, TTD, or QID).
  • the subject has a weight of from about 25 kg to about 29 kg, and the subject is administered about 110 mg to about 130 mg or about 170 mg to about 190 mg of Compound 1 or a dose equivalent of a pharmaceutically acceptable salt thereof twice per day.
  • the subject has a weight of from about 30 kg to about 34 kg, and the subject is administered about 130 mg to about 150 mg or about 190 mg to about 210 mg of Compound 1 or a dose equivalent of a pharmaceutically acceptable salt thereof at least once per day (e.g., QD, BID, TTD, or QID).
  • the subject has a weight of from about 30 kg to about 34 kg, and the subject is administered about 130 mg to about 150 mg or about 190 mg to about 210 mg of Compound 1 or a dose equivalent of a pharmaceutically acceptable salt thereof twice per day.
  • the subject has a weight of from about 35 kg to about 39 kg, and the subject is administered about 130 mg to about 150 mg or about 210 mg to about 230 mg of Compound 1 or a dose equivalent of a pharmaceutically acceptable salt thereof at least once per day (e.g., QD, BID, TTD, or QID).
  • the subject has a weight of from about 35 kg to about 39 kg, and the subject is administered about 130 mg to about 150 mg or about 210 mg to about 230 mg of Compound 1 or a dose equivalent of a pharmaceutically acceptable salt thereof twice per day.
  • the subject has a weight of from about 40 kg to about 44 kg, and the subject is administered about 150 mg to about 170 mg or about 230 mg to about 250 mg of Compound 1 or a dose equivalent of a pharmaceutically acceptable salt thereof at least once per day (e.g., QD, BID, TTD, or QID).
  • the subject has a weight of from about 40 kg to about 44 kg, and the subject is administered about 150 mg to about 170 mg or about 230 mg to about 250 mg of Compound 1 or a dose equivalent of a pharmaceutically acceptable salt thereof twice per day.
  • the subject has a weight of from about 45 kg to about 49 kg, and the subject is administered about 170 mg to about 190 mg or about 230 mg to about 250 mg of Compound 1 or a dose equivalent of a pharmaceutically acceptable salt thereof at least once per day (e.g., QD, BID, TTD, or QID).
  • the subject has a weight of from about 45 kg to about 49 kg, and the subject is administered about 170 mg to about 190 mg or about 230 mg to about 250 mg of Compound 1 or a dose equivalent of a pharmaceutically acceptable salt thereof twice per day.
  • the subject has a weight of from about 50 kg to about 54 kg, and the subject is administered about 170 mg to about 190 mg or about 250 mg to about 270 mg of Compound 1 or a dose equivalent of a pharmaceutically acceptable salt thereof at least once per day (e.g., QD, BID, TTD, or QID).
  • the subject has a weight of from about 50 kg to about 54 kg, and the subject is administered about 170 mg to about 190 mg or about 250 mg to about 270 mg of Compound 1 or a dose equivalent of a pharmaceutically acceptable salt thereof twice per day.
  • the subject has a weight of from about 55 kg to about 59 kg, and the subject is administered about 170 mg to about 190 mg or about 270 mg to about 290 mg of Compound 1 or a dose equivalent of a pharmaceutically acceptable salt thereof at least once per day (e.g., QD, BID, TTD, or QID).
  • the subject has a weight of from about 55 kg to about 59 kg, and the subject is administered about 170 mg to about 190 mg or about 270 mg to about 290 mg of Compound 1 or a dose equivalent of a pharmaceutically acceptable salt thereof twice per day.
  • the subject has a weight of greater than 60 kg, and the subject is administered about 190 mg to about 210 mg or about 290 mg to about 310 mg of Compound 1 or a dose equivalent of a pharmaceutically acceptable salt thereof at least once per day (e.g., QD, BID, TID, or QID).
  • the subject has a weight of greater than 60 kg, and the subject is administered about 190 mg to about 210 mg or about 290 mg to about 310 mg of Compound 1 or a dose equivalent of a pharmaceutically acceptable salt thereof twice per day.
  • the subject is at least 18 years of age. In some implementations, the subject is administered from about 95 mg to about 325 mg of Compound 1 or a dose equivalent of a pharmaceutically acceptable salt thereof at least once per day (e.g., QD, BID, TID, or QID). In other implementations, the subject is administered from about 95 mg to about 325 mg of Compound 1 or a dose equivalent of a pharmaceutically acceptable salt thereof twice per day. In some implementations, the subject is administered from about 95 mg to about 105 mg, from about 195 mg to about 205 mg, or from about 295 mg to about 305 mg of Compound 1 or a dose equivalent of a pharmaceutically acceptable salt thereof twice per day.
  • a pharmaceutically acceptable salt thereof at least once per day (e.g., QD, BID, TID, or QID). In other implementations, the subject is administered from about 95 mg to about 325 mg of Compound 1 or a dose equivalent of a pharmaceutically acceptable salt thereof twice per day. In some implementations, the subject is administered from about 95
  • the subject is administered from about 295 mg to about 305 mg of Compound 1 or a dose equivalent of a pharmaceutically acceptable salt thereof twice per day. And, in some implementations, the subject is administered about 100 mg, about 200 mg, or about 300 mg of Compound 1 or a dose equivalent of a pharmaceutically acceptable salt thereof twice per day.
  • the subject experiences a reduction in all seizure frequency of about 25% or more beginning at least 23 weeks after treatment onset. In some implementations, the subject experiences a reduction in all seizure frequency of about 50% or more beginning at least 61 weeks after treatment onset. In other implementations, the subject experiences a reduction in convulsive seizure frequency of about 25% or more beginning at least 23 weeks after treatment onset. In some implementations, the subject experiences a reduction in convulsive seizure frequency of about 30% or more beginning at least 25 weeks after treatment onset. And, in some implementations, the subject experiences a reduction in convulsive seizure frequency of about 40% or more beginning at least 61 weeks after treatment onset.
  • the subject is administered (e.g., concomitantly administered) at least one additional therapeutic agent with Compound 1 or a pharmaceutically acceptable salt thereof.
  • the additional therapeutic agent is a barbiturate, a benzodiazepine derivative, a carboxamide derivative, a fatty acid derivative, a glucocorticoid, a herbal antiepileptic, a hydantoin derivative, an antiepileptic, a hypnotic/sedative, a succinimide derivative, or any combination thereof.
  • the additional therapeutic agent is phenobarbital, primidone, clobazam, clonazepam, clorazepate dipotassium, diazepam, lorazepam, midazolam, nitrazepam, carbamazepine, eslicarbazepine acetate, oxcarbazepine, rufinamide, valproate magnesium, valproate semisodium, valproate sodium, valproate sodium/valproic acid, valproic acid, vigabatrin, methylprednisolone, cannabis sativa, fosphenytoin, phenytoin, phenytoin sodium, brivaracetam, cannabidoil, cannabinoids, felbamate, lacosamide, lamotrigine, levetiracetam, stiripentol, sultiame, topiramate, zonisamide, potassium bromide, ethosux
  • Compound 1 or a pharmaceutically acceptable salt thereof is administered orally or administered through a gastrostomy tube or percutaneous endoscopic gastrostomy tube.
  • Compound 1 or a pharmaceutically acceptable salt thereof is administered orally.
  • the present invention provides a method of treating a seizure disorder in a subject in need thereof comprising administering to the subject a dose of from about 75 mg to about 650 mg of Compound 1 (Compound 1), or a dose equivalent of a pharmaceutically acceptable salt thereof, at least once per day, wherein
  • the method further comprises administering Compound 1 or a pharmaceutically acceptable salt thereof for a treatment period of at least about 12 weeks, at least about 24 weeks, or at least about 36 weeks.
  • the subject is from about 2 years to about 17 years of age.
  • the subject is administered Compound 1 or a dose equivalent of a pharmaceutically acceptable salt thereof at a weight-adjusted dosage amount.
  • the subject is administered from about 75 mg to about 325 mg of Compound 1 or a dose equivalent of a pharmaceutically acceptable salt thereof at least once per day (e.g., QD, BID, TID, or QID). In some implementations, the subject is administered from about 75 mg to about 325 mg of Compound 1 or a dose equivalent of a pharmaceutically acceptable salt thereof twice per day.
  • a pharmaceutically acceptable salt thereof at least once per day (e.g., QD, BID, TID, or QID).
  • the subject is administered from about 75 mg to about 325 mg of Compound 1 or a dose equivalent of a pharmaceutically acceptable salt thereof twice per day.
  • the subject is administered from about 75 mg to about 85 mg, from about 95 mg to about 105 mg, from about 115 mg to about 125 mg, from about 135 mg to about 145 mg, from about 155 mg to about 165 mg, from about 175 mg to about 185 mg, from about 195 mg to about 205 mg, from about 215 mg to about 225 mg, from about 235 mg to about 245 mg, from about 255 mg to about 265 mg, from about 275 mg to about 285 mg or from about 295 mg to about 305 mg of Compound 1 or a dose equivalent of a pharmaceutically acceptable salt thereof twice per day.
  • the subject is administered from about 105 mg to about 115 mg, from about 125 mg to about 130 mg, from about 155 mg to about 160 mg, or from about 175 mg to about 185 mg of Compound 1 or a dose equivalent of a pharmaceutically acceptable salt thereof twice per day. And, in some implementations, the subject is administered about 80 mg, about 100 mg, about 110 mg, about 120 mg, about 130 mg, about 140 mg, about 160 mg, about 180 mg, about 200 mg, about 220 mg, about 240 mg, about 260 mg, about 280 mg, or about 300 mg of Compound 1 or a dose equivalent of a pharmaceutically acceptable salt thereof twice per day.
  • the subject has a weight of from about 10 kg to about 14 kg, and the subject is administered about 30 mg to about 50 mg, about 70 mg to about 90 mg, or about 100 to about 120 mg of Compound 1 or a dose equivalent of a pharmaceutically acceptable salt thereof at least once per day (e.g., QD, BID, TID, or QID).
  • the subject has a weight of from about 10 kg to about 14 kg, and the subject is administered about 30 mg to about 50 mg, about 70 mg to about 90 mg, or about 100 to about 120 mg of Compound 1 or a dose equivalent of a pharmaceutically acceptable salt thereof twice per day.
  • the subject has a weight of from about 15 kg to about 19 kg, and the subject is administered about 50 mg to about 70 mg, about 90 mg to about 110 mg, or about 120 mg to about 140 mg of Compound 1 or a dose equivalent of a pharmaceutically acceptable salt thereof at least once per day (e.g., QD, BID, TID, or QID).
  • the subject has a weight of from about 15 kg to about 19 kg, and the subject is administered about 50 mg to about 70 mg, about 90 mg to about 110 mg, or about 120 mg to about 140 mg of Compound 1 or a dose equivalent of a pharmaceutically acceptable salt thereof twice per day.
  • the subject has a weight of from about 20 kg to about 24 kg, and the subject is administered about 50 mg to about 70 mg, about 110 mg to about 130 mg, or about 150 mg to about 170 mg of Compound 1 or a dose equivalent of a pharmaceutically acceptable salt thereof at least once per day (e.g., QD, BID, TID, or QID).
  • the subject has a weight of from about 20 kg to about 24 kg, and the subject is administered about 50 mg to about 70 mg, about 110 mg to about 130 mg, or about 150 mg to about 170 mg of Compound 1 or a dose equivalent of a pharmaceutically acceptable salt thereof twice per day.
  • the subject has a weight of from about 25 kg to about 29 kg, and the subject is administered about 50 mg to about 70 mg, about 110 mg to about 130 mg, or about 170 mg to about 190 mg of Compound 1 or a dose equivalent of a pharmaceutically acceptable salt thereof at least once per day (e.g., QD, BID, TID, or QID).
  • the subject has a weight of from about 25 kg to about 29 kg, and the subject is administered about 50 mg to about 70 mg, about 110 mg to about 130 mg, or about 170 mg to about 190 mg of Compound 1 or a dose equivalent of a pharmaceutically acceptable salt thereof twice per day.
  • the subject has a weight of from about 30 kg to about 34 kg, and the subject is administered about 70 mg to about 90 mg, about 130 mg to about 150 mg, or about 190 mg to about 210 mg of Compound 1 or a dose equivalent of a pharmaceutically acceptable salt thereof at least once per day (e.g., QD, BID, TID, or QID).
  • the subject has a weight of from about 30 kg to about 34 kg, and the subject is administered about 70 mg to about 90 mg, about 130 mg to about 150 mg, or about 190 mg to about 210 mg of Compound 1 or a dose equivalent of a pharmaceutically acceptable salt thereof twice per day.
  • the subject has a weight of from about 35 kg to about 39 kg, and the subject is administered about 70 mg to about 90 mg, about 130 mg to about 150 mg, or about 210 mg to about 230 mg of Compound 1 or a dose equivalent of a pharmaceutically acceptable salt thereof at least once per day (e.g., QD, BID, TID, or QID).
  • the subject has a weight of from about 35 kg to about 39 kg, and the subject is administered about 70 mg to about 90 mg, about 130 mg to about 150 mg, or about 210 mg to about 230 mg of Compound 1 or a dose equivalent of a pharmaceutically acceptable salt thereof twice per day.
  • the subject has a weight of from about 40 kg to about 44 kg, and the subject is administered about 70 mg to about 90 mg, about 150 mg to about 170 mg, or about 230 mg to about 250 mg of Compound 1 or a dose equivalent of a pharmaceutically acceptable salt thereof at least once per day (e.g., QD, BID, TID, or QID).
  • the subject has a weight of from about 40 kg to about 44 kg, and the subject is administered about 70 mg to about 90 mg, about 150 mg to about 170 mg, or about 230 mg to about 250 mg of Compound 1 or a dose equivalent of a pharmaceutically acceptable salt thereof twice per day.
  • the subject has a weight of from about 45 kg to about 49 kg, and the subject is administered about 90 mg to about 110 mg, about 170 mg to about 190 mg, or about 230 mg to about 250 mg of Compound 1 or a dose equivalent of a pharmaceutically acceptable salt thereof at least once per day (e.g., QD, BID, TID, or QID).
  • the subject has a weight of from about 45 kg to about 49 kg, and the subject is administered about 90 mg to about 110 mg, about 170 mg to about 190 mg, or about 230 mg to about 250 mg of Compound 1 or a dose equivalent of a pharmaceutically acceptable salt thereof at least twice per day.
  • the subject has a weight of from about 50 kg to about 54 kg, and the subject is administered about 90 mg to about 110 mg, about 170 mg to about 190 mg, or about 250 mg to about 270 mg of Compound 1 or a dose equivalent of a pharmaceutically acceptable salt thereof at least once per day (e.g., QD, BID, TID, or QID).
  • the subject has a weight of from about 50 kg to about 54 kg, and the subject is administered about 90 mg to about 110 mg, about 170 mg to about 190 mg, or about 250 mg to about 270 mg of Compound 1 or a dose equivalent of a pharmaceutically acceptable salt thereof twice per day.
  • the subject has a weight of from about 55 kg to about 59 kg, and the subject is administered about 90 mg to about 110 mg, about 170 mg to about 190 mg, or about 270 mg to about 290 mg of Compound 1 or a dose equivalent of a pharmaceutically acceptable salt thereof at least once per day (e.g., QD, BID, TID, or QID).
  • the subject has a weight of from about 55 kg to about 59 kg, and the subject is administered about 90 mg to about 110 mg, about 170 mg to about 190 mg, or about 270 mg to about 290 mg of Compound 1 or a dose equivalent of a pharmaceutically acceptable salt thereof twice per day.
  • the subject has a weight of greater than 60 kg, and the subject is administered about 90 mg to about 110 mg, about 190 mg to about 210 mg, or about 290 mg to about 310 mg of Compound 1 or a dose equivalent of a pharmaceutically acceptable salt thereof at least once per day (e.g., QD, BID, TID, or QID).
  • the subject has a weight of greater than 60 kg, and the subject is administered about 90 mg to about 110 mg, about 190 mg to about 210 mg, or about 290 mg to about 310 mg of Compound 1 or a dose equivalent of a pharmaceutically acceptable salt thereof twice per day.
  • the subject has a weight of from about 10 kg to about 14 kg, and the subject is administered about 60 mg to about 70 mg or about 100 mg to about 120 mg of Compound 1 or a dose equivalent of a pharmaceutically acceptable salt thereof at least once per day (e.g., QD, BID, TID, or QID).
  • the subject has a weight of from about 10 kg to about 14 kg, and the subject is administered about 60 mg to about 70 mg or about 100 mg to about 120 mg of Compound 1 or a dose equivalent of a pharmaceutically acceptable salt thereof twice per day.
  • the subject has a weight of from about 15 kg to about 19 kg, and the subject is administered about 90 mg to about 110 mg or about 120 mg to about 140 mg of Compound 1 or a dose equivalent of a pharmaceutically acceptable salt thereof at least once per day (e.g., QD, BID, TID, or QID).
  • the subject has a weight of from about 15 kg to about 19 kg, and the subject is administered about 90 mg to about 110 mg or about 120 mg to about 140 mg of Compound 1 or a dose equivalent of a pharmaceutically acceptable salt thereof twice per day.
  • the subject has a weight of from about 20 kg to about 24 kg, and the subject is administered about 110 mg to about 130 mg or about 150 mg to about 170 mg of Compound 1 or a dose equivalent of a pharmaceutically acceptable salt thereof at least once per day (e.g., QD, BID, TTD, or QID).
  • the subject has a weight of from about 20 kg to about 24 kg, and the subject is administered about 110 mg to about 130 mg or about 150 mg to about 170 mg of Compound 1 or a dose equivalent of a pharmaceutically acceptable salt thereof twice per day.
  • the subject has a weight of from about 25 kg to about 29 kg, and the subject is administered about 110 mg to about 130 mg or about 170 mg to about 190 mg of Compound 1 or a dose equivalent of a pharmaceutically acceptable salt thereof at least once per day (e.g., QD, BID, TTD, or QID).
  • the subject has a weight of from about 25 kg to about 29 kg, and the subject is administered about 110 mg to about 130 mg or about 170 mg to about 190 mg of Compound 1 or a dose equivalent of a pharmaceutically acceptable salt thereof twice per day.
  • the subject has a weight of from about 30 kg to about 34 kg, and the subject is administered about 130 mg to about 150 mg or about 190 mg to about 210 mg of Compound 1 or a dose equivalent of a pharmaceutically acceptable salt thereof at least once per day (e.g., QD, BID, TTD, or QID).
  • the subject has a weight of from about 30 kg to about 34 kg, and the subject is administered about 130 mg to about 150 mg or about 190 mg to about 210 mg of Compound 1 or a dose equivalent of a pharmaceutically acceptable salt thereof twice per day.
  • the subject has a weight of from about 35 kg to about 39 kg, and the subject is administered about 130 mg to about 150 mg or about 210 mg to about 230 mg of Compound 1 or a dose equivalent of a pharmaceutically acceptable salt thereof at least once per day (e.g., QD, BID, TTD, or QID).
  • the subject has a weight of from about 35 kg to about 39 kg, and the subject is administered about 130 mg to about 150 mg or about 210 mg to about 230 mg of Compound 1 or a dose equivalent of a pharmaceutically acceptable salt thereof twice per day.
  • the subject has a weight of from about 40 kg to about 44 kg, and the subject is administered about 150 mg to about 170 mg or about 230 mg to about 250 mg of Compound 1 or a dose equivalent of a pharmaceutically acceptable salt thereof at least once per day (e.g., QD, BID, TTD, or QID).
  • the subject has a weight of from about 40 kg to about 44 kg, and the subject is administered about 150 mg to about 170 mg or about 230 mg to about 250 mg of Compound 1 or a dose equivalent of a pharmaceutically acceptable salt thereof twice per day.
  • the subject has a weight of from about 45 kg to about 49 kg, and the subject is administered about 170 mg to about 190 mg or about 230 mg to about 250 mg of Compound 1 or a dose equivalent of a pharmaceutically acceptable salt thereof at least once per day (e.g., QD, BID, TTD, or QID).
  • the subject has a weight of from about 45 kg to about 49 kg, and the subject is administered about 170 mg to about 190 mg or about 230 mg to about 250 mg of Compound 1 or a dose equivalent of a pharmaceutically acceptable salt thereof twice per day.
  • the subject has a weight of from about 50 kg to about 54 kg, and the subject is administered about 170 mg to about 190 mg or about 250 mg to about 270 mg of Compound 1 or a dose equivalent of a pharmaceutically acceptable salt thereof at least once per day (e.g., QD, BID, TTD, or QID).
  • the subject has a weight of from about 50 kg to about 54 kg, and the subject is administered about 170 mg to about 190 mg or about 250 mg to about 270 mg of Compound 1 or a dose equivalent of a pharmaceutically acceptable salt thereof twice per day.
  • the subject has a weight of from about 55 kg to about 59 kg, and the subject is administered about 170 mg to about 190 mg or about 270 mg to about 290 mg of Compound 1 or a dose equivalent of a pharmaceutically acceptable salt thereof at least once per day (e.g., QD, BID, TTD, or QID).
  • the subject has a weight of from about 55 kg to about 59 kg, and the subject is administered about 170 mg to about 190 mg or about 270 mg to about 290 mg of Compound 1 or a dose equivalent of a pharmaceutically acceptable salt thereof twice per day.
  • the subject has a weight of greater than 60 kg, and the subject is administered about 190 mg to about 210 mg or about 290 mg to about 310 mg of Compound 1 or a dose equivalent of a pharmaceutically acceptable salt thereof at least once per day (e.g., QD, BID, TID, or QID).
  • the subject has a weight of greater than 60 kg, and the subject is administered about 190 mg to about 210 mg or about 290 mg to about 310 mg of Compound 1 or a dose equivalent of a pharmaceutically acceptable salt thereof twice per day.
  • the subject is at least 18 years of age. In some implementations, the subject is administered from about 95 mg to about 325 mg of Compound 1 or a dose equivalent of a pharmaceutically acceptable salt thereof at least once per day (e.g., QD, BID, TID, or QID). In other implementations, the subject is administered from about 95 mg to about 325 mg of Compound 1 or a dose equivalent of a pharmaceutically acceptable salt thereof twice per day. In some implementations, the subject is administered from about 95 mg to about 105 mg, from about 195 mg to about 205 mg, or from about 295 mg to about 305 mg of Compound 1 or a dose equivalent of a pharmaceutically acceptable salt thereof twice per day.
  • a pharmaceutically acceptable salt thereof at least once per day (e.g., QD, BID, TID, or QID). In other implementations, the subject is administered from about 95 mg to about 325 mg of Compound 1 or a dose equivalent of a pharmaceutically acceptable salt thereof twice per day. In some implementations, the subject is administered from about 95
  • the subject is administered from about 295 mg to about 305 mg of Compound 1 or a dose equivalent of a pharmaceutically acceptable salt thereof twice per day. And, in some implementations, the subject is administered about 100 mg, about 200 mg, or about 300 mg of Compound 1 or a dose equivalent of a pharmaceutically acceptable salt thereof twice per day.
  • the subject experiences a reduction in convulsive seizure frequency of about 10% or more beginning at least 23 weeks after treatment onset. In other implementations, the subject experiences a reduction in convulsive seizure frequency of about 30% or more beginning at least 25 weeks after treatment onset. And, in some implementations, the subject experiences a reduction in convulsive seizure frequency of about 40% or more beginning at least 61 weeks after treatment onset.
  • the subject is administered (e.g., concomitantly administered) at least one additional therapeutic agent with Compound 1 or a pharmaceutically acceptable salt thereof.
  • the additional therapeutic agent is a barbiturate, a benzodiazepine derivative, a carboxamide derivative, a fatty acid derivative, a glucocorticoid, a herbal antiepileptic, a hydantoin derivative, an antiepileptic, a hypnotic/sedative, a succinimide derivative, or any combination thereof.
  • the additional therapeutic agent is phenobarbital, primidone, clobazam, clonazepam, clorazepate dipotassium, diazepam, lorazepam, midazolam, nitrazepam, carbamazepine, eslicarbazepine acetate, oxcarbazepine, rufinamide, valproate magnesium, valproate semisodium, valproate sodium, valproate sodium/valproic acid, valproic acid, vigabatrin, methylprednisolone, cannabis sativa, fosphenytoin, phenytoin, phenytoin sodium, brivaracetam, cannabidoil, cannabinoids, felbamate, lacosamide, lamotrigine, levetiracetam, stiripentol, sultiame, topiramate, zonisamide, potassium bromide, ethosux
  • Compound 1 or a pharmaceutically acceptable salt thereof is administered orally or administered through a gastrostomy tube or percutaneous endoscopic gastrostomy tube.
  • Compound 1 or a pharmaceutically acceptable salt thereof is administered orally.
  • Example 1 Compound 1 Formulation (Film Coated Tablet)
  • Compound 1 was formulated into a film coated tablet according to Table 1, below.
  • Table 1 Film Coated Tablet.
  • Example 2 Antecedent Studies.
  • Example 2A A Phase lb/2a Multicenter, Randomized, Double-Blind, Placebo- Controlled, Parallel-Group, Dose-Escalation Study With an Open-Label Part to Examine the Safety, Tolerability, Pharmacokinetics, and Pharmacodynamics of Compound 1 as an Adjunctive Therapy in Subjects With Developmental and/or Epileptic Encephalopathies (“DEE Study”).
  • DEE Study A Phase lb/2a Multicenter, Randomized, Double-Blind, Placebo- Controlled, Parallel-Group, Dose-Escalation Study With an Open-Label Part to Examine the Safety, Tolerability, Pharmacokinetics, and Pharmacodynamics of Compound 1 as an Adjunctive Therapy in Subjects With Developmental and/or Epileptic Encephalopathies (“DEE Study”).
  • Study Design- Study participants (18 participants) were randomly assigned to one of two treatment groups: Compound 1 and placebo. Participants received either placebo or 100 mg Compound 1 tablets, orally or through stable G-tube/PEG tube, twice per day (BID), in Part 1 (Day 1) and dose was increased to 200 mg (Day 11) BID and to 300 mg (Day 21) BID in the dose titration period.
  • Cmax,ss Maximum observed plasma concentration for Compound 1 at steady state.
  • AUC0-tau,ss Area under the plasma concentration-time curve over the dosing interval for Compound 1 at steady state.
  • Ctrough,ss Plasma concentration immediately prior to dosing for Compound 1 at steady state.
  • G-tubes/PEG tubes should have been placed and been functioning for at least 3 months prior to screening. Naso-gastric tubes are not allowed.
  • ketogenic diet that has been started within 6 months of the Screening Visit, has been changed within 1 month of the Screening Visit, or is anticipated to change during the study.
  • C-SSRS Columbia-Suicide Severity Rating Scale
  • hepatitis B positive for human immunodeficiency virus, hepatitis B, or hepatitis C infections.
  • participants who have been vaccinated against hepatitis B [hepatitis B surface antibody (Ab)-positive] who are negative for other markers of prior hepatitis B infection [example, negative for hepatitis B core Ab] are eligible.
  • participants who are positive for hepatitis C Ab are eligible as long as they have a negative hepatitis C viral load by quantitative polymerase chain reaction [qPCR]).
  • Example 2B A Phase 2, Multicenter, Randomized, Double-blind, Placebo- controlled Study to Evaluate the Efficacy, Safety, and Tolerability of Compound 1 as an Adjunctive Therapy in Pediatric Participants With Developmental and/or Epileptic Encephalopathies (“DS and LGS Study”).
  • Study Design - Study participants (141 participants) were assigned to one of two groups based on their diagnosis: Dravet syndrome (DS) and Lennox-Gastaut syndrome (LGS). Study participants in each of the D S and LGS groups were then randomly assigned to one of two treatment groups: Compound 1 and placebo.
  • Compound 1 In the placebo groups, participants were given placebo tablets, orally or via gastrostomy tube (G-tube)/percutaneous endoscopic gastrostomy (PEG), twice a day (BID) up to Week 20.
  • G-tube gastrostomy tube
  • PEG percutaneous endoscopic gastrostomy
  • BID twice a day
  • Percentage of participants with LGS stratum considered treatment responders throughout the maintenance period.
  • Percentage of participants with dravet syndrome (DS) stratum considered treatment responders throughout the maintenance period.
  • CGI-S Clinical global impression of severity
  • CGI-C Percentage of participants with clinical global impression of change
  • Example 2C A Multicenter, Open-label, Pilot Study of Compound 1 in Participants With 15Q Duplication Syndrome (Dupl5q) or Cyclin-Dependent Kinase- Like 5 (CDD) Deficiency Disorder (“Dupl5q and CDD Study”).
  • Participants weighing >60 kg at Baseline were administered with 200 mg/day followed by 400 mg/day, then 600 mg/day, up to Week 20.
  • the study comprised of 2 periods: a Screening/Baseline Period and a Treatment Period (Dose Optimization and Maintenance).
  • the overall time to participate in this study is approximately 30 weeks, including 4 to 6 weeks Screening/Baseline Period, 20 weeks Treatment Period, 2 weeks Taper, and 2 weeks safety follow up period.
  • Example 3 A Phase 2, Interventional Open-Label, Extension Study to Assess the Long-Term Safety and Tolerability of Compound 1 in Individuals with Rare Epilepsy.
  • this is a multi-site, open-label extension (OLE) study designed to obtain additional safety and tolerability data related to Compound 1 administered longterm (up to 2 years) in patients with developmental and epileptic encephalopathies who participated in a previous Compound 1 clinical study described in Examples 2A, 2B, and 2C above. Additional aims included exploring the long-term effects of Compound 1 on seizure frequency and to assess the effects of Compound 1 on quality-of-life measures.
  • OEL open-label extension
  • the patient provides written informed consent, or the patient’s legal representative (i.e., parent or legal guardian) provides written informed consent and the patient provides assent, before any study procedures are performed.
  • the patient and patient’s legal representative i.e., parent or legal guardian (as applicable) are willing to comply with all study requirements.
  • Patient is currently pregnant or breastfeeding or is planning to become pregnant during the study or within 90 days of the last study drug administration.
  • Study design including timing of enrollment and dosing and titration schedule, is based upon the age of the patient (pediatric or adult), the type of antecedent study completed (blinded or unblinded), and how many days elapsed between completing the antecedent study and the Screening Visit in this study ( ⁇ 15 days or >15 days). In this study, adults are defined as patients who are 18 years or older.
  • the seizure diary data collected during a 4-week period was used as the baseline seizure data for endpoint analysis.
  • the 4-week Baseline Period seizure diary recording began the day after informed consent was obtained.
  • At the end of the 4-week Baseline Period patients will return to the clinic on Visit 2 (Day 1).
  • Dosing and Titration Schedule Patients were initiated with Compound 1 at Dose 1, and the dose was titrated up every 7 days (Day 8 and Day 15) as shown in Table 2. Two days after each change in dose, patients were contacted by phone to monitor study drug compliance, concomitant medication use, and AEs. Patients who could not tolerate Dose 1, if any, were withdrawn from the study. After up-titration, patients who could not tolerate the new dose may have had their dose reduced, based on the Investigator’s judgment and in consultation with the patient’s caregiver, when applicable. Patients were contacted by phone 2 days following escalation to the maximum dose to assess safety and tolerability of the study drug. Dosing may have been adjusted at the Investigator’s discretion throughout the study; however, frequent adjustments were discouraged.
  • Table 2 Dosing Schedule by Weight for Patients Who Complete the Antecedent Study > 15 Days Before the Screening Visit of This Study.
  • a Compound 1 dosing will be calculated based on body weight in pediatric patients only. b Daily doses are divided and administered twice daily.
  • Dosing and titration schedule Patients were initiated with Compound 1 at Dose 1 and the dose will be titrated up at Day 8 as shown in Table 3. After up-titration, patients who could not tolerate the new dose may have had their dose reduced, based on the investigator’s judgment and in consultation with the patient’s caregiver, when applicable. Patients were contacted by phone 2 days following escalation to the maximum dose to assess safety and tolerability of the study drug. Dosing may have been adjusted at the Investigator’s discretion throughout the study; however, frequent adjustments were discouraged.
  • Table 3 Dosing Schedule by Weight for Patients Who Complete the Double-blind Antecedent Study ⁇ 15 Days Before the Screening Visit of This Study. a Compound 1 dosing will be calculated based on body weight in pediatric patients only. b Daily doses are divided and administered twice daily.
  • Table 3 Demographic Characteristics for Patients that Completed the Antecedent Study of Example 2B.
  • the physical examination consisted of the following body systems: (1) head, eyes, ears, nose, and throat; (2) cardiovascular system; (3) respiratory system; (4) gastrointestinal system; (5) dermatologic system; (6) extremities; (7) musculoskeletal system; (8) lymph nodes; (9) psychiatric status; and (10) other. All examinations are to be performed by the Investigator or a qualified site staff member. The physical examination was recorded.
  • Neurological Examination Procedure A separate neurological examination was performed and recorded. This included testing mental status, gait, cerebellar function, cranial nerves, motor function, and sensation. As part of the neurological exam, vision testing included fimdoscopy and best corrected visual acuity using a pocket vision screening card where possible.
  • Height and Weight Height and weight were collected at Screening/Baseline (Visit 1). Height and weight were measured while the patient was wearing indoor clothing and with shoes off. If it was not possible to obtain height or weight, data was collected from other sources (e.g., medical records or the patient’s caretaker). The investigator documented the reason for not obtaining height or weight (e.g., the patient is in a wheelchair).
  • Vital Sign Measurements Vital signs measured were temperature, blood pressure, heart rate (beats per minute), and respiratory rate. Vital signs were measured at the same time of day across visits, if possible. When vital signs were scheduled at the same time as blood draws, the blood draw took priority and vital signs were obtained within 15 minutes before or after the scheduled blood draw, if possible. All vital sign data collected at study visits were recorded.
  • Seizure Diary Procedure At Visit 1 and at every subsequent clinic visit, the patient and/or patient’s caregiver was given a seizure diary and specific instructions to ensure compliance with the seizure recording. The seizure events were recorded starting at the Screening/Baseline Period up until the Follow-up Visit. At each clinic visit, the diary was collected and reviewed by the investigator with the patient and/or patient’s caregiver for proper recording and accountability. The 28-day seizure frequency will be calculated from the seizure diary using the following formula (2):
  • a dosing card was provided to the patient and/or caregiver at each clinic visit to record the actual time of dose administration for the last 2 doses taken before sample collection for Compound 1 concentration, to record exact time of the last meal relative to dosing before sample collection for Compound 1 concentration, and to record any changes in dosing regimen that may occur between visits and during the de- escalation period of the study.
  • Concomitant medication is any drug given in addition to the study drug. These may have been prescribed by a physician or obtained by the patient over the counter. At each study visit, patients and/or caregivers were asked whether patients had taken any medication other than the study drug (used from signing of informed consent through the end of the study), and all medication including vitamin supplements, over-the-counter medications, and herbal preparations including (medical) marijuana and cannabidiol products, were recorded. Documentation included generic medication name, dose, unit, frequency, route of administration, start and end dates, and reason for use.
  • Concurrent medical conditions are those significant ongoing conditions or diseases that were present at signing of informed consent. These included clinically significant laboratory, ECG, or physical examination abnormalities noted at Screening (Visit 1), according the judgment of the investigator. The condition (i.e., diagnosis) was recorded.
  • ABC-C Aberrant Behavior Checklist-Community Edition
  • AED antiepileptic drug
  • C-SSRS Columbia- Suicide Severity Rating Scale
  • eCRF electronic case report form
  • ID identification number
  • IWRS interactive web response system
  • PK pharmacokinetic
  • QoLCE Quality of Life in Childhood Epilepsy
  • SDNRS Sleep Disruption Numerical Rating Scale
  • VABS Vineland Adaptive Behavior Scale.
  • the Screening/Baseline visit may occur within 15 days of the end of treatment visit for the antecedent study and may occur on the same day.
  • Contraception and Pregnancy Avoidance Procedure Patients were provided with information on acceptable methods of contraception as part of the patient informed consent process and were asked to sign a consent form stating that they understand the requirements for avoidance of pregnancy, donation of ova, and sperm donation during the course of the study and for 90 days after the last dose of study drug.
  • Electrocardiogram Procedure A 12-lead ECG was recorded as indicated in Table XX, above. If patients receive the Compound 1 dose in the clinic, the ECG was performed approximately 30 min ( ⁇ 10 min) after dosing. If the patient could not tolerate being supine, a sitting ECG was obtained. The Investigator (or a qualified observer at the study site) interpreted the ECG using 1 of the following categories: within normal limits, abnormal but not clinically significant, or abnormal and clinically significant. The interpretation of the ECG was recorded. The time that the ECG was performed was recorded. The following parameters were recorded from the patient’s ECG trace: heart rate, RR interval, PR interval, QT interval, QRS interval with QTcF (corrected QT interval). ECG traces recorded on thermal paper were photocopied to avoid degradation of trace over time.
  • Suicidal ideation and behavior was assessed in patients at least 6 years of age using the C-SSRS.
  • the C-SSRS is a 3 -part scale that measures suicidal ideation (e.g., patient endorses thoughts about a wish to be dead or has other thoughts of suicide), intensity of ideation (frequency), and suicidal behavior (actually, interrupted, and aborted attempts at suicide).
  • the Columbia- Suicide Severity Rating Scale initial validity and internal consistency findings from three multisite studies with adolescents and adults. Am J Psychiatry 2011;168(12): 1266-77.
  • ABC-C Aberrant Behavior Checklist
  • the language barrier e.g., unavailability of validated test in patient’s language
  • VABS-3 Parent Caregiver Form The VABS, 3 rd edition, Parent Caregiver Form (VABS-3 Parent Caregiver Form), is a parent-report questionnaire of adaptive functioning or how an individual behaves in their day-to-day life at home and in the community, deritat A, Kraijer D, Sytema S, Minderaa R. The psychometric properties of the vineland adaptive behavior scales in children and adolescents with mental retardation. J Autism Dev Disord. 2005;35(l):53-62. It assesses adaptive functioning across 4 domains: motor, communication, daily living, and socialization. The interview takes about 20 minutes to complete. If the patient is unable to comply with the VABS due to the language barrier (e.g., unavailability of validated test in patient’s language), the investigator may also use clinical judgment to assess for adaptive function and behavior.
  • VABS-3 Parent Caregiver Form The psychometric properties of the vineland adaptive behavior scales in children and adolescents with mental retardation. J Autism Dev Disord. 2005;35(l
  • Quality of Life in Childhood Epilepsy The Quality of Life in Childhood Epilepsy is a parent-reported questionnaire that evaluates health-related quality of life in children ages 4 to 18 years old. Sabaz M, Caines DR, et al. Validation of a new quality of life measure for children with epilepsy. Epilepsia. 2000; 41(6):765-774. It contains 76 items with 16 subscales covering 7 domains of life function: physical activities, social activities, cognition, emotional wellbeing, behavior, general health, and general quality of life. This scale was only be used for pediatric patients.
  • An adverse event is any untoward medical occurrence in a patient or clinical study patient administered a medicinal product and which does not necessarily have a causal relationship with this treatment.
  • An AE can therefore be any unfavorable or unintended sign (for example, an abnormal laboratory finding), symptom, or disease temporally associated with the use of a medicinal product, whether considered related to this medicinal product.
  • the definition of an AE also covers medication errors and uses outside what is foreseen in the protocol only if an AE results from the error, including intentional misuse, abuse, and overdose of the product.
  • Seizures in this patient population were measured using the seizure diary and seizure frequency as a primary study endpoint. As seizures were considered a baseline condition, seizures were reported as an AE/SAE if 1) there was a clear increase in the frequency of seizures compared to the patient’s baseline, 2) there was an emergence of a new seizure type, or 3) the patient experiences status epilepticus, and 4) any other time the investigator determined that the seizure should be captured as an AE/SAE.
  • Moderate Events result in a low level of inconvenience or concerns with the therapeutic measures. Moderate events may cause some interference with functioning.
  • Severe Events interrupt a patient’s usual daily activity and may require systemic drug therapy or other treatment. Severe events are usually incapacitating.
  • Baseline refers to the prospective 4- week Baseline Period of the antecedent study or historical baseline seizure frequency from the last 3 months before entering the study (as per investigator), unless a patient had 4-week baseline data in this extension study.
  • Safety Analysis Set All enrolled patients who take at least 1 dose of Compound 1 in this study were included in the safety analysis set.
  • Modified Intent-to-Treat Analysis Set The Modified Intent-to-Treat analysis set consists of all patients who received at least 1 dose of Compound 1 and were assessed for at least 1 day in the treatment period.
  • Descriptive statistics are used to summarize all efficacy endpoints (seizure frequencies over a 28-day period). Seizure frequencies were derived from data in seizure diaries collected throughout the study. Changes in drop, convulsive, and motor seizure frequency from baseline to Weeks 12, 24, 36, 48, 64, 80, 104, and 108 were calculated and summarized.
  • Convulsive seizures include generalized tonic-clonic, focal to bilateral tonic-clonic with impaired awareness, and simultaneous bilateral clonic (generalized clonic) seizures. In patients with Dravet syndrome, hemi-clonic seizures were counted as convulsive seizures.
  • Drop seizures are defined as involving the entire body, trunk, or head that leads to a fall, injury, slumping in a chair, or head hitting a surface, or that could have led to a fall or injury, depending on the position of the patient at the time of the seizure or spell.
  • Examples of seizures causing drop include, but are not limited to, atonic, clonic, and tonic seizures.
  • Generalized tonic-clonic and focal to bilateral tonic-clonic with impaired awareness will not be counted as drop seizures.
  • Motor seizures includes drop seizures, tonic-clonic, tonic, bilateral clonic, atonic, myoclonic-atonic, myoclonic-tonic-clonic, focal seizures with bilateral hyperkinetic motor features.
  • Table 6 Median % Change From Baseline in All Seizure Frequency Per 28 Days in Subjects with DS or LGS.
  • Table 7 Median % Change From Baseline in All Seizure Frequency Per 28 Days in Subjects with DS.
  • Table 10 Median % Change From Baseline in Drop Seizure Frequency Per 28 Days in Subjects with LGS.
  • Table 11 Median % Change From Baseline in Convulsive Seizure Frequency Per 28 Days in Subjects with DS.
  • Table 12 Median % Change From Baseline in Convulsive Seizure Frequency Per 28 Days in Subjects with LGS.
  • Table 13 Median % Change From Baseline in Motor Seizure Frequency Per 28 Days in Subjects with CDD.
  • FIG. 2A-2C Additional median percent change from baseline data is set forth in Figures 2A-2C.
  • the placebo and Compound 1 treatment groups refer to patient groups in the antecedent study. The patients in this study each received Compound 1, irrespective of whether they were in the placebo or Compound 1 group in the antecedent study.
  • Figure 2 A provides median percent change from baseline in seizure frequency of the Modified Intent-to-Treat analysis set for subjects with DS and that completed the antecedent study of Example 2B.
  • Figure 2B provides median percent change from baseline in seizure frequency of the Modified Intent-to-Treat analysis set for subjects with LGS and that completed the antecedent study of Example 2B.
  • Figure 2C provides median percent change from baseline in seizure frequency of the Modified Intent-to-Treat analysis set for subjects with LGS or DS and that completed the antecedent study of Example 2B.
  • Table 14 TEAEs for Safety Analysis Set of Patients with DS or LGS.
  • Table 15 TEAEs for Safety Analysis Set of Patients with DS.
  • Table 16 TEAEs for Safety Analysis Set of Patients with LGS.
  • Table 17 TEAEs for Safety Analysis Set of Patients with CDD.
  • Table 18 Concomitant Medications for Patients with DS or LGS.
  • 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.
  • 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.
  • 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.

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Abstract

La présente invention concerne une méthode de traitement de troubles épileptiques chez un sujet en ayant besoin, comprenant l'administration du composé 1, ou d'un sel pharmaceutiquement acceptable de celui-ci, ou d'une composition pharmaceutique comprenant le composé 1 ou un sel pharmaceutiquement acceptable de celui-ci, le sujet présentant (a) une réduction de la fréquence de crise épileptique suite à un début de traitement.
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WO2025126159A1 (fr) * 2023-12-15 2025-06-19 Takeda Pharmaceutical Company Limited Procédé de traitement d'une maladie neurologique chez un utilisateur de drogue récréative

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