WO2024100531A1

WO2024100531A1 - Method of treating seizure disorders

Info

Publication number: WO2024100531A1
Application number: PCT/IB2023/061196
Authority: WO
Inventors: Mahnaz ASGHARNEJAD; Wei Yin; Naga Venkatesha Murthy Pathi Jagannatham
Original assignee: Takeda Pharmaceutical Co Ltd
Current assignee: Takeda Pharmaceutical Co Ltd
Priority date: 2022-11-07
Filing date: 2023-11-06
Publication date: 2024-05-16
Anticipated expiration: 2025-05-07

Abstract

The present invention provides a method of treating seizure disorders in a subject in need thereof comprising administering Compound 1, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising Compound 1 or a pharmaceutically acceptable salt thereof, wherein the subject experiences (a) a reduction in seizure frequency following treatment onset.

Description

METHOD OF TREATING SEIZURE DISORDERS

CROSS-REFERENCE TO RELATED APPLICATIONS

[0001] This International PCT Application claims priority to and the benefit of U.S. Provisional Application No. 63/423,358 filed on November 7, 2022, the contents of which are herein incorporated by reference in their entirety.

FIELD OF THE INVENTION

[0002] The present invention relates to compounds and methods of treating seizure disorders in a subject in need thereof.

BACKGROUND

[0003] The enzyme cholesterol 24-hydroxylase (CH24H), also known as cytochrome P450 46 Al (CYP461) is largely expressed in neurons where it catalyzes the hydroxylation of cholesterol to the oxysterol 24-hydroxycholesterol (24HC) in the endoplasmic reticulum. 24HC has rapid efflux from neurons into the extracellular space and moves through the blood brain barrier into systemic circulation for hepatic elimination. However, 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. 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.

[0004] 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. 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. [0005] 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. Accordingly, postmortem CH24H levels are significantly higher in glia cells from Alzheimer’s disease patient’s brains than from cognitive controls. Yet, 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. Moreover, 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.

[0006] In summary, decreasing CH24H activity by pharmacological intervention could have therapeutic value for patients with epilepsy and neurodegenerations. Compound 1 (as defined below) selectively binds to CH24H inhibiting enzyme activity. Thus, Compound 1 may have significant therapeutic potential for treating disorders caused by 24HC-mediated neuronal hyperactivity, such as DEE and other neurodegenerations.

SUMMARY OF THE INVENTION

[0007] 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.

[0008] 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

(a) 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.

[0009] In some implementations, 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. For example, the subject experiences a reduction in all seizure frequency of about 30% or more for at least 72 weeks during the treatment period. In other examples, the subject experiences a reduction in all seizure frequency of about 40% or more for at least 72 weeks during the treatment period. [0010] In some implementations, 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. For example, 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. And, in some 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.

[0011] In some implementations, 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. For example, the subject experiences a reduction in all seizure frequency of about 40% or more for at least 72 weeks during the treatment period. In other examples, the subject experiences a reduction in all seizure frequency of about 45% or more for at least 72 weeks during the treatment period. [0012] In some implementations, 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. For example, wherein the subject experiences a reduction in convulsive seizure frequency of about 30% or more for at least 72 weeks during the treatment period. In other examples, the subject experiences a reduction in convulsive seizure frequency of about 40% or more for at least 100 weeks during the treatment period.

[0013] In some implementations, 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. For example, the subject experiences a reduction in all seizure frequency of about 20% or more for at least 72 weeks during the treatment period. In other examples, the subject experiences a reduction in all seizure frequency of about 25% or more for at least 72 weeks during the treatment period. [0014] In some implementations, 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. For example, 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. In other examples, the subject experiences a reduction in convulsive seizure frequency of about 25% or more, wherein the reduction in seizure frequency lasts for at least 72 weeks during the treatment period.

[0015] 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

(a) the subject is diagnosed with CDD, DS, or LGS, and

(b) the subject experiences a reduction in all seizure frequency of about 10% or more beginning at least 23 weeks after treatment onset.

[0016] In some implementations, 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.

[0017] In some implementations, 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.

[0018] In some implementations, 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.

[0020] In some implementations, 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.

[0021] In some implementations, 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. And, in other examples, the subject experiences a reduction in convulsive seizure frequency of about 40% or more beginning at least 61 weeks after treatment onset. [0023] In some implementations, such as any of those described herein, the subject is from about 2 years to about 17 years of age. In some of these examples, the subject is administered Compound 1 or a dose equivalent of a pharmaceutically acceptable salt thereof at a weight-adjusted dosage amount. For example, 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 other examples, 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. For instance, 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. In some examples, 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. In other examples, 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.

[0024] In some implementations, such as any of those described herein, the subject is at least 18 years of age. In some of these examples, 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). For instance, 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 other examples, 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. And, in still other examples, 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. For instance, 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.

[0025] In some implementations, such as any of those described herein, the subject is administered (e.g., concomitantly administered) at least one additional therapeutic agent. In some of these examples, 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. For instance, 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, ethosuximide, or any combination thereof.

[0026] In some implementations, Compound 1 or a pharmaceutically acceptable salt thereof is administered orally or administered through a gastrostomy tube or percutaneous endoscopic gastrostomy tube. For example, Compound 1 or a pharmaceutically acceptable salt thereof is administered orally.

[0027] 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

(a) the subject is diagnosed with CDD, and

(b) the subject experiences a reduction in all seizure frequency of about 40% or more beginning at least 23 weeks after treatment onset.

[0028] In some implementations, the subject is from about 2 years to about 17 years of age. In other implementations, the subject is administered Compound 1 or a dose equivalent of a pharmaceutically acceptable salt thereof at a weight-adjusted dosage amount.

[0029] 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 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. In other implementations, 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. In some implementations, 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.

[0030] In some implementations, the subject is at least 18 years of age.

[0031] 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. In some implementations, 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.

[0032] In some implementations, 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. [0033] In some implementations, 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.

[0034] 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

(a) the subject is diagnosed with DS, and

(b) the subject experiences a reduction in all seizure frequency of about 20% or more beginning at least 23 weeks after treatment onset.

[0035] In some implementations, the subject is from about 2 years to about 17 years of age. In other implementations, the subject is administered Compound 1 or a dose equivalent of a pharmaceutically acceptable salt thereof at a weight-adjusted dosage amount.

[0036] 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 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. In other implementations, 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. In some implementations, 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.

[0037] In some implementations, the subject is at least 18 years of age.

[0038] 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. In some implementations, 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.

[0039] In some implementations, 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.

[0040] 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

(a) the subject is diagnosed with LGS, and

[0041] In some implementations, the subject is from about 2 years to about 17 years of age. In other implementations, the subject is administered Compound 1 or a dose equivalent of a pharmaceutically acceptable salt thereof at a weight-adjusted dosage amount.

[0042] 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 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. In other implementations, 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. In some implementations, 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.

[0043] In some implementations, the subject is at least 18 years of age.

[0044] 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. In some implementations, 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.

[0045] In some implementations, 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.

[0046] In some implementations, the subject is administered at least one additional therapeutic agent. In some implementations, 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. And, in some implementations, 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, ethosuximide, or any combination thereof.

BRIEF DESCRIPTION OF THE DRAWINGS

[0047] The figures below are provided by way of example and are not intended to limit the scope of the claimed invention.

[0048] Figure 1 is a flow-chart of the clinical study according to Example 3.

[0049] 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.

[0050] 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. [0051] 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. [0052] 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.

[0053] 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.

DETAILED DESCRIPTION

[0054] The present invention provides 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.

[0055] 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.

[0056] I. DEFINITIONS

[0057] As used herein, 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.

[0058] As used herein, the term "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.

[0059] As used herein, 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.

[0060] As used herein, 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.

[0061] As used herein "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.

[0062] As used herein, the term "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.

[0063] As used herein, the term "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.

[0064] As used herein, 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. In certain embodiments, the subject is a mammal. In other embodiments, the subject is a human.

[0065] As used herein, the terms "disease", "disorder", and "condition" are used interchangeably herein.

[0066] As used herein, and unless otherwise specified, the terms "treat," "treating" and "treatment" contemplate an action that occurs while a subject is suffering from the specified disease, disorder or condition, which reduces the severity of the disease, disorder or condition (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.

[0067] As used herein, and unless otherwise specified, a "therapeutically effective amount" of a compound is an amount sufficient to provide a therapeutic benefit in the treatment of a disease, disorder or condition, or to delay or minimize one or more symptoms associated with the disease, disorder or condition. A therapeutically effective amount of a compound means an amount of therapeutic agent, alone or in combination with other therapies, which provides a therapeutic benefit in the treatment of the disease, disorder or condition. The term "therapeutically effective amount" can encompass an amount that improves overall therapy, reduces or avoids symptoms or causes of disease or condition, or enhances the therapeutic efficacy of another therapeutic agent.

[0068] In an alternate embodiment, 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. As used herein, and unless otherwise specified, 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.

[0069] As used herein, the terms "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. For example, the day of treatment onset is the day in which a chemotherapy is first administered. For dosage regimes comprising the administration of two or more therapies, treatment onset is the day in which Compound 1 or a pharmaceutically acceptable salt thereof is first administered.

[0070] 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. [0071] As used herein, 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.

[0072] 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.

[0073] As used herein, the terms "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. 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.

[0074] As used herein, the terms "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.

[0075] As used herein, the term "dose equivalent" means a bioequivalent dose. For example, 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.

[0076] II. COMPOUND OF THE PRESENT INVENTION

[0077] The present invention provides a compound useful for treating seizures.

[0078] One aspect of the present invention provides Compound 1

(Compound 1).

[0079] Another aspect of the present invention provides a pharmaceutically acceptable salt of

Compound 1

(Compound 1).

[0080] In some embodiments, the pharmaceutically acceptable salt of Compound 1 is nontoxic, and may be inorganic or organic acid addition salts and base addition salts. Specifically, 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 ethanesulfonic acid, benzenesulfonic acid, 4-chlorobenzenesulfonic acid, 2-naphthalenesulfonic acid, 4- toluenesulfonic acid, camphorsulfonic acid, 4-methylbicyclo[2.2.2]-oct-2-ene-l -carboxylic acid, glucoheptonic acid, 3 -phenylpropionic acid, trimethylacetic acid, tertiary butylacetic acid, lauryl sulfuric acid, gluconic acid, glutamic acid, hydroxynaphthoic acid, salicylic acid, stearic acid, muconic acid, and the like; or (2) salts formed when an acidic proton present in the parent compound either is replaced by a metal ion, e.g., an alkali metal ion, an alkaline earth ion, or an aluminum ion; or coordinates with an organic base such as ethanolamine, diethanolamine, triethanolamine, N-methylglucamine and the like. 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.

[0081] III. PHARMACEUTICAL COMPOSITIONS/FORMULATIONS

[0082] The compounds described herein can be formulated into pharmaceutical compositions that further comprise a pharmaceutically acceptable carrier, diluent, adjuvant or vehicle. In one embodiment, the present invention provides a pharmaceutical composition comprising a compound of the invention described above, and a pharmaceutically acceptable carrier, diluent, adjuvant or vehicle. In one embodiment, 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. In some embodiments, 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.

[0083] According to another embodiment, 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.

[0084] It also will be appreciated that certain of the compounds of the present invention can exist in free form for treatment, or where appropriate, as a pharmaceutically acceptable derivative (e.g., a salt) thereof. According to the present invention, 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.

[0085] As used herein, 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. [0086] 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. Other pharmaceutically acceptable 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, pectinate, persulfate, 3 -phenylpropionate, phosphate, picrate, pivalate, propionate, stearate, succinate, sulfate, tartrate, thiocyanate, p-toluenesulfonate, undecanoate, valerate salts, and the like. 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.

[0087] 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.

[0088] The pharmaceutically acceptable carrier, adjuvant, or vehicle, as used herein, 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. Except insofar as 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. As used herein, the phrase "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.

[0089] 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 acetate; powdered tragacanth; malt; gelatin; talc; excipients such as cocoa butter and suppository waxes; oils such as peanut oil, cottonseed oil; safflower oil; sesame oil; olive oil; corn oil and soybean oil; glycols; such a propylene glycol or polyethylene glycol; esters such as ethyl oleate and ethyl laurate; agar; buffering agents such as magnesium hydroxide and aluminum hydroxide; alginic acid; pyrogen-free water; isotonic saline; Ringer's solution; ethyl alcohol, and phosphate buffer solutions, as well as other non-toxic compatible lubricants such as sodium lauryl sulfate and magnesium stearate, as well as coloring agents, releasing agents, coating agents, sweetening, flavoring and perfuming agents. Preservatives and antioxidants can also be present in the composition, according to the judgment of the formulator.

[0090] The compositions of the present invention may be administered orally, parenterally, by inhalation spray, topically, rectally, nasally, buccally, vaginally or via an implanted reservoir. As used herein, the term "parenteral" includes subcutaneous, intravenous, intramuscular, intra-articular, intra-synovial, intrasternal, intrathecal, intraocular, intrahepatic, intralesional and intracranial injection or infusion techniques. Preferably, the compositions are administered orally, intraperitoneally or intravenously. Sterile injectable forms of the compositions of this invention may be aqueous or oleaginous suspension. These suspensions may be formulated according to techniques known in the art using suitable dispersing or wetting agents and suspending agents. 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. Among the acceptable vehicles and solvents that may be employed are water, Ringer's solution and isotonic sodium chloride solution. In addition, sterile, fixed oils are conventionally employed as a solvent or suspending medium. [0091] For this purpose, any bland fixed oil may be employed including synthetic mono- or di-glycerides. Fatty acids, such as oleic acid and its glyceride derivatives, 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. 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.

[0092] The pharmaceutically acceptable 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. In the case of tablets for oral use, carriers commonly used include lactose and com starch. Lubricating agents, such as magnesium stearate, are also typically added. For oral administration in a capsule form, useful diluents include lactose and dried cornstarch. When 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.

[0093] Alternatively, the pharmaceutically acceptable compositions of this invention may be administered in the form of 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. Such materials 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.

[0094] The pharmaceutically acceptable 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.

[0095] 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.

[0096] For topical applications, 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. Alternatively, 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.

[0097] For ophthalmic use, 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. Alternatively, for ophthalmic uses, 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. Such 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.

[0098] Liquid dosage forms for oral administration include, but are not limited to, pharmaceutically acceptable emulsions, microemulsions, solutions, suspensions, syrups and elixirs. In addition to the active compounds, 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. Besides inert diluents, the oral compositions also can include adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, and perfuming agents.

[0099] 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. Among the acceptable vehicles and solvents that may be employed are water, Ringer's solution, U.S.P. and isotonic sodium chloride solution. In addition, sterile, fixed oils are conventionally employed as a solvent or suspending medium. For this purpose any bland fixed oil can be employed including synthetic mono- or diglycerides. In addition, fatty acids such as oleic acid may be used in the preparation of injectables.

[0100] 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.

[0101] 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. Depending upon the ratio of compound to polymer and the nature of the particular polymer employed, the rate of compound release can be controlled. Examples of other 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.

[0102] Solid dosage forms for oral administration include capsules, tablets, pills, powders, and granules. In such solid dosage forms, 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 glycerol mono stearate, h) absorbents such as kaolin and bentonite clay, and i) lubricants such as talc, calcium stearate, magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate, and mixtures thereof. In the case of capsules, tablets and pills, the dosage form also may comprise buffering agents.

[0103] 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.

[0104] 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. In such solid dosage forms 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. In the case of capsules, tablets and pills, 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. Examples of embedding compositions that can be used include polymeric substances and waxes.

[0105] 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. Additionally, 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.

[0106] The compounds of the invention preferably are formulated in dosage unit form for ease of administration and uniformity of dosage. As used herein, the phrase "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.

[0107] Compounds and/or compositions of the invention can be delivered in a controlled release system. In one embodiment, 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)). In another embodiment, 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. 25:351(1989); Howard et al., J. Neurosurg. 71 : 105 (1989); Remington's Pharmaceutical Sciences, 18th Ed., (Mack Publishing Company, Easton, Pa., 1990)). Other controlled-release systems discussed in the review by Langer (Science 249: 1527-1533 (1990)) can be used.

[0108] The amount of the compounds of the present invention that may be combined with the carrier materials to produce a composition in a single dosage form will vary depending upon the host treated, the particular mode of administration, and other factors. Preferably, the 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.

[0109] Depending upon the particular condition, or disease, to be treated or prevented, additional therapeutic agents, which are normally administered to treat or prevent that condition, also may be present in the compositions of this invention. As used herein, additional therapeutic agents that are normally administered to treat or prevent a particular disease, or condition, are known as "appropriate for the disease, or condition, being treated." [0110] In one aspect, 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.

[0111] IV. METHODS OF TREATING SEIZURE DISORDERS

[0112] In one aspect, 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

(a) 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 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).

[0113] 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.

[0114] In some implementations, 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. In some examples, the reduction in all seizure frequency lasts for at least about 52 weeks. [0115] In some implementations, 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), or at least about 108 weeks) during the treatment period. For example, the subject experiences a reduction in all seizure frequency of about 50% or more for at least about 72 weeks during the treatment period.

[0116] In some implementations, 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. For example, 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. And, in some 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.

[0117] In some implementations, 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. For example, the subject experiences a reduction in all seizure frequency of about 25% or more for at least about 72 weeks during the treatment period.

[0118] In some implementations, 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. For example, the subject experiences a reduction in convulsive seizure frequency of about 30% or more for at least 72 weeks during the treatment period. In other examples, the subject experiences a reduction in convulsive seizure frequency of about 40% or more for at least 100 weeks during the treatment period. [0119] In some implementations, 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. For example, the subject experiences a reduction in all seizure frequency of about 25% or more for at least about 72 weeks during the treatment period.

[0120] In some implementations, 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. For example, 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. In other examples, the subject experiences a reduction in convulsive seizure frequency of about 25% or more, wherein the reduction in seizure frequency lasts for at least 72 weeks during the treatment period.

[0121] In some implementations, such as any of those described herein, the subject is from about 2 years to about 17 years of age. In some of these examples, the subject is administered Compound 1 or a dose equivalent of a pharmaceutically acceptable salt thereof at a weight-adjusted dosage amount. For example, 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 other examples, 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. For instance, 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. In some examples, 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. In other examples, 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.

[0122] In some implementations, 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). In other implementations, 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. [0123] In some implementations, 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). In other implementations, 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.

[0124] In some implementations, 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). In other implementations, 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.

[0125] In some implementations, 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). In other implementations, 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.

[0126] In some implementations, 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). In other implementations, 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.

[0127] In some implementations, 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). In other implementations, 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.

[0128] In some implementations, 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). In other implementations, 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.

[0129] In some implementations, 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). In other implementations, 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.

[0130] In some implementations, 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). In other implementations, 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.

[0131] In some implementations, 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). In other implementations, 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.

[0132] In some implementations, 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). In other implementations, 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.

[0133] In some implementations, 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). In other implementations, 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.

[0134] In some implementations, 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). In other implementations, 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.

[0135] In some implementations, 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). In other implementations, 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. [0136] In some implementations, 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). In some implementations, 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.

[0137] In some implementations, 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). In other implementations, 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.

[0138] In some implementations, 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). In other implementations, 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.

[0139] In some implementations, 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). In other implementations, 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.

[0140] In some implementations, 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). In other implementations, 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.

[0141] In some implementations, 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). In other implementations, 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.

[0142] In some implementations, 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). In other implementations, 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.

[0143] In some implementations, 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). In other implementations, 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.

[0144] In some implementations, such as any of those described herein, the subject is at least 18 years of age. In some of these examples, 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). For instance, 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 other examples, 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. And, in still other examples, 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. For instance, 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.

[0145] In the implementations and examples above, the subject is administered (e.g., concomitantly administered) at least one additional therapeutic agent with Compound 1 or a pharmaceutically acceptable salt thereof. In some of these examples, 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. For instance, 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, ethosuximide, or any combination thereof.

[0146] In some implementations, Compound 1 or a pharmaceutically acceptable salt thereof is administered orally or administered through a gastrostomy tube or percutaneous endoscopic gastrostomy tube. For example, Compound 1 or a pharmaceutically acceptable salt thereof is administered orally.

[0147] 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

(a) the subject is diagnosed with CDD, DS, or LGS, and

[0148] In some implementations, the method further comprises administering Compound 1 or a pharmaceutically acceptable salt thereof for a treatment of period of at least about 12 weeks. In some implementations, the treatment period has a duration of at least about 24 weeks. In implementations, the treatment period has a duration of at least about 36 weeks. In implementations, the treatment period has a duration of at least about 48 weeks. In implementations, the treatment period has a duration of at least about 60 weeks. In implementations, the treatment period has a duration of at least about 72 weeks.

[0149] In some implementations, 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.

[0150] In some implementations, 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.

[0151] In some implementations, 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.

[0152] In some implementations, 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. For example, 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. In some examples, 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. And, in other examples, the subject experiences a reduction in convulsive seizure frequency of about 40% or more beginning at least 61 weeks after treatment onset. [0153] In some implementations, such as any of those described herein, the subject is from about 2 years to about 17 years of age. In some of these examples, the subject is administered Compound 1 or a dose equivalent of a pharmaceutically acceptable salt thereof at a weight-adjusted dosage amount. For example, 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 other examples, 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. For instance, 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. In some examples, 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. In other examples, 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.

[0154] In some implementations, 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). In other implementations, 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.

[0155] In some implementations, 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). In other implementations, 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.

[0156] In some implementations, 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). In other implementations, 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.

[0157] In some implementations, 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). In other implementations, 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.

[0158] In some implementations, 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). In other implementations, 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. [0159] In some implementations, 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). In other implementations, 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.

[0160] In some implementations, 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). In other implementations, 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.

[0161] In some implementations, 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). In other implementations, 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.

[0162] In some implementations, 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). In other implementations, 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.

[0163] In some implementations, 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). In other implementations, 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.

[0164] In some implementations, 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). In other implementations, 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.

[0165] In some implementations, 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). In other implementations, 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.

[0166] In some implementations, 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). In other implementations, 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.

[0167] In some implementations, 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). In other implementations, 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.

[0168] In some implementations, 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). In some implementations, 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.

[0169] In some implementations, 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). In other implementations, 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.

[0170] In some implementations, 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). In other implementations, 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.

[0171] In some implementations, 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). In other implementations, 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.

[0172] In some implementations, 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). In other implementations, 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.

[0173] In some implementations, 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). In other implementations, 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.

[0174] In some implementations, 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). In other implementations, 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.

[0175] In some implementations, 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). In other implementations, 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.

[0176] In some implementations, such as any of those described herein, the subject is at least 18 years of age. In some of these examples, 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). For instance, 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 other examples, 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. And, in still other examples, 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. For instance, 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.

[0177] In some implementations, such as any of those described herein, the subject is administered (e.g., concomitantly administered) at least one additional therapeutic agent. In some of these examples, 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. For instance, 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, ethosuximide, or any combination thereof.

[0178] In some implementations, Compound 1 or a pharmaceutically acceptable salt thereof is administered orally or administered through a gastrostomy tube or percutaneous endoscopic gastrostomy tube. For example, Compound 1 or a pharmaceutically acceptable salt thereof is administered orally.

[0179] In some implementations, the subject is a human. In other implementations, the human is an adult or child.

[0180] In some implementations, 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.

[0181] In some implementations, the subject is administered Compound 1 or a dose equivalent of a pharmaceutically acceptable salt thereof at a weight-adjusted dosage amount. [0182] 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 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. In other implementations, 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. In some implementations, 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.

[0183] In some implementations, 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). In other implementations, 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.

[0184] In some implementations, 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). In other implementations, 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.

[0185] In some implementations, 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). In other implementations, 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.

[0186] In some implementations, 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). In other implementations, 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.

[0187] In some implementations, 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). In other implementations, 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.

[0188] In some implementations, 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). In other implementations, 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.

[0189] In some implementations, 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). In other implementations, 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. [0190] In some implementations, 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). In other implementations, 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.

[0191] In some implementations, 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). In other implementations, 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.

[0192] In some implementations, 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). In other implementations, 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.

[0193] In some implementations, 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). In other implementations, 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.

[0194] In some implementations, 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). In other implementations, 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.

[0195] In some implementations, 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). In other implementations, 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.

[0196] In some implementations, 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). In other implementations, 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.

[0197] In some implementations, 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). In some implementations, 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.

[0198] In some implementations, 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). In other implementations, 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. [0199] In some implementations, 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). In other implementations, 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.

[0200] In some implementations, 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). In other implementations, 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.

[0201] In some implementations, 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). In other implementations, 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.

[0202] In some implementations, 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). In other implementations, 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.

[0203] In some implementations, 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). In other implementations, 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.

[0204] In some implementations, 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). In other implementations, 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.

[0205] In some implementations, 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.

[0206] 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. In some implementations, 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.

[0207] In the implementations and examples above, the subject is administered (e.g., concomitantly administered) at least one additional therapeutic agent with Compound 1 or a pharmaceutically acceptable salt thereof. In some of these examples, 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. For instance, 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, ethosuximide, or any combination thereof.

[0208] In some implementations, Compound 1 or a pharmaceutically acceptable salt thereof is administered orally or administered through a gastrostomy tube or percutaneous endoscopic gastrostomy tube. For example, Compound 1 or a pharmaceutically acceptable salt thereof is administered orally.

[0209] A. Subjects with CDD

[0210] In another aspect, 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

(a) the subject is diagnosed with CDD, and

[0211] In some implementations, 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.

[0212] In some implementations, the subject is from about 2 years to about 17 years of age. In other implementations, the subject is administered Compound 1 or a dose equivalent of a pharmaceutically acceptable salt thereof at a weight-adjusted dosage amount.

[0213] 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 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. In other implementations, 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. In some implementations, 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.

[0214] In some implementations, 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). In other implementations, 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.

[0215] In some implementations, 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). In other implementations, 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.

[0216] In some implementations, 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). In other implementations, 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.

[0217] In some implementations, 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). In other implementations, 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.

[0218] In some implementations, 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). In other implementations, 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.

[0219] In some implementations, 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). In other implementations, 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.

[0220] In some implementations, 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). In other implementations, 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.

[0221] In some implementations, 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). In other implementations, 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.

[0222] In some implementations, 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). In other implementations, 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.

[0223] In some implementations, 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). In other implementations, 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.

[0224] In some implementations, 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). In other implementations, 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. [0225] In some implementations, 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). In other implementations, 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.

[0226] In some implementations, 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). In other implementations, 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.

[0227] In some implementations, 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). In other implementations, 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.

[0228] In some implementations, 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). In some implementations, 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.

[0229] In some implementations, 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). In other implementations, 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.

[0230] In some implementations, 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). In other implementations, 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.

[0231] In some implementations, 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). In other implementations, 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.

[0232] In some implementations, 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). In other implementations, 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.

[0233] In some implementations, 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). In other implementations, 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.

[0234] In some implementations, 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). In other implementations, 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.

[0235] In some implementations, 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). In other implementations, 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.

[0236] In some implementations, 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. In some implementations, 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.

[0237] In some implementations, 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. In some implementations, 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.

[0238] In the implementations and examples above, the subject is administered (e.g., concomitantly administered) at least one additional therapeutic agent with Compound 1 or a pharmaceutically acceptable salt thereof. In some of these examples, 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. For instance, 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, ethosuximide, or any combination thereof.

[0239] In some implementations, Compound 1 or a pharmaceutically acceptable salt thereof is administered orally or administered through a gastrostomy tube or percutaneous endoscopic gastrostomy tube. For example, Compound 1 or a pharmaceutically acceptable salt thereof is administered orally.

[0240] B . Subj ects with D S

[0241] In another aspect, 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

(a) the subject is diagnosed with DS, and

(b) the subject experiences a reduction in all seizure frequency of about 20% or more beginning at least 23 weeks after treatment onset. [0242] In some implementations, 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.

[0243] In some implementations, the subject is from about 2 years to about 17 years of age. In other implementations, the subject is administered Compound 1 or a dose equivalent of a pharmaceutically acceptable salt thereof at a weight-adjusted dosage amount.

[0244] 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 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. In other implementations, 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. In some implementations, 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.

[0245] In some implementations, 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). In other implementations, 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. [0246] In some implementations, 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). In other implementations, 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.

[0247] In some implementations, 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). In other implementations, 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.

[0248] In some implementations, 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). In other implementations, 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.

[0249] In some implementations, 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). In other implementations, 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.

[0250] In some implementations, 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). In other implementations, 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.

[0251] In some implementations, 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). In other implementations, 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.

[0252] In some implementations, 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). In other implementations, 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.

[0253] In some implementations, 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). In other implementations, 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.

[0254] In some implementations, 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). In other implementations, 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.

[0255] In some implementations, 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). In other implementations, 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.

[0256] In some implementations, 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). In other implementations, 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.

[0257] In some implementations, 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). In other implementations, 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.

[0258] In some implementations, 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). In other implementations, 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. [0259] In some implementations, 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). In some implementations, 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.

[0260] In some implementations, 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). In other implementations, 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.

[0261] In some implementations, 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). In other implementations, 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.

[0262] In some implementations, 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). In other implementations, 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.

[0263] In some implementations, 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). In other implementations, 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.

[0264] In some implementations, 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). In other implementations, 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.

[0265] In some implementations, 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). In other implementations, 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.

[0266] In some implementations, 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). In other implementations, 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.

[0267] In some implementations, 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. In some implementations, 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.

[0268] In some implementations, 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.

[0269] In the implementations and examples above, the subject is administered (e.g., concomitantly administered) at least one additional therapeutic agent with Compound 1 or a pharmaceutically acceptable salt thereof. In some of these examples, 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. For instance, 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, ethosuximide, or any combination thereof.

[0270] In some implementations, Compound 1 or a pharmaceutically acceptable salt thereof is administered orally or administered through a gastrostomy tube or percutaneous endoscopic gastrostomy tube. For example, Compound 1 or a pharmaceutically acceptable salt thereof is administered orally.

[0271] C. Subjects with LGS

[0272] In another aspect, 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

(c) the subject is diagnosed with LGS, and

(d) the subject experiences a reduction in all seizure frequency of about 10% or more beginning at least 23 weeks after treatment onset.

[0273] In some implementations, 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.

[0274] In some implementations, the subject is from about 2 years to about 17 years of age. In other implementations, the subject is administered Compound 1 or a dose equivalent of a pharmaceutically acceptable salt thereof at a weight-adjusted dosage amount.

[0275] 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 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. In other implementations, 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. In some implementations, 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. [0276] In some implementations, 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). In other implementations, 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.

[0277] In some implementations, 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). In other implementations, 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.

[0278] In some implementations, 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). In other implementations, 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.

[0279] In some implementations, 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). In other implementations, 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.

[0280] In some implementations, 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). In other implementations, 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.

[0281] In some implementations, 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). In other implementations, 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.

[0282] In some implementations, 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). In other implementations, 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.

[0283] In some implementations, 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). In other implementations, 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.

[0284] In some implementations, 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). In other implementations, 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.

[0285] In some implementations, 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). In other implementations, 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.

[0286] In some implementations, 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). In other implementations, 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.

[0287] In some implementations, 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). In other implementations, 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.

[0288] In some implementations, 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). In other implementations, 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. [0289] In some implementations, 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). In other implementations, 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.

[0290] In some implementations, 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). In some implementations, 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.

[0291] In some implementations, 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). In other implementations, 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.

[0292] In some implementations, 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). In other implementations, 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.

[0293] In some implementations, 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). In other implementations, 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.

[0294] In some implementations, 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). In other implementations, 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.

[0295] In some implementations, 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). In other implementations, 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.

[0296] In some implementations, 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). In other implementations, 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.

[0297] In some implementations, 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). In other implementations, 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.

[0298] In some implementations, 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. In some implementations, 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.

[0299] In some implementations, 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.

[0300] In the implementations and examples above, the subject is administered (e.g., concomitantly administered) at least one additional therapeutic agent with Compound 1 or a pharmaceutically acceptable salt thereof. In some of these examples, 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. For instance, 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, ethosuximide, or any combination thereof.

[0301] In some implementations, Compound 1 or a pharmaceutically acceptable salt thereof is administered orally or administered through a gastrostomy tube or percutaneous endoscopic gastrostomy tube. For example, Compound 1 or a pharmaceutically acceptable salt thereof is administered orally.

[0302] V. EXAMPLES [0303] In order that the invention described herein may be more fully understood, the following examples are set forth. The synthetic and biological examples described in this application are offered to illustrate the compounds, pharmaceutical compositions, and methods provided herein and are not to be construed in any way as limiting their scope. In some of the tables and figures presented or referenced below, Compound 1 is referred to as "Cmpd 1."

[0304] Example 1: Compound 1 Formulation (Film Coated Tablet)

[0305] Compound 1 was formulated into a film coated tablet according to Table 1, below.

[0306] Table 1: Film Coated Tablet.

¹ These ingredients are components of OPADRY® Red 03F45081 and OPADRY® Yellow 03F42240 (premixed coating materials). [0307] Example 2: Antecedent Studies.

[0308] Patients from the following three (3) studies formed the potential patient population for the clinical study described in Example 3 below.

[0309] 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”).

[0310] Purpose -. The purpose of this study was to characterize the multiple-dose safety and tolerability profile of Compound 1 in adult participants with developmental and/or epileptic encephalopathies.

[0311] 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. All participants who completed the Double-Blind Treatment Period in Part 1 had the option to continue directly into the Open-Label Treatment Period in Part 2 where they received Compound 1 as two 100 mg tablets (total dose was 200 mg Compound 1) orally or through G-tube/PEG tube, BID and dose was increased to three 100 mg tablets (total dose was 300 mg Compound 1), orally, BID (Day 41). This dose level was maintained until the final visit (Day 85) for the dose de-escalation phase.

[0312] Primary Outcome -. Percentage of participants with at least one treatment-emergent adverse event (TEAE), as reported by the participants or participant's caregivers or observed by the investigator, after Compound 1 treatment.

[0313] Secondary Outcomes

[0314] Drug clearance (CL) and intercompartmental clearance (Q) for Compound 1 calculated using the observed value of the last quantifiable concentration.

[0315] Apparent volume of distribution (Vz/F) of central compartment (Vc) and peripheral compartment (Vp) for Compound 1 calculated using the observed value of the last quantifiable concentration.

[0316] Absorption rate constant (Ka) for Compound 1.

[0317] Cmax,ss: Maximum observed plasma concentration for Compound 1 at steady state. [0318] AUC0-tau,ss: Area under the plasma concentration-time curve over the dosing interval for Compound 1 at steady state.

[0319] Ctrough,ss: Plasma concentration immediately prior to dosing for Compound 1 at steady state.

[0320] Percentage of participants with at least 1 markedly abnormal value for clinical laboratory evaluations after Compound 1.

[0321] Percentage of participants with at least 1 markedly abnormal value for vital signs after Compound 1.

[0322] Percentage of participants with at least 1 markedly abnormal value for electrocardiogram (ECG) parameters after Compound 1.

[0323] Inclusion Criteria

[0324] 18 years to 65 years old.

[0325] Has a documented clinical diagnosis of developmental and/or epileptic encephalopathies with countable bilateral motor seizures, defined as an average of greater than or equal to (>=) 2 per month during the past 3 months, based on the investigator's assessment, and a monthly average of >=1 per month during the Baseline Period, based on the seizure diary record.

[0326] Has been taking 1 to 4 antiepileptic drug (AEDs) at a stable dose for >=4 weeks before Screening and the participant or participant's legally acceptable representative is willing to keep the regimen(s) stable throughout the study.

[0327] Has an average of >=1 bilateral motor seizure per month during the 4-week Baseline Period (i.e., drop seizures, tonic-clonic, tonic, bilateral clonic, atonic, myoclonic-atonic, myoclonic-tonic-clonic, focal seizures with bilateral hyperkinetic motor features).

[0328] Must agree to not post any participant's personal medical data related to the study or information related to the study on any web site or social media site until the study has been completed.

[0329] For participants with G-tube/PEG tube, 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.

[0330] Exclusion Criteria

[0331] Has received Compound 1 in a previous clinical study or as a therapeutic agent. [0332] Was admitted to a medical facility for treatment of status epilepticus requiring mechanical respiration within 3 months before Screening. [0333] Had a vagal nerve stimulator implanted within 6 months before Screening and settings have been changed within 1 month of the Screening Visit and/or anticipated to change during the study.

[0334] Is on 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.

[0335] Has degenerative eye disease.

[0336] Has a history of suicidal behavior or any suicidal ideation of type 4 or 5 on the Columbia-Suicide Severity Rating Scale (C-SSRS) at Screening. If the participant is unable to comply with the C-SSRS due to developmental status, a parent proxy may be used for the completion of the C-SSRS. The Investigator may also use clinical judgment, which must then be documented in the source document.

[0337] Positive for human immunodeficiency virus, hepatitis B, or hepatitis C infections. (Note that 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. Also note that 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]).

[0338] Has an abnormal and clinically significant ECG at Screening in the opinion of the investigator, for example, second or third degree heart block or a corrected QT interval (QTc) greater than (>) 450 millisecond (msec). Entry of any participant with an abnormal but not clinically significant ECG must be approved and documented by signature by the principal investigator or appropriately qualified delegate.

[0339] Has abnormal clinical laboratory test results at Screening that suggest a clinically significant underlying disease. If the participant has alanine aminotransferase (ALT) and/or aspartate aminotransferase (AST) >2.5*the upper limit of normal (ULN), the Medical Monitor should be consulted.

[0340] Has received any excluded medications, procedures, or treatments during the time periods.

[0341] Has any a history of alcohol, opioid, or other drug use disorder, as per the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition, within the previous 2 years before Screening. Medical marijuana use is allowed.

[0342] Has unstable, clinically significant neurologic (other than the disease being studied), psychiatric, cardiovascular, pulmonary, hepatic, renal, metabolic, gastrointestinal, urologic, immunologic, hematopoietic, or endocrine disease or other abnormality, which may impact the ability of the participant to participate or potentially confound the study results.

[0343] 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”).

[0344] Purpose '. The purpose of this study was to investigate the effect on the frequency of all seizures (convulsive and drop) in participants treated with Compound 1 compared to placebo.

[0345] 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. 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. In the Compound 1 groups, participants were given Compound 1 tablets orally or via G-tube/PEG tube, BID.

Participants weighing <60 kg received total daily dose of Compound 1 calculated based on body weight. 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 will consisted of 2 periods: Screening Period and Treatment Period. The overall duration of Treatment Period was up to 20 weeks including an 8-week Dose Optimization Period and a 12-week Maintenance Period.

[0346] Primary Outcome'. Percent change from baseline in seizure frequency per 28 days during the maintenance period.

[0347] Secondary Outcomes'.

[0348] Percent change from baseline in seizure frequency per 28 days during the treatment period.

[0349] Percent change from baseline in convulsive seizure frequency per 28 days in participants with dravet syndrome stratum during the maintenance period.

[0350] Percent change from baseline in drop seizure frequency per 28 days in participants with the Lennox-Gastaut syndrome (LGS) stratum during the maintenance period.

[0351] Percentage of participants with LGS stratum considered treatment responders throughout the maintenance period. [0352] Percentage of participants with dravet syndrome (DS) stratum considered treatment responders throughout the maintenance period.

[0353] Change from baseline in clinician's clinical global impression of severity (CGI-S) responses of investigator reported impression of efficacy and tolerability of study drug. [0354] Percentage of participants with clinical global impression of change (CGI-C) responses as per the investigator reported impression of efficacy and tolerability Compound 1

[0355] Percentage of participants with caregiver global impression of change (Care GI-C) responses as per the parent/family reported impression of efficacy and tolerability of Compound 1.

[0356] Change from baseline in plasma 24S-hydroxycholesterol (24HC) levels in participants treated with Compound 1 as an adjunctive therapy.

[0357] Change from baseline in seizure frequency in participants treated with Compound 1 as an adjunctive therapy.

[0358] Inclusion Criteria

[0359] Male and female participants aged greater than or equal to (>=) 2 and less than or equal to (<=) 17 years.

[0360] Clinical diagnosis of DS or LGS.

[0361] Weight of >=10 kilogram (kg) at the Screening visit.

[0362] Currently taking 1 to 4 anti-epileptic drugs (AEDs) at a stable dose.

[0363] Failed to become and remain seizure free with trials of at least 2 AEDs.

[0364] Exclusion Criteria

[0365] Has been admitted to a medical facility and intubated for treatment of status epilepticus 2 or more times in the 3 months immediately prior to the screening visit. [0366] Non-epileptic events that cannot be reliably distinguished from epileptic seizures. [0367] Participation in a clinical study involving another study drug in the previous month.

[0368] 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”).

[0369] Purpose '. The purpose of this study was to investigate the effect of Compound 1 on the frequency of motor seizures for participants with Dupl5q or CDD during the Maintenance Period. [0370] Study Design '. Study participants (20) were assigned to one of two groups based on their diagnosis: 15Q duplication syndrome (Dupl5q) or CDD. Participants in each group took Compound 1 twice per day with or without food. Participants in the Dupl5q and CDD groups received Compound 1 tablets twice daily (BID) orally or via gastrostomy tube (G- tube)/ percutaneous endoscopic gastrostomy (PEG) tube. Participants weighing <60 kg at Baseline received total daily dose of study drug calculated based on body weight.

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.

[0371] Primary Outcome'. Percent change from baseline in motor seizure frequency per 28 days during the maintenance period.

[0372] Secondary Outcomes'.

[0373] Percent change from baseline in motor seizure frequency per 28 days during the treatment period.

[0374] Percentage of participants considered as treatment responders during the maintenance period.

[0375] Percent change from baseline in frequency of motor seizures longer than 5 minutes in participants with CDD.

[0376] Proportion of motor seizure-free days in participants during the maintenance period. [0377] Change from baseline in clinician's global impression of severity (CGI-S) responses of investigator.

[0378] Percentage of participants with clinical global impression of change (CGI-C) responses as per the investigator reported impression.

[0379] Percentage of participants with care clinical global impression of change (CGI-C) responses of parent/family.

[0380] Change from baseline of plasma 24S-hydroxycholesterol (24HC) levels.

[0381] Change from baseline in seizure frequency in participants treated with Compound 1 as an adjunctive therapy.

[0382] Inclusion Criteria

[0383] 2 years old to 55 years old.

[0384] Clinical diagnosis of Dupl5q or CDKL5 deficiency disorder. [0385] Currently taking 1 to 6 antiepileptic drugs (AEDs) at a stable dose.

[0386] Exclusion Criteria

[0387] Two or more episodes of convulsive status epilepticus per 3 months requiring hospitalization and intubation.

[0388] Currently receiving a study drug or participated in a clinical study involving another investigational product in the previous month.

[0389] 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.

[0390] Referring to Figure 1, 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.

[0391] Primary Objective '. To assess the long-term safety and tolerability of Compound 1 when administered for 2 years as adjunctive therapy in patients with rare epilepsies.

[0392] Secondary Objectives'.

[0393] To evaluate the effect of Compound 1 on seizure frequency over 2 years

[0394] Other Objectives:

[0395] To assess the quality of life of patients receiving Compound 1 as an adjunctive therapy.

[0396] To assess the sleep disruption of patients receiving Compound 1 as an adjunctive therapy.

[0397] Study Endpoints

[0398] Primary Endpoints - Safety:

[0399] Incidence of adverse events (AEs)

[0400] Change from Baseline in behavioral and adaptive functional measures using the Vineland Adaptive Behavior Scale.

[0401] Change from Baseline in behavior measures using total scores and subscale scores of the Aberrant Behavior Checklist-Community Edition for patients >6 years of age.

[0402] Change from Baseline in the Columbia- Suicide Severity Rating Scale categorization based on Columbia Classification Algorithm of Suicide Assessment categories 1, 2, 3, 4, and 7 for patients >6 years of age. [0403] Absolute values and change from Baseline in clinical laboratory assessments, vital sign measurements, body weight, and electrocardiogram (ECG) parameters.

[0404] Incidence of potentially clinically significant clinical safety laboratory test values, vital signs, weight, height/length, and ECG evaluations.

[0405] Secondary Endpoints - Efficacy:

[0406] Change from Baseline in all seizure frequency over 28-days at Weeks 12, 24, 36, 48, 64, 80, 104, and 108.

[0407] Change from Baseline in mean drop seizure frequency over 28-days at Weeks 12, 24, 36, 48, 64, 80, 104, and 108.

[0408] Change from Baseline in mean convulsive seizure frequency over 28-days at Weeks 12, 24, 36, 48, 64, 80, 104, and 108.

[0409] Change from Baseline in mean motor seizure frequency over 28-days at Weeks 12, 24, 36, 48, 64, 80, 104, and 108.

[0410] Exploratory Endpoints - Safety:

[0411] Change from Baseline in overall Quality of Life Childhood Epilepsy score (pediatric patients).

[0412] Change from Baseline in the Sleep Disruption Numerical Rating Scale.

[0413] Study Population'. Pediatric (i.e., < 18 years old) and adult patients (i.e., > 18 years old) with epilepsy who participated in a previous study of Compound 1 (i.e., a study of Examples 2A, 2B, or 2C).

[0414] Inclusion Criteria'.

[0415] Patients must have participated in a previous Compound 1 study and meet one of the following conditions:

• Successfully completed a Compound 1 clinical study.

• Received at least 10 weeks of treatment (combined dose optimization and maintenance period) with the study drug in an antecedent placebo-controlled blinded Compound 1 clinical study and the patient did not have a serious or severe AE that, in the investigator’s or Sponsor’s opinion, was related to the study drug and would make it unsafe for the patient to continue receiving the study drug.

[0416] In the opinion of the investigator, the patient has the potential to benefit from the administration of Compound 1.

[0417] 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. [0418] The patient and patient’s legal representative (i.e., parent or legal guardian) (as applicable) are willing to comply with all study requirements.

[0419] Sexually active female patients of childbearing potential (defined as first menarche) must agree to use a highly effective method of birth control during the study and for 30 days after the last dose of study drug. Highly effective contraceptive methods are as follows: a. Combined (estrogen and progestogen containing) hormonal contraception associated with inhibition of ovulation: oral, intravaginal, transdermal b. Progestogen-only hormonal contraception associated with inhibition of ovulation: oral, injectable, implantable c. Intrauterine device d. Intrauterine hormone-releasing system e. Bilateral tubal occlusion f. Vasectomized partner g. Sexual abstinence

[0420] Sexually active male patients (post-pubertal unless permanently sterilized by bilateral orchi-dectomy) must agree to use male contraception (condom) during the study and for a mini-mum of 90 days following the last dose of study drug. Male patients must also not donate sperm during the Screening and Treatment Periods and for at least 90 days after the last dose of study drug.

[0421] Exclusion Criteria.

[0422] Clinically significant disease that, in the investigator’s opinion, precludes study participation.

[0423] Enrollment in any other clinical trial involving an investigational drug, device, or treatment in the past 90 days (with the exception of an antecedent study involving Compound 1).

[0424] 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.

[0425] Suicide attempt within the last year, at significant risk of suicide (either in the opinion of the investigator or defined as ‘yes’ to suicidal ideation question 4 or 5 on the C-SSRS at Screening) or appearing suicidal per investigator judgment.

[0426] Treatment

[0427] All patients received Compound 1 BID orally or via G-tube/PEG tube with or without food. No patient received placebo treatment in this study. The maximum dose available for this study was 600 mg/day (300 mg BID). [0428] Tablets/mini -tablets may have been crushed and mixed well in applesauce or thick liquid, for taste masking, prior to dosing. The amount of applesauce or liquid needed is dependent upon the number of tablets/mini -tablets the patient is taking. One-half teaspoon or 2.5 mL of applesauce or thick liquid is needed for each mini-tablet taken and 2 teaspoons or 10 rnL, respectively, is needed for each tablet taken.

[0429] For patients receiving Compound 1 via G-tube/PEG tube, tablets/mini-tablets were crushed, suspended in water, and the suspension was administered via the G-tube/PEG tube using a syringe.

[0430] If a patient missed a dose, the missed dose was skipped, and the patient continued with his/her normal dosing schedule. Skipped missed doses were reported as missed doses.

[0431] Patients from several antecedent studies were rolled over into this study (i.e., the antecedent studies of Examples 2 A, 2B, and 2C). Patients were eligible for screening within 15 days of completing the last visit of the antecedent Compound 1 study (except for adult patients enrolled in the Example 2A study, who were eligible for screening in this study up to 15 months after completion of the antecedent study). A patient who completed the antecedent study between 15 and 30 days before the Screening Visit of this study could be entered in this study with the approval of the Sponsor after considering the patient’s overall compliance in the antecedent study and after the patient met all inclusion and no exclusion criteria for this study.

[0432] 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.

[0433] 1. Patients Who Complete Antecedent Studies > 15 Days Before

Screening in This Study.

[0434] Patients who complete an antecedent study > 15 days before screening in this study were managed as follows:

• 4-week Screening/Baseline Period

• 2-week Dose Optimization Period (Table 2)

• 103 -week Maintenance Period

• 4-week Safety Follow-up Period of Compound 1 dose tapering (up to 2 weeks) and safety follow-up (Week 108). [0435] At the Screening Visit (Visit 1), informed consent and/or assent (if applicable) was obtained from the patients and/or patients’ legally acceptable representative. Patients underwent screening procedures to assess study eligibility in accordance with the study entry criteria. Identical clinical laboratory assessments for patients who completed the last visit of their antecedent protocol < 30 days before the Screening Visit in this study did not need to be repeated. At this Screening Visit and at subsequent visits, patients and/or patients’ caregivers were provided with a seizure diary and were instructed to record seizure data on a daily basis. 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).

[0436] 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.

[0437] Adult patients who could not tolerate at least 100 mg BID dosing were withdrawn from the study. Pediatric patients who could not tolerate Dose 1 were withdrawn from the study.

[0438] 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.

[0439] 2. Patients Who Complete Double-blind Antecedent Studies < 15 Days

Before Screening in This Study.

[0440] Patients who completed a double-blind antecedent study < 15 days before screening in this study were managed as follows:

• 1-week Dose Optimization Period (Table 3)

• 103 -week Maintenance Period

• 4-week Safety Follow-up Period of Compound 1 dose tapering (up to 2 weeks) and safety follow-up (Week 108)

[0441] Patients who completed the antecedent study < 15 days before the Screening Visit of this study did not undergo the 4-week Baseline Period. These patients may have completed Visit 1 (Screening) and Visit 2 on the same day. At Visit 1, informed consent and/or assent (if applicable) was obtained from the patients and/or patients’ legally acceptable representative. Patients then underwent screening procedures to assess study eligibility in accordance with the study entry criteria. Identical clinical laboratory assessments for patients who complete the last visit of their antecedent protocol < 30 days before the Screening Visit in this study did not need to be repeated. Patients and/or patients’ caregivers were provided with a seizure diary and were instructed to record seizure data on a daily basis. For patients in this group, the seizure diary data collected during the 4-week prospective Baseline Period of the antecedent study was used as the baseline seizure data for endpoint analysis in this study. The seizure diary recording can began as soon as the informed consent was obtained.

[0442] 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.

[0443] Adult patients who could not tolerate at least 100 mg BID dosing were withdrawn from the study. Pediatric patients who could not tolerate Dose 1 were withdrawn from the study.

[0444] Table 3: Dosing Schedule by Weight for Patients Who Complete the Double-blind Antecedent Study < 15 Days Before the Screening Visit of This Study.

[0445] 3. Patients Who Complete Double-blind Antecedent Studies < 15 Days

Before Screening in This Study.

[0446] Patients who complete the open-label antecedent study < 15 days before screening in this study were managed as follows:

• 103 -week Maintenance Period • 4-week Safety Follow-up Period of Compound 1 dose tapering (up to 2 weeks) and safety follow-up (Week 108)

[0447] Patients who completed the open-label antecedent study < 15 days before the Screening Visit of this study did not undergo the 4-week Baseline Period or the 2-week Dose Optimization Period. These patients may have completed Visit 1 (Screening) and Visit 2 (Day 1) on the same day. At Visit 1, informed consent and/or assent (if applicable) was obtained from the patients and/or patients’ legally acceptable representative. Patients will then underwent screening procedures to assess study eligibility in accordance with the study entry criteria. Identical clinical laboratory assessments for patients who completed the last visit of their antecedent protocol < 30 days before the Screening Visit in this study did not need to be repeated. Patients and/or patients’ caregivers were provided with a seizure diary and were be instructed to record seizure data on a daily basis. For patients in this group, the seizure diary data collected during the 4-week prospective Baseline Period of the antecedent study was used as the baseline seizure data for endpoint analysis in this study. The seizure diary recording can begin as soon as informed consent was obtained.

[0448] Dosing and Titration Schedule: Pediatric and adult patients whose antecedent study was an open-label study were started on the same Compound 1 dose that they had maintained at the end of the antecedent study. Dosing may have been adjusted at the Investigator’s discretion throughout the study; however, frequent adjustments were discouraged.

[0449] Dose Tapering

[0450] During the tapering period of not more than 14 days following the Week 104 visit, the Compound 1 dose was decreased to the next lower level no more frequently than every 3 days based on the Investigator’s discretion until Compound 1 was discontinued. After tapering, patients completed a safety Follow-up visit (Visit 11) approximately 15 days after the last dose of study drug and exit the study.

[0451] Patient Demographics

[0452] Patient demographics in this study that completed the antecedent study of Example 2B are set forth in Table 3.

[0453] Table 3: Demographic Characteristics for Patients that Completed the Antecedent Study of Example 2B.

[0454] Patient demographics in this study that completed the antecedent study of Example 2C are set forth in Table 4.

[0455] Table 4: Demographic Characteristics for Patients that Completed the

Antecedent Study of Example 2C.

[0456] Study Procedures

[0457] Physical Examination Procedure: 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.

[0458] 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.

[0459] 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).

[0460] 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.

[0461] 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):

(2) (# of seizures) / (# of days seizures were assessed) x 28

[0462] Documentation of Study Drug: 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.

[0463] Documentation of Concomitant Medications: 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.

[0464] Documentation of Concurrent Medical Conditions: 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.

[0465] Procedures for Clinical Laboratory Samples: Blood samples were collected at the time points stipulated in the Schedule of Assessments (i.e., Table 5). Samples were collected in accordance with acceptable laboratory procedures.

[0466] Table 5: Schedule of Assessments.

Abbreviations: 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. ^a 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. Identical clinical laboratory assessments taken at the patient’s last visit of the antecedent study did not need to be repeated at Visit 1 of this study if these 2 visits were < 30 days apart. Baseline evaluations were done for patients who completed the antecedent study > 30 days before Screening in this study. The last visit in the antecedent study can be combined with the first visit in this study. ^b Medical history data from antecedent studies was carried over and recorded in this study if these data were available; otherwise, new medical history data was collected at the Screening Visit of this study. For patients with ongoing AEs in the antecedent study, their ongoing AEs were recorded as medical history in this study. ^c Concomitant medication data from antecedent studies were carried over and recorded in the in this study if these data were available; otherwise, new concomitant medication data was collected at the Screening Visit of this study. ^d Eye examination (including fimdoscopy and visual acuity) was part of the neurological examination. ^e Hematology and serum chemistry assessments were optional at Weeks 24 (Day 169), 48 (Day 337), and 80 (Day 561). ^f One PK blood sample was collected at Week 1 (Day 1), Week 48 (Day 337), and Week 104 (Day 729). The blood sample collection was performed at any time during the visit and could be either before or after dosing. ^g ECGs were conducted and analyzed locally according to the site’s standard operating procedures. If patients received the Compound 1 dose in the clinic, the ECG was performed approximately 30 min (±10 min) after dosing.

[0467] 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.

[0468] All sexually active female patients of childbearing potential were required to return a negative urine or serum human chorionic gonadotropin pregnancy test at Screening (Visit 1) before receiving any dose of study drug. An additional serum pregnancy test was performed at the patient’s last clinic visit. During the course of the study, male patients received continued guidance with respect to the avoidance of pregnancy and ova or sperm donation as part of the study procedures.

[0469] Sexually active male patients (post-pubertal unless permanently sterilized by bilateral orchidectomy) agreed to use male contraception (condom) during the study and for a minimum of 90 days following the last dose of study drug. Male patients also agreed not to donate sperm during the Screening and Treatment Periods and for at least 90 days after the last dose of study drug.

[0470] 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.

[0471] Clinical Assessment of Suicidal Ideation and Behavior: 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). Posner K, Brown GK, Stanley B, Brent DA, Yershova KV, Oquendo MA, et al. 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.

[0472] Two versions of the C-SSRS were used in this study, the Screening/Baseline C-SSRS Lifetime and the Since-Last- Visit C-SSRS.

[0473] Study staff trained in the administration of the C-SSRS assessed patient suicidality using the C-SSRS, eliciting answers from the patient or the patient’s legal representative. Ultimately, the determination of the presence of suicidal ideation or behavior depends on the clinical judgment of the Investigator. If a patient exhibited signs of suicidal ideation, the patient may have been discontinued.

[0474] Aberrant Behavior Checklist: Behavior was assessed with the ABC-C questionnaire, which is a rating scale that measures the severity of a range of problem behaviors commonly observed in individuals with intellectual and developmental disabilities. Aman MG, Singh NN, Stewart AW, et al. Psychometric characteristics of the Aberrant Behavior Checklist. Am J Ment Defic. 1985;89(5):492-502. It was completed by the caregiver. It is an empirically developed scale designed to measure psychiatric symptoms and behavioral disturbance exhibited by individuals across 5 domains with 58 items: irritability, agitation, and crying (15 items); lethargy, social withdrawal (16 items); stereotypy (7 items); hyperactivity/noncompliance (16 items); and inappropriate speech (4 items). If the patient is unable to comply with the ABC-C 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 behavior.

[0475] Vineland Adaptive Behavior Scale: 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, de Bildt 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.

[0476] 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.

[0477] Sleep Disruption Numerical Rating Scale: The patient’s caregiver was asked: “On a scale of ‘0 to 10’, please circle the number that best describes your child’s sleep disruption in the last week.” The markers ranged from 0 (slept extremely well) to 10 (unable to sleep at all). If the main caregiver was not available at the appropriate visit then this information was captured over the telephone, ideally on the day of the visit or otherwise within 3 days.

[0478] Safety Evaluations

[0479] An adverse event (AE) 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.

[0480] Situations where an untoward medical occurrence did not occur (social and/or convenience admission to a hospital) and anticipated day-to-day fluctuations of pre-existing disease(s) or condition(s) present or detected at the start of the study that do not worsen are not AEs.

[0481] 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.

[0482] After informed consent was obtained, site personnel recorded any change in the condition(s) and the occurrence and nature of any AEs. If a patient experienced an AE after signing informed consent, but prior to receiving study drug, the event was reported, but was included in the patient’s medical history unless the event was serious, or the investigator determined that the event may have been caused by a protocol procedure.

[0483] For patients with ongoing AEs in the antecedent study, their ongoing AE was recorded as medical history in this study.

[0484] Severity Assessment: Investigators rated the severity of AEs using the following criteria:

Mild Events require minimal or no treatment and do not interfere with the patient’s daily activities.

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.

[0485] Change in severity of an AE was documented. Severity and seriousness were differentiated: severity describes the intensity of an AE, while the term seriousness refers to an AE that has met the criteria for an SAE.

[0486] Causality Assessment: Investigators reported their assessment of the potential relatedness of each AE to protocol procedure and/or Compound 1.

[0487] An Investigator causality assessment was provided and recorded for all AEs (both serious and non-serious). [0488] Relationship of AEs to the defined study treatment (Compound 1 [after the start of Compound 1 on Day 1]), were determined by the Investigator according to the following criteria:

[0489] Not Related - Exposure to the defined study treatment did not occur, or the occurrence of the AE is not reasonably related in time

[0490] Unlikely Related - The AE occurred in a reasonable time after the defined study treatment and is doubtfully related to the investigational agent/procedure

[0491] Possibly Related - The defined study treatment and the AE were reasonably related in time, and the AE could be explained equally well by causes other than exposure to the defined study treatment

[0492] Related - The defined study treatment and the AE were reasonably related in time, and the AE was more likely explained by exposure to the defined study treatment than by other causes, or the defined study treatment was the most likely cause of the AE

[0493] Serious Adverse Events: An SAE is any AE from this study that resulted in one (1) or more of the following outcomes:

• Results in death

• Requires or prolongs hospitalization

• Is life threatening (that is, immediate risk of dying)

• Persistent or significant disability/incapacity

• Congenital anomaly or birth defect

• Other medically important serious event

[0494] Statistical Analysis

[0495] For efficacy analyses, "Baseline", as used in this Example, 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.

[0496] 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.

[0497] 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.

[0498] Efficacy Analysis:

[0499] 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. [0500] 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. [0501] 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.

[0502] Motor seizures includes drop seizures, tonic-clonic, tonic, bilateral clonic, atonic, myoclonic-atonic, myoclonic-tonic-clonic, focal seizures with bilateral hyperkinetic motor features.

[0503] Results

[0504] The median % change from baseline in all seizure frequency for the Modified Intent- to-Treat analysis set of patients with DS or LGS and that completed the antecedent study of Example 2B is set forth below in Table 6.

[0505] Table 6: Median % Change From Baseline in All Seizure Frequency Per 28 Days in Subjects with DS or LGS.

[0506] The results show that the reduction from baseline for patients with DS or LGS that completed the antecedent study of Example 2B and completed this study was 47.2%.

[0507] The median % change from baseline in all seizure frequency for the Modified Intent- to-Treat analysis set of patients with DS and that completed the antecedent study of Example 2B is set forth below in Table 7.

[0508] Table 7: Median % Change From Baseline in All Seizure Frequency Per 28 Days in Subjects with DS.

[0509] The results show that the reduction from baseline for patients with DS that completed the antecedent study of Example 2B and completed this study was 53.4%.

[0510] The median % change from baseline in all seizure frequency for the Modified Intent- to-Treat analysis set of patients with LGS and that completed the antecedent study of Example 2B is set forth below in Table 8. [0511] Table 8: Median % Change From Baseline in All Seizure Frequency Per 28 Days in Subjects with LGS.

[0512] The results show that the reduction from baseline for patients with LGS that completed the antecedent study of Example 2B and completed this study was 27.7%.

[0513] The median % change from baseline in all seizure frequency for the Safety analysis set of patients with CDD and that completed the antecedent study of Example 2C is set forth below in Table 9.

[0514] Table 9: Median % Change From Baseline in All Seizure Frequency Per 28 Days in Subjects with CDD.

too

[0515] The results show that the reduction from baseline for patients with CDD that completed the antecedent study of Example 2C and completed this study was 55.8%. This data is also reflected in the graph of Figure 3, wherein the maintenance period refers to the determined median % change from baseline for the antecedent study (i.e., prior to week 1 of this study).

[0516] The median % change from baseline in drop seizure frequency for the Modified Intent- to-Treat analysis set of patients with LGS and that completed the antecedent study of Example 2B is set forth below in Table 10.

[0517] Table 10: Median % Change From Baseline in Drop Seizure Frequency Per 28 Days in Subjects with LGS.

[0518] The results show that the reduction from baseline for patients with LGS that completed the antecedent study of Example 2B and completed this study was 36.6%. [0519] The median % change from baseline in Convulsive seizure frequency for the Modified Intent-to-Treat analysis set of patients with DS and that completed the antecedent study of Example 2B is set forth below in Table 11.

[0520] Table 11: Median % Change From Baseline in Convulsive Seizure Frequency Per 28 Days in Subjects with DS.

[0521] The results show that the reduction from baseline for patients with DS that completed the antecedent study of Example 2B and completed this study was 58.2%.

[0522] The median % change from baseline in Convulsive seizure frequency for the Modified Intent-to-Treat analysis set of patients with LGS and that completed the antecedent study of Example 2B is set forth below in Table 12.

[0523] Table 12: Median % Change From Baseline in Convulsive Seizure Frequency Per 28 Days in Subjects with LGS.

[0524] The results show that the reduction from baseline for patients with LGS that completed the antecedent study of Example 2B and completed this study was 64.7%.

[0525] The median % change from baseline in Convulsive seizure frequency for the Safety analysis set of patients with CDD and that completed the antecedent study of Example 2C is set forth below in Table 13.

[0526] Table 13: Median % Change From Baseline in Motor Seizure Frequency Per 28 Days in Subjects with CDD.

[0527] The results show that the reduction from baseline for patients with CDD that completed the antecedent study of Example 2C and completed this study was 80.2%. This data is also reflected in the graph of Figure 4, wherein the maintenance period refers to the determined median % change from baseline for the antecedent study (i.e., prior to week 1 of this study).

[0528] Additional median percent change from baseline data is set forth in Figures 2A-2C. Referring to 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.

[0529] 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.

[0530] A summary of the TEAEs for the Safety analysis set of patients with DS or LGS and that completed the antecedent study of Example 2B is set forth below in Table 14.

[0531] Table 14: TEAEs for Safety Analysis Set of Patients with DS or LGS.

[0532] A summary of the TEAEs for the Safety analysis set of patients with DS and that completed the antecedent study of Example 2B is set forth below in Table 15.

[0533] Table 15: TEAEs for Safety Analysis Set of Patients with DS.

[0534] A summary of the TEAEs for the Safety analysis set of patients with LGS and that completed the antecedent study of Example 2B is set forth below in Table 16.

[0535] Table 16: TEAEs for Safety Analysis Set of Patients with LGS.

[0536] A summary of the TEAEs for the Safety analysis set of patients with CDD and that completed the antecedent study of Example 2C is set forth below in Table 17.

[0537] Table 17: TEAEs for Safety Analysis Set of Patients with CDD.

[0538] A listing of concomitant medications for Safety analysis set of patients with DS or LGS and that completed the antecedent study of Example 2B is set forth in Table 18.

[0539] Table 18: Concomitant Medications for Patients with DS or LGS.

EQUIVALENTS AND SCOPE

[0540] In the claims articles such as "a," "an," and "the" may mean one or more than one unless indicated to the contrary or otherwise evident from the context. Claims or descriptions that include "or" between one or more members of a group are considered satisfied if one, more than one, or all of the group members are present in, employed in, or otherwise relevant to a given product or process unless indicated to the contrary or otherwise evident from the context. The invention includes embodiments in which exactly one member of the group is present in, employed in, or otherwise relevant to a given product or process. The invention includes embodiments in which more than one, or all of the group members are present in, employed in, or otherwise relevant to a given product or process.

[0541] Furthermore, the invention encompasses all variations, combinations, and permutations in which one or more limitations, elements, clauses, and descriptive terms from one or more of the listed claims is introduced into another claim. For example, any claim that is dependent on another claim can be modified to include one or more limitations found in any other claim that is dependent on the same base claim. Where elements are presented as lists, e.g., in Markush group format, each subgroup of the elements is also disclosed, and any element(s) can be removed from the group. It should it be understood that, in general, where the invention, or aspects of the invention, is/are referred to as comprising particular elements and/or features, certain embodiments of the invention or aspects of the invention consist, or consist essentially of, such elements and/or features. For purposes of simplicity, those embodiments have not been specifically set forth in haec verba herein. It is also noted that the terms "comprising" and "containing" are intended to be open and permits the inclusion of additional elements or steps. Where ranges are given, endpoints are included. Furthermore, unless otherwise indicated or otherwise evident from the context and understanding of one of ordinary skill in the art, values that are expressed as ranges can assume any specific value or sub-range within the stated ranges in different embodiments of the invention, to the tenth of the unit of the lower limit of the range, unless the context clearly dictates otherwise.

[0542] This application refers to various issued patents, published patent applications, journal articles, and other publications, all of which are incorporated herein by reference. If there is a conflict between any of the incorporated references and the instant specification, the specification shall control. In addition, any particular embodiment of the present invention that falls within the prior art may be explicitly excluded from any one or more of the claims. Because such embodiments are deemed to be known to one of ordinary skill in the art, they may be excluded even if the exclusion is not set forth explicitly herein. Any particular embodiment of the invention can be excluded from any claim, for any reason, whether or not related to the existence of prior art.

[0543] Those skilled in the art will recognize or be able to ascertain using no more than routine experimentation many equivalents to the specific embodiments described herein. The scope of the present embodiments described herein is not intended to be limited to the above Description, but rather is as set forth in the appended claims. Those of ordinary skill in the art will appreciate that various changes and modifications to this description may be made without departing from the spirit or scope of the present invention, as defined in the following claims.

Claims

WHAT IS CLAIMED IS:

1. 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

(a) the subject is diagnosed with CDD, DS, or 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 about 12 weeks during the treatment period.

2. The method of claim 1, wherein 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.

3. The method of claim 2, wherein the subject experiences a reduction in motor seizure frequency of about 50% or more for at least 72 weeks during the treatment period.

4. The method of claim 3, wherein the subject experiences a reduction in motor seizure frequency of about 55% or more for at least 100 weeks during the treatment period.

5. The method of any one of claims 2-4, wherein 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.

6. The method of claim 1 wherein 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.

7. The method of claim 6, wherein the subject experiences a reduction in convulsive seizure frequency of about 30% or more for at least 72 weeks during the treatment period.

8. The method of claim 7, wherein the subject experiences a reduction in convulsive seizure frequency of about 40% or more for at least 100 weeks during the treatment period.

9. The method of claim 1, wherein 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.

10. The method of claim 1, wherein 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.

11. The method of claim 10, wherein the subject experiences a reduction in convulsive seizure frequency of about 25% or more, wherein the reduction in seizure frequency lasts for at least 72 weeks during the treatment period.

12. 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

(a) the subject is diagnosed with CDD, DS, or LGS, and

13. The method of claim 12, wherein 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.

14. The method of claim 13, wherein the subject experiences a reduction in all seizure frequency of about 45% or more beginning at least 23 weeks after treatment onset.

15. The method of claim 14, wherein the subject experiences a reduction in all seizure frequency of about 45% or more beginning at least 61 weeks after treatment onset.

16. The method of claim 13, wherein the subject experiences a reduction in motor seizure frequency of about 50% or more beginning at least 23 weeks after treatment onset.

17. The method of claim 16, wherein the subject experiences a reduction in motor seizure frequency of about 55% or more beginning at least 25 weeks after treatment onset.

18. The method of claim 17, wherein the subject experiences a reduction in motor seizure frequency of about 60% or more beginning at least 61 weeks after treatment onset.

19. The method of any one of claims 16-18, wherein 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.

20. The method of claim 12, wherein 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.

21. The method of claim 20, wherein the subject experiences a reduction in all seizure frequency of about 30% or more beginning at least 36 weeks after treatment onset.

22. The method of claim 20, wherein the subject experiences a reduction in convulsive seizure frequency of about 20% or more beginning at least 23 weeks after treatment onset.

23. The method of claim 20, wherein the subject experiences a reduction in convulsive seizure frequency of about 40% or more beginning at least 60 weeks after treatment onset.

24. The method of claim 12, wherein 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.

25. The method of claim 24, wherein the subject experiences a reduction in drop seizure frequency of about 10% or more beginning at least 23 weeks after treatment onset.

26. The method of claim 25, wherein the subject experiences a reduction in drop seizure frequency of about 15% or more beginning at least 61 weeks after treatment onset.

27. The method of claim 24, wherein the subject experiences a reduction in convulsive seizure frequency of about 10% or more beginning at least 23 weeks after treatment onset.

28. The method of claim 27, wherein the subject experiences a reduction in convulsive seizure frequency of about 30% or more beginning at least 25 weeks after treatment onset.

29. The method of claim 28, wherein the subject experiences a reduction in convulsive seizure frequency of about 40% or more beginning at least 61 weeks after treatment onset.

30. The method of any one of claims 1-29, wherein the subject is from about 2 years to about 17 years of age.

31. The method of claim 30, wherein the subject is administered Compound 1 or a dose equivalent of a pharmaceutically acceptable salt thereof at a weight-adjusted dosage amount.

32. The method of claim 28, wherein 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.

33. The method of claim 29, wherein 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.

34. The method of claim 30, wherein 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.

35. The method of claim 30, wherein 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.

36. The method of claim 30, wherein 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.

37. The method of any one of claims 1-26, wherein the subject is at least 18 years of age.

38. The method of claim 34, wherein 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.

39. The method of claim 35, wherein 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.

40. The method of claim 36, wherein 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.

41. The method of claim 37, wherein 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.

42. The method of claim 37, wherein 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.

43. The method of any one of claims 1-39, wherein the subject is administered at least one additional therapeutic agent.

44. The method of claim 40, wherein 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.

45. The method of claim 41, wherein 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, ethosuximide, or any combination thereof.

46. The method of any one of claims 1-42, wherein Compound 1 or a pharmaceutically acceptable salt thereof are administered orally or administered through a gastrostomy tube or percutaneous endoscopic gastrostomy tube.

47. The method of any one of preceding claims, wherein the treatment duration is at least as long as the period during which the reduction in seizure frequency is observed.

48. The method of claim 47, wherein the treatment duration 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.