Treatment

Abstract

5-hydroxytryptamine (HT), comprising prescribing and / or administering to an individual in need of treatment (R)-N-(2,2-difluoroethyl)-7-methyl-1,2,3,4,6,7-hexahydro-[1,4]diazepino[6,7,l-hi]indole-8-carboxamide (Compound 1), or a pharma- ceutical acceptable salt, hydrate or solvate thereof. 2C Methods for treating receptor-associated disorders are provided. TIFF2025507156000008.tif4126(1)

Description

[Background technology]

[0001] Developmental epileptic encephalopathies (DEEs) are a heterogeneous group of rare neurodevelopmental disorders. They are characterized by early-onset seizures that are often refractory and are accompanied by EEG abnormalities, developmental delay or regression that may worsen over time, and in some cases early death. These disorders are commonly diagnosed in childhood and adolescence, but are variable in etiology, seizure type, EEG patterns, cognitive impairment, and prognosis. The International League Against Epilepsy has recently expanded the definition to disorders that may cause developmental delay before the onset of epilepsy, and uses the term DEE to encompass this broader population.

[0002] 5-HT2 receptor agonists have been shown to be effective treatments for a variety of motor seizure and seizure disorders. 2C , 5-HT 2B and 5-HT 2A Low-dose fenfluramine (Fintepla®), a mixed receptor agonist for 5-HT, was recently approved for the treatment of Dravet syndrome (US Food and Drug Administration (FDA) label approval in June 2020) and was shown to be superior to placebo in reducing the frequency of drop attacks in patients with Lennox-Gastaut syndrome in a phase 3 study. However, Fintepla® inhibits 5-HT 2B The drug was given a boxed warning requiring cardiac monitoring due to an association between serotonergic drugs with receptor agonist activity and valvular heart disease.

[0003] There is a large unmet need for safe and effective treatments for DEE. 2C There remains a need for alternative compounds for the treatment of diseases and disorders associated with the 5-HT receptor. The compounds described herein meet these needs and also provide related advantages. 2C The present disclosure satisfies this need and provides related advantages as well. Summary of the Invention

[0004] 5-hydroxytryptamine (HT), comprising prescribing and / or administering to an individual in need of treatment (R)-N-(2,2-difluoroethyl)-7-methyl-1,2,3,4,6,7-hexahydro-[1,4]diazepino[6,7,l-hi]indole-8-carboxamide (Compound 1), or a pharma- ceutical acceptable salt, hydrate or solvate thereof. 2C Provided is a method of treating a receptor-associated disorder, wherein Compound 1, or a pharma- ceutically acceptable salt, hydrate or solvate thereof, is administered by a dose titration scheme involving titration of Compound 1, or a pharma- ceutically acceptable salt, hydrate or solvate thereof, until an optimized dose is administered.

[0005] Also provided is a method of treating epilepsy comprising prescribing and / or administering (R)-N-(2,2-difluoroethyl)-7-methyl-1,2,3,4,6,7-hexahydro-[1,4]diazepino[6,7,l-hi]indole-8-carboxamide (Compound 1), or a pharma- ceutically acceptable salt, hydrate or solvate thereof, to an individual in need of treatment, wherein Compound 1, or a pharma- ceutically acceptable salt, hydrate or solvate thereof, is administered by a dose titration scheme comprising titrating Compound 1, or a pharma- ceutically acceptable salt, hydrate or solvate thereof, until an optimized dose is administered.

[0006] Also provided is a method of reducing the severity of epileptic seizures comprising prescribing and / or administering (R)-N-(2,2-difluoroethyl)-7-methyl-1,2,3,4,6,7-hexahydro-[1,4]diazepino[6,7,l-hi]indole-8-carboxamide (Compound 1), or a pharma- ceutically acceptable salt, hydrate or solvate thereof, to an individual in need thereof, wherein Compound 1, or a pharma- ceutically acceptable salt, hydrate or solvate thereof, is administered by a dose titration scheme comprising titrating Compound 1, or a pharma- ceutically acceptable salt, hydrate or solvate thereof, until an optimized dose is administered.

[0007] Also provided is a method of treating a seizure disorder comprising prescribing and / or administering (R)-N-(2,2-difluoroethyl)-7-methyl-1,2,3,4,6,7-hexahydro-[1,4]diazepino[6,7,l-hi]indole-8-carboxamide (Compound 1), or a pharma- ceutically acceptable salt, hydrate or solvate thereof, to an individual in need of treatment, wherein Compound 1, or a pharma- ceutically acceptable salt, hydrate or solvate thereof, is administered by a dose titration scheme comprising titrating Compound 1, or a pharma- ceutically acceptable salt, hydrate or solvate thereof, until an optimized dose is administered.

[0008] Also provided is a method of treating developmental epileptic encephalopathy (DEE) and other refractory epilepsies comprising prescribing and / or administering (R)-N-(2,2-difluoroethyl)-7-methyl-1,2,3,4,6,7-hexahydro-[1,4]diazepino[6,7,l-hi]indole-8-carboxamide (Compound 1), or a pharma- ceutically acceptable salt, hydrate or solvate thereof, to an individual in need of treatment, wherein Compound 1, or a pharma- ceutically acceptable salt, hydrate or solvate thereof, is administered by a dose titration scheme comprising titrating Compound 1, or a pharma- ceutically acceptable salt, hydrate or solvate thereof, until an optimized dose is administered.

[0009] These and other aspects of the invention disclosed herein will be described in greater detail as the patent disclosure proceeds. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0010] As used herein, the following words and phrases generally have the meanings set forth below, unless the context in which they are used dictates otherwise.

[0011] Compound 1: As used herein, "Compound 1" refers to (R)-N-(2,2-difluoroethyl)-7-methyl-1,2,3,4,6,7-hexahydro-[1,4]diazepino[6,7,l-hi]indole-8-carboxamide. [ka] compound 1 Compound 1, or a pharma- ceutically acceptable salt, hydrate or solvate thereof, is a potent and selective 5-hydroxytryptamine (HT) inhibitor. 2C Receptor agonist, 5-HT 2C 5-HT binds to the ligand-binding site of the receptor 2A and 5-HT 2B Compound 1 shows higher selectivity than that of human 5-HT 2C It exhibits a binding affinity of 44 nM at the 5-HT receptor, which is comparable to previously developed antagonists such as Fintepla® (low-dose fenfluramine). 2C 5-HT receptors 2A and 5-HT 2B It shows more than 227-fold selectivity.

[0012] Methods of using Compound 1, or a pharma- ceutically acceptable salt, hydrate or solvate thereof, are disclosed in U.S. Pat. No. 10,392,390, which is incorporated herein by reference in its entirety for all purposes.

[0013] Convulsive / Motor Seizures: As used herein, "convulsive / motor seizures" refers to rectus clonic, tonic, tonic-atonic to falls, focal movements, epileptic spasms, myoclonic atonic to falls and seizures. Non-convulsive seizures include myoclonic, absence, atypical absence or atonic seizures, and focal seizures without an observable motor component.

[0014] Convulsive / Motor Seizure Free Days: As used herein, "convulsive / motor seizure free days" refers to days for which diary data was available and no convulsive / motor seizures were reported.

[0015] Drop Attack: As used herein, the term "drop attack" refers to a attack involving the whole body, trunk, or head that may result in a fall, injury, slumping in a chair or hitting the head on the ground, or may result in a fall or injury due to the position of the subject at the time of the attack or spell.

[0016] Agonist: As used herein, the term "agonist" refers to an antagonist of 5-HT 2C The moiety that interacts with and activates a receptor, such as the serotonin receptor, initiating the physiological or pharmacological response characteristic of that receptor.

[0017] Administration: As used herein, "administration" means providing a compound or other therapy, remedy or treatment such that an individual takes up the compound.

[0018] Oral or peroral: As used herein, "peroral" or "peroral" refers to administering a compound or composition to an individual by a route or mode along the digestive tract. Examples of enteral administration routes include, but are not limited to, oral administration by swallowing solid (e.g. tablet) or liquid (e.g. syrup) form; sublingual (sublingual absorption); nasojejunal or gastrostomy tube (to stomach); intraduodenal administration; and rectal administration (e.g. suppository for releasing and absorbing compound or composition in the lower intestinal tract of the digestive tract).

[0019] Prescription: As used herein, "prescription" means to direct, authorize or recommend the use of a drug or other therapy, remedy or treatment. In some embodiments, a medical practitioner may verbally advise, recommend or authorize the use of a compound, dosage regimen or other treatment to an individual. In this case, the medical practitioner may or may not provide a prescription for the compound, dosage regimen or treatment. Also, the medical practitioner may or may not provide the recommended compound or treatment. For example, the medical practitioner may advise the individual where to obtain the compound without providing the compound. In some embodiments, the medical practitioner may provide the individual with a prescription for the compound, dosage regimen or treatment. For example, the medical practitioner may provide the individual with the prescription in writing or verbally. The prescription may be written on paper, or on an electronic medium, such as a computer file, such as a portable computer device. For example, the medical practitioner may convert the prescription for the compound, dosage regimen or treatment into paper or electronic medium. Furthermore, the prescription can be submitted to a pharmacy or dispensing pharmacy by telephone (verbal), fax (written) or electronically via the Internet. In some embodiments, a sample of the compound or treatment can be given to an individual. As used herein, giving a sample of the compound constitutes an implicit prescription of the compound. Various medical systems around the world use different methods for prescribing and / or administering compounds or treatments, and these methods are encompassed by the present disclosure.

[0020] A prescription may, for example, include the individual's name and / or identifying information, such as date of birth. Also, for example, a prescription may include the name of the drug, the strength of the drug, the dosage, frequency of administration, route of administration, number or amount prescribed, number of refills, physician's name, physician's signature, etc. Additionally, for example, a prescription may include a DEA number and / or state number.

[0021] A medical practitioner may include, for example, a physician, nurse, nurse practitioner, or other related medical professional who may prescribe or administer a compound (drug) for the treatment of a condition described herein, and may also include anyone who may recommend, prescribe, administer, or prevent the administration of a compound or drug to an individual, including, for example, an insurance provider.

[0022] Prevent, preventing or prophylaxis: As used herein, the terms "prevent", "preventing" or "prevention" refer to the prevention of a particular disorder, or the occurrence or onset of one or more symptoms associated with a particular disorder, and do not necessarily refer to complete prevention of the disorder. For example, the terms "prevent", "preventing" and "prevention" refer to administering a prophylactic or preventative treatment to an individual who may eventually develop at least one symptom of a disease or condition, but has not yet done so. Such individuals may be identified based on risk factors known to correlate with subsequent development of the disease. Alternatively, as a preventative measure, a prophylactic treatment may be administered without prior identification of risk factors. Delaying the onset of at least one symptom may also be considered as prevention or prophylaxis.

[0023] Treat, Treating or Treatment: As used herein, the terms "treat", "treating" or "treatment" refer to the administration of therapy to an individual who is already experiencing at least one symptom of a disease or condition, or who has previously experienced at least one symptom of a disease or condition. For example, "treatment" can include reducing, alleviating or ameliorating the symptoms of a disease or condition, preventing further symptoms, improving the underlying metabolic cause of the symptoms, inhibiting the disease or condition, e.g., arresting the progression of the disease or condition, relieving the disease or condition, causing regression of the disease or condition, relieving the condition caused by the disease or condition, or halting the symptoms of the disease or condition. For example, the term "treating" in reference to a disorder refers to reducing the severity of one or more symptoms associated with that particular disorder. Thus, treating a disorder does not necessarily mean reducing the severity of all symptoms associated with the disorder, nor does it necessarily mean a complete reduction in the severity of one or more symptoms associated with the disorder.

[0024] Tolerance: As used herein, an individual is said to "tolerate" a dose of a compound if administration of the dose to the individual does not result in unacceptable adverse events or a combination of unacceptable adverse events.Those skilled in the art understand that tolerance is a subjective measure, and what is tolerable to one individual may not be tolerable to another individual.For example, one individual may not tolerate headache, whereas a second individual may tolerate headache but not vomit, whereas a third individual may tolerate only headache or only vomit, but not tolerate the combination of headache and vomit, even if the severity of each is less than that experienced alone.

[0025] Intolerance: As used herein, "intolerance" refers to significant toxicity and / or tolerability issues that lead to dose reduction or discontinuation. As used herein, "intolerance" may be interchanged with the term "unacceptable."

[0026] Adverse event: As used herein, "adverse event" refers to an undesirable medical event associated with treatment with compound 1, or its pharma- ceutically acceptable salt, hydrate or solvate. In one embodiment, the adverse event is selected from leukopenia, constipation, diarrhea, nausea, abdominal pain, neutropenia, vomiting, back pain and menstrual disorders. In one embodiment, the adverse event is heart block, for example, first degree atrioventricular block. In one embodiment, the adverse event is acute heart rate reduction. In one embodiment, the adverse event is abnormal pulmonary function test findings, such as FEV1 less than 80%, FVC, etc. In one embodiment, the adverse event is macular edema.

[0027] Needing and in need of treatment: As used herein, "needing treatment" and "in need of" when referring to treatment are used interchangeably to mean a judgment made by a caregiver (e.g., a physician, nurse, nurse practitioner, etc.) that an individual needs or would benefit from treatment. This judgment is made based on a variety of factors, including knowledge that the individual is suffering or will suffer as a result of a disease, condition, or disorder treatable by the compounds of the invention, although this is within the expertise of the caregiver. Thus, the compounds of the invention may be used protectively or prophylactically; alternatively, the compounds of the invention may be used to alleviate, inhibit, or ameliorate a disease, condition, or disorder.

[0028] Individual: As used herein, "individual" refers to any human being. In some embodiments, a human individual is referred to as a "subject" or a "patient."

[0029] Dose: As used herein, "dose" refers to the amount of Compound 1, or a pharma- ceutically acceptable salt, hydrate or solvate thereof, given to an individual at a particular time to treat or prevent a disease or disorder.

[0030] Therapeutically effective amount: As used herein, the "therapeutically effective amount" of a drug, compound, drug, composition or combination is a non-toxic and effective amount that produces some desired therapeutic effect when administered to a subject or patient (e.g., a human subject or patient). The exact therapeutically effective amount for a subject may depend, for example, on the subject's body size and health condition, the nature and extent of the condition, the therapeutic agent or combination of therapeutic agents selected for administration, and other variables known to those skilled in the art. The effective amount for a given situation is determined by routine experimentation and is within the judgment of the clinician. In some embodiments, the therapeutically effective amount is a standard dose.

[0031] Pharmaceutical composition: As used herein, "pharmaceutical composition" refers to a composition that includes at least one active ingredient, such as Compound 1 (including but not limited to salts of Compound 1), such that the composition can be examined for a specified efficacious outcome. Those of skill in the art will understand and appreciate the techniques appropriate for determining whether an active ingredient has a desired efficacious outcome based on the needs of the artisan.

[0032] The compounds according to the present invention may optionally be present as pharma- ceutically acceptable salts, including pharma-ceutically acceptable acid addition salts, prepared from pharma-ceutically acceptable non-toxic acids, including inorganic and organic acids. Representative acids include, but are not limited to, acetic acid, benzenesulfonic acid, benzoic acid, camphorsulfonic acid, citric acid, ethylenesulfonic acid, dichloroacetic acid, formic acid, fumaric acid, gluconic acid, glutamic acid, hippuric acid, hydrobromic acid, hydrochloric acid, isethionic acid, lactic acid, maleic acid, malic acid, mandelic acid, methanesulfonic acid, mucic acid, nitric acid, oxalic acid, pamoic acid, pantothenic acid, phosphoric acid, succinic acid, sulfuric acid, tartaric acid, oxalic acid, p-toluenesulfonic acid, and the like, for example, the pharma-ceutically acceptable salts described in Berge et al., Journal of Pharmaceutical Sciences, 66:1-19 (1977), which is incorporated herein by reference in its entirety.

[0033] The acid addition salts may be obtained as the direct product of compound synthesis. Alternatively, the salts may be isolated by dissolving the free base in a suitable solvent containing the appropriate acid and evaporating the solvent or by separating the salt and the solvent. The compounds of the present invention may form solvates with standard low molecular weight solvents using methods known to those skilled in the art.

[0034] When the term "pharmaceutical acceptable salts, solvates and hydrates" or the term "pharmaceutical acceptable salts, solvates or hydrates" is used in reference to Compound 1, it is understood to include pharmaceutical acceptable solvates and / or hydrates of Compound 1, pharmaceutical acceptable salts of Compound 1, and pharmaceutical acceptable solvates and / or hydrates of pharmaceutical acceptable salts of Compound 1. Also, when the term "pharmaceutical acceptable solvates and hydrates" or the term "pharmaceutical acceptable solvates or hydrates" is used in reference to Compound 1, which is a salt, it is understood to include pharmaceutical acceptable solvates and / or hydrates of the salt.

[0035] It is clear to those skilled in the art that the dosage forms described herein may contain, as active ingredient, either Compound 1 or a pharma-ceutically acceptable salt or its solvate or hydrate.In addition, various hydrates and solvates of Compound 1 and its salts are used as intermediates in the preparation of pharmaceutical compositions.Other than those mentioned herein, typical procedures for preparing and identifying suitable hydrates and solvates are well known to those skilled in the art; for example, see pages 202-209 of KJ Guillory, "Generation of Polymorphs, Hydrates, Solvates, and Amorphous Solids," in: Polymorphism in Pharmaceutical Solids, ed. Harry G. Britain, Vol. 95, Marcel Dekker, Inc., New York, 1999. Thus, one aspect of the present disclosure relates to methods of formulating and / or administering hydrates and solvates of Compound 1 and / or its pharma- ceutical acceptable salts, which can be isolated and characterized by methods known in the art, such as thermogravimetric analysis (TGA), TGA-mass spectrometry, TGA-infrared spectroscopy, powder X-ray diffraction (XRPD), Karl Fischer titration, high resolution X-ray diffraction, etc. There are several commercial entities that provide rapid and efficient services for routine identification of solvates and hydrates. Examples of companies that provide these services include Wilmington PharmaTech (Wilmington, DE), Avantium Technologies (Amsterdam) and Aptuit (Greenwich, CT).

[0036] When integers are used in the methods herein, the term "about" may be inserted before the integer.

[0037] Throughout this specification, unless the context requires otherwise, the term "comprise", or variations such as "comprises" or "comprising", will be understood to imply the inclusion of a stated step or element or integer or group of steps or elements or integers, but not the exclusion of other steps or elements or integers or groups of elements or integers.

[0038] Throughout this specification, unless expressly stated otherwise or the context otherwise requires, a reference to a single step, composition of matter, group of steps, or group of compositions of matter will be deemed to encompass one and more (i.e., one or more) of that step, composition of matter, group of steps, or group of compositions of matter.

[0039] Each embodiment described in this specification applies mutatis mutandis to all other embodiments unless expressly stated otherwise.

[0040] Those skilled in the art will understand that the invention described herein may be subject to variations and modifications other than those specifically described. It is understood that the present invention includes all such variations and modifications. The present invention includes all steps, features, compositions and compounds referred to or shown in this specification, individually or collectively, and any combination or any two or more of such steps or features, unless expressly stated otherwise.

[0041] The present invention is intended for illustrative purposes only, and is not limited in scope by the specific embodiments described herein. Functionally equivalent products, compositions and methods are clearly within the scope of the invention described herein.

[0042] It is understood that certain features of the invention described for clarity in the context of separate embodiments may also be provided in combination in a single embodiment. Conversely, various features of the invention described for brevity in the context of a single embodiment may also be provided separately or in any suitable subcombination. For example, a method describing formulating and / or administering Compound 1, or a pharma- ceutically acceptable salt, hydrate or solvate thereof, may be separated into two methods, one describing formulating Compound 1, or a pharma- ceutically acceptable salt, hydrate or solvate thereof, and the other describing administering Compound 1, or a pharma- ceutically acceptable salt, hydrate or solvate thereof. Also, for example, separate methods of the invention describing formulating Compound 1, or a pharma- ceutically acceptable salt, hydrate or solvate thereof and administering Compound 1, or a pharma- ceutically acceptable salt, hydrate or solvate thereof may be combined into a single method describing formulating and / or administering Compound 1, or a pharma- ceutically acceptable salt, hydrate or solvate thereof.

[0043] method 5-hydroxytryptamine (HT), comprising prescribing and / or administering to an individual in need of treatment (R)-N-(2,2-difluoroethyl)-7-methyl-1,2,3,4,6,7-hexahydro-[1,4]diazepino[6,7,l-hi]indole-8-carboxamide (Compound 1), or a pharma- ceutical acceptable salt, hydrate or solvate thereof. 2C Provided is a method of treating a receptor-associated disorder, wherein Compound 1, or a pharma- ceutically acceptable salt, hydrate or solvate thereof, is administered by a dose titration scheme involving titration of Compound 1, or a pharma- ceutically acceptable salt, hydrate or solvate thereof, until an optimized dose is administered.

[0044] Also provided is a method of treating epilepsy comprising prescribing and / or administering (R)-N-(2,2-difluoroethyl)-7-methyl-1,2,3,4,6,7-hexahydro-[1,4]diazepino[6,7,l-hi]indole-8-carboxamide (Compound 1), or a pharma- ceutically acceptable salt, hydrate or solvate thereof, to an individual in need of treatment, wherein Compound 1, or a pharma- ceutically acceptable salt, hydrate or solvate thereof, is administered by a dose titration scheme comprising titrating Compound 1, or a pharma- ceutically acceptable salt, hydrate or solvate thereof, until an optimized dose is administered.

[0045] Also provided is a method of reducing the severity of epileptic seizures comprising prescribing and / or administering (R)-N-(2,2-difluoroethyl)-7-methyl-1,2,3,4,6,7-hexahydro-[1,4]diazepino[6,7,l-hi]indole-8-carboxamide (Compound 1), or a pharma- ceutically acceptable salt, hydrate or solvate thereof, to an individual in need thereof, wherein Compound 1, or a pharma- ceutically acceptable salt, hydrate or solvate thereof, is administered by a dose titration scheme comprising titrating Compound 1, or a pharma- ceutically acceptable salt, hydrate or solvate thereof, until an optimized dose is administered.

[0046] Also provided is a method of treating a seizure disorder comprising prescribing and / or administering (R)-N-(2,2-difluoroethyl)-7-methyl-1,2,3,4,6,7-hexahydro-[1,4]diazepino[6,7,l-hi]indole-8-carboxamide (Compound 1), or a pharma- ceutically acceptable salt, hydrate or solvate thereof, to an individual in need of treatment, wherein Compound 1, or a pharma- ceutically acceptable salt, hydrate or solvate thereof, is administered by a dose titration scheme comprising titrating Compound 1, or a pharma- ceutically acceptable salt, hydrate or solvate thereof, until an optimized dose is administered.

[0047] In some embodiments, the seizure disorder is selected from epilepsy, epilepsy with generalized tonic-clonic seizures, epilepsy with myoclonic absences, frontal lobe epilepsy, temporal lobe epilepsy, Landau-Kleffner syndrome, Rasmussen syndrome, Dravet syndrome, Douse syndrome, CDKL5 disorder, infantile spasms (West syndrome), juvenile myoclonic epilepsy (JME), vaccine-associated encephalopathy, refractory childhood epilepsy (ICE), Lennox-Gastaut syndrome (LGS), Rett syndrome, Ohtahara syndrome, CDKL5 disorder, childhood absence epilepsy, essential tremor, acute repetitive seizures, benign rolandic epilepsy, status epilepticus, refractory status epilepticus, very refractory status epilepticus (SRSE), PCDH19 childhood epilepsy, drug withdrawal induced seizures, alcohol withdrawal induced seizures, increased seizure activity and breakthrough seizures.

[0048] Also provided is a method of treating developmental epileptic encephalopathy (DEE) and other refractory epilepsies comprising prescribing and / or administering (R)-N-(2,2-difluoroethyl)-7-methyl-1,2,3,4,6,7-hexahydro-[1,4]diazepino[6,7,l-hi]indole-8-carboxamide (Compound 1), or a pharma- ceutically acceptable salt, hydrate or solvate thereof, to an individual in need of treatment, wherein Compound 1, or a pharma- ceutically acceptable salt, hydrate or solvate thereof, is administered by a dose titration scheme comprising titrating Compound 1, or a pharma- ceutically acceptable salt, hydrate or solvate thereof, until an optimized dose is administered.

[0049] In some embodiments, the DEE is selected from Lennox-Gastaut syndrome, Dravet syndrome, Douzet syndrome (epilepsy with myoclonic atonic seizures (EM AS)), West syndrome (infantile spasms), Landau-Kleffner syndrome, and a predisposing disorder, such as CDKL5 encephalopathy or CHD2 encephalopathy.

[0050] In some embodiments, the DEE is selected from Ohtahara syndrome, Lennox-Gastaut syndrome, Dravet syndrome, Douzet syndrome, West syndrome, Landau-Kleffner syndrome, tuberous sclerosis, CDKL5 encephalopathy, CHD2 encephalopathy, early myoclonic encephalopathy, infantile epilepsy with migratory focal seizures, epilepsy with myoclonic atonic seizures, and continuous spike-and-wave epileptic encephalopathy with sleep.

[0051] In some embodiments, the individual has a co-occurring condition, such as intellectual disability, an autism spectrum disorder, and / or a behavioral disorder.

[0052] In some embodiments, the method provides improvement in at least one symptom selected from ataxia, gait disturbance, speech disorder, vocalization, cognitive impairment, abnormal motor activity, clinical seizures, subclinical seizures, hypotonia, hypertonia, drooling, mouthing behavior, aura, convulsions, repetitive movements, abnormal sensations, seizure frequency, and seizure severity.

[0053] In some embodiments, administration results in an improvement in the frequency of convulsive / motor seizures and other seizure types. the frequency of countable motor seizures observed; total number of seizures; frequency of nonconvulsive seizures; number of episodes of status epilepticus; Frequency of rescue medication use; and / or Number of days without countable motor seizures This results in improvement in one or more of the following:

[0054] In some embodiments, administration results in improvement in subject / caregiver and investigator's Clinical Global Impression of Improvement (CGI-I), investigator's Global Impression of Severity (CGI-S), and / or the 55-item Quality of Life in Childhood Epilepsy Questionnaire (QOLCE-55). In some embodiments, administration results in at least a 1 point change from baseline in the CGI-I and / or CGI-S.

[0055] In some embodiments, prior to administration, the individual has treatment-resistant countable motor seizures with an average of 4 or more observed / countable motor seizures per 4 weeks while receiving stable ASM treatment.

[0056] In some embodiments, the individual has DEE but does not have Dravet syndrome or Lennox-Gastaut syndrome.

[0057] In some embodiments, where the individual has DEE but does not have Dravet syndrome or Lennox-Gastaut syndrome, the individual is History of onset of unprovoked seizures before age 5 years; History of developmental delay; a history of generalized focal combined epilepsy type or multiple generalized epilepsy types; A history of slow or disorganized EEG; and / or No history of idiopathic generalized epilepsy It has.

[0058] In some embodiments, the individual has Dravet Syndrome.

[0059] In some embodiments, wherein the individual has Dravet syndrome, prior to administration, the individual: Onset of seizures in an otherwise healthy infant between 3 and 12 months of age; History of seizures, either generalized tonic-clonic or unilateral-clonic or bilateral-clonic; Normal early development; and / or History of developmental delay It has.

[0060] In some embodiments, wherein the individual has Dravet syndrome, prior to administration, the individual: The appearance of a different seizure type; Seizures triggered by warm temperatures and / or prolonged exposure to heat due to illness or vaccination, hot baths, high levels of activity and seizures associated with sudden temperature changes, and / or Seizures triggered by bright natural light and / or fluorescent lighting It has.

[0061] In some embodiments in which the individual has Dravet Syndrome, prior to administration, the individual has genetic test results consistent with a diagnosis of Dravet Syndrome.

[0062] In some embodiments, the individual has Lennox-Gastaut Syndrome.

[0063] In some embodiments, wherein the individual has Lennox-Gastaut syndrome, prior to administration, the individual is history of tonic or tonic / atonic seizures; Two or more types of generalized epilepsy, including but not limited to generalized tonic-clonic, tonic-atonic, atonic, tonic, myoclonic, or drop seizures; history of seizures before age 8 years; History of delayed achievement; A previous EEG reporting diagnostic criteria for Lennox-Gastaut syndrome (abnormal interictal EEG background activity with interictal slow spike-and-wave pattern below 2.5 Hertz, or generalized interictal spontaneous fast activity); and / or Observation of an average of 4 or more drop attacks per 4 weeks while receiving stable ASM treatment It has.

[0064] In some embodiments, the dose of Compound 1, or a pharma- ceutically acceptable salt, hydrate, or solvate thereof, is selected from at or about 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, or 72 mg per day. In some embodiments, the dose of Compound 1, or its pharma- ceutically acceptable salt, hydrate or solvate, is selected from 9, 12, 15, 18, 21, 24, 27, 30, 33, 36, 39, 42, 45, 48, 51, 54, 57, 60, 63, 66, 69, or 72 mg per day. In some embodiments, the dose of Compound 1, or its pharma-ceutically acceptable salt, hydrate or solvate, is 9 mg per day. In some embodiments, the dose of Compound 1, or its pharma-ceutically acceptable salt, hydrate or solvate, is 18 mg per day. In some embodiments, the dose of Compound 1, or its pharma-ceutically acceptable salt, hydrate or solvate, is 36 mg per day. In some embodiments, the dose of Compound 1, or its pharma-ceutically acceptable salt, hydrate or solvate, is 54 mg per day. In some embodiments, the dose of Compound 1, or a pharma- ceutically acceptable salt, hydrate or solvate thereof, is 72 mg per day.

[0065] In some embodiments, the dose of Compound 1, or a pharma- ceutically acceptable salt, hydrate or solvate thereof, is 3mg TID. In some embodiments, the dose is 3mg TID. In some embodiments, the dose is 6mg TID. In some embodiments, the dose is 9mg TID. In some embodiments, the dose is 12mg TID. In some embodiments, the dose is 9mg TID. In some embodiments, the dose is 18mg TID. In some embodiments, the dose is 9mg TID. In some embodiments, the dose is 24mg TID.

[0066] In some embodiments, the dose of Compound 1, or its pharma- ceutically acceptable salt, hydrate, or solvate, is titrated to 9 mg per day. In some embodiments, the dose of Compound 1, or its pharma-ceutically acceptable salt, hydrate, or solvate, is titrated to 18 mg per day. In some embodiments, the dose of Compound 1, or its pharma-ceutically acceptable salt, hydrate, or solvate, is titrated to 36 mg per day. In some embodiments, the dose of Compound 1, or its pharma-ceutically acceptable salt, hydrate, or solvate, is titrated to 54 mg per day. In some embodiments, the dose of Compound 1, or its pharma-ceutically acceptable salt, hydrate, or solvate, is titrated to 72 mg per day.

[0067] In some embodiments, the dose of Compound 1 or its pharmaceutically acceptable salt, hydrate or solvate is tapered to exactly or about 54, 53, 52, 51, 50, 49, 48, 47, 46, 45, 44, 43, 42, 41, 40, 39, 38, 37, 36, 35, 34, 33, 32, 31, 30, 29, 28, 27, 26, 25, 24, 23, 22, 21, 20, 19, 18, 17mg per day.In some embodiments, the dose of Compound 1 or its pharmaceutically acceptable salt, hydrate or solvate is tapered to 54mg per day.In some embodiments, the dose of Compound 1 or its pharmaceutically acceptable salt, hydrate or solvate is tapered to 36mg per day. In some embodiments, the dose of Compound 1, or a pharma- ceutically acceptable salt, hydrate, or solvate thereof, is tapered to 18 mg per day. In some embodiments, the dose of Compound 1, or a pharma-ceutically acceptable salt, hydrate, or solvate thereof, is tapered to 9 mg per day.

[0068] In some embodiments, the dose of Compound 1, or its pharma- ceutically acceptable salt, hydrate or solvate, is increased by 3mg TID every 5 days until the optimized dose is administered.In some embodiments, the optimized dose is 3mg TID.In some embodiments, the optimized dose is 6mg TID.In some embodiments, the optimized dose is 9mg TID.In some embodiments, the optimized dose is 12mg TID.

[0069] In some embodiments, the dose titration scheme involves prescribing and / or administering Compound 1, or a pharma- ceutically acceptable salt, hydrate or solvate thereof, at an initial dose equivalent to 6 mg of Compound 1 three times daily for about 5 days, and increasing the dose if the individual tolerates the initial dose and if the individual does not respond adequately.

[0070] In some embodiments, the increased dose corresponds to 9 mg of Compound 1 three times daily.

[0071] In some embodiments, the dose titration scheme further comprises administering Compound 1, or a pharma- ceutically acceptable salt, hydrate or solvate thereof, at increased doses for about 5 days.

[0072] In some embodiments, the optimized dose is the initial dose if the individual does not tolerate the increased dose.

[0073] In some embodiments, if the individual tolerates the increased dose and the individual shows an adequate response, the optimized dose is the increased dose.

[0074] In some embodiments, the dose adjustment scheme further comprises administering an optimized dose of Compound 1, or a pharma- ceutically acceptable salt, hydrate or solvate thereof, to the individual.

[0075] In some embodiments, the individual tolerates the increased dose, but if the individual does not respond adequately, the method further comprises increasing the dose.

[0076] In some embodiments, the increased dose corresponds to about 12 mg of Compound 1 three times a day.

[0077] In some embodiments, the optimized dose is an increased dose if the individual does not tolerate a further increased dose.

[0078] In some embodiments, if the individual tolerates the further increased dose and if the individual shows an adequate response, the optimized dose is the further increased dose.

[0079] In some embodiments, the dose adjustment scheme further comprises administering an optimized dose of Compound 1, or a pharma- ceutically acceptable salt, hydrate or solvate thereof, to the individual.

[0080] In some embodiments, for example, when an individual does not tolerate the optimized dose of compound 1, or its pharma- ceutically acceptable salt, hydrate or solvate, the method further comprises a tapering scheme.In some embodiments, the tapering scheme comprises reducing the dose of compound 1, or its pharma-ceutically acceptable salt, hydrate or solvate administered to an individual by exactly or about 1, 2, 3, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12 mg per day.In some embodiments, the tapering scheme comprises reducing the dose of compound 1, or its pharma-ceutically acceptable salt, hydrate or solvate administered to an individual once.In some embodiments, the tapering scheme comprises reducing the dose of compound 1, or its pharma-ceutically acceptable salt, hydrate or solvate administered to an individual two or more times. In some embodiments, the tapering scheme involves decreasing the dose of Compound 1, or a pharma- ceutically acceptable salt, hydrate, or solvate thereof, administered to the individual by 3 mg TID every 5 days until the individual is no longer administered Compound 1, or a pharma- ceutically acceptable salt, hydrate, or solvate thereof.

[0081] In some embodiments, the dose of Compound 1, or its pharmaceutically acceptable salt, hydrate or solvate, is tapered to address observed side effects.In some embodiments, the dose of Compound 1, or its pharmaceutically acceptable salt, hydrate or solvate, is tapered to minimize the risk of withdrawal-induced side effects.

[0082] In some embodiments, the individual is also administered an anticonvulsant or antiseizure drug. In some embodiments, the individual is also administered an anticonvulsant (e.g., benzodiazepines, valproic acid and lamotrigine) that is effective in suppressing interictal epileptiform discharges. In some embodiments, the individual is also administered an immunomodulatory treatment (e.g., corticosteroids, intravenous immunoglobulin (IVIG), plasmapheresis). In some embodiments, the individual is also administered a ketogenic diet.

[0083] Also provided is a pharmaceutical composition comprising a standard dose of Compound 1, or a pharma- ceutically acceptable salt, hydrate or solvate thereof, and optionally one or more pharma- ceutically acceptable carriers. Also provided is a pharmaceutical composition comprising Compound 1, or a pharma- ceutically acceptable salt, hydrate or solvate thereof, and optionally one or more pharma- ceutically acceptable carriers. A carrier must be "acceptable" in the sense of being compatible with the other ingredients of the formulation and not unduly deleterious to the recipient thereof.

[0084] In some embodiments, Compound 1, or a pharma- ceutically acceptable salt, hydrate or solvate thereof, is administered as the raw or pure chemical, for example, as a powder in a capsule formulation.

[0085] In some embodiments, Compound 1, or a pharma- ceutically acceptable salt, hydrate or solvate thereof, is formulated as a pharmaceutical composition further comprising one or more pharma- ceutically acceptable carriers.

[0086] The pharmaceutical compositions may be prepared by any suitable method, typically by uniformly admixing the active compound with a liquid or finely divided solid carrier, or both, in the required proportions, and then, if necessary, shaping the resulting mixture into the desired presentation.

[0087] Conventional additives, such as binders, excipients, acceptable wetting agents, tableting lubricants and disintegrants, may be used in tablets or capsules for oral administration. The compounds described herein may be formulated into pharmaceutical compositions using techniques well known to those skilled in the art. Suitable pharmacologic acceptable carriers other than those mentioned herein are known in the art and are described, for example, in Remington, The Science and Practice of Pharmacy, 20 th Edition, 2000, Lippincott Williams & Wilkins, (Editors: Gennaro et al.).

[0088] In some embodiments, Compound 1, or a pharma- ceutically acceptable salt, hydrate or solvate thereof, is formulated in a manner suitable for oral administration.

[0089] For oral administration, the pharmaceutical composition may be in the form of, for example, tablets or capsules. The pharmaceutical composition is preferably made in the form of a dosage unit containing a specific amount of active ingredient. Examples of such dosage units are caplets, tablets, powders, granules or suspensions, which contain conventional additives such as lactose, mannitol, cornstarch or potato starch; binders such as crystalline cellulose, cellulose derivatives, acacia, cornstarch or gelatins; disintegrants such as cornstarch, potato starch or sodium carboxymethylcellulose; and lubricants such as talc or magnesium stearate. Solid form preparations include powders, tablets, pills, caplets, cachets, suppositories and dispersible granules. A solid carrier may be one or more substances that can function as diluents, flavoring agents, solubilizers, lubricants, suspending agents, binders, preservatives, tablet disintegrating agents or encapsulating materials.

[0090] In powders, the carrier is a finely divided solid which is in admixture with the finely divided active component.

[0091] In tablets, the active component is mixed with the carrier having the necessary binding capacity in suitable proportions and compacted to the desired shape and size.

[0092] Powders and tablets may contain various percentage amounts of active compound. A typical amount in powders and tablets may be 0.5 to about 90% of active compound. However, one skilled in the art will know when amounts outside this range are necessary. Suitable carriers for powders and tablets include magnesium carbonate, magnesium stearate, talc, sugar, lactose, pectin, dextrin, starch, gelatin, tragacanth, methylcellulose, sodium carboxymethylcellulose, low melting point wax, cocoa butter, and the like. The term "preparation" includes formulations of active compound and encapsulating material as a carrier to provide a capsule in which the active compound, with or without a carrier, is surrounded by and thus bound to the carrier. Similarly, cachets and lozenges are included. Tablets, powders, caplets, pills, cachets, and lozenges may be used as solid forms suitable for oral administration.

[0093] For oral administration, the pharmaceutical composition can be in a form suitable for administration via a gastrostomy tube or a percutaneous endoscopic gastrostomy tube.

[0094] The pharmaceutical preparation is preferably in unit dosage form.In such form, the preparation is divided into unit doses containing an appropriate amount of active ingredient.The unit dosage form can be a packaged preparation, and the package contains a discrete amount of the preparation, for example, a packaged tablet or caplet.The unit dosage form can also be a capsule or tablet itself, or the appropriate number of either of these in a packaged form.

[0095] Further embodiments include those described in the examples below, which should not be construed as limiting in any way. EXAMPLES

[0096] Example 1: Single ascending dose study in healthy subjects A single ascending dose study in healthy subjects was conducted to evaluate the pharmacokinetics (PK), pharmacodynamics (PD), safety and tolerability of single doses of Compound 1 ("Test Drug") administered to healthy subjects.

[0097] The test drug was human 5-HT 2c With a low nanomolar binding affinity of 44 nM to the receptor, 5-HT 2a and 5-HT 2b A potent and highly selective 5-HT1 inhibitor with over 200-fold selectivity over 2c It is a superagonist. The experimental drug is being developed for the treatment of developmental epileptic encephalopathies (DEE).

[0098] This includes people aged 18-55 years and with a body mass index (BMI) of 18.5-30.0 kg / m 2 This was a randomized, double-blind, placebo-controlled, single ascending dose study in healthy adults. Subjects were randomized to receive a single dose of 1, 3, 6, 12 or 24 mg powder in capsule formulation under fasting conditions. Each cohort consisted of 6 active and 2 placebo subjects. Serial plasma and urinary PK, and prolactin samples were collected up to 72 hours. Safety was assessed continuously from signing of informed consent until follow-up visits.

[0099] Average age: 35.0 years, BMI: 24.0 kg / m 2 Forty female subjects were enrolled. The study drug was rapidly absorbed, reaching peak plasma concentrations 1 to 1.5 hours after dosing. The elimination half-life was approximately 5 to 7 hours. Peak and total exposure increased with dose, but the increases appeared to be slightly more than dose proportional, especially at the higher doses. Less than five percent (<5%) of the administered dose was excreted via the kidney; therefore, metabolism appears to be the major clearance pathway.

[0100] The mean PK parameters (SD) after a single dose under fasting conditions are shown below. [Table 1]

[0101] Prolactin increased dose- and concentration-dependently within 2 hours, with a greater than dose-proportional increase between the 6 mg and 12 mg doses. Prolactin levels in subjects receiving study drug varied widely between doses, with considerable overlap, but mean %CFB at 2 hours increased dose-dependently, with a greater than dose-proportional increase between the 6 mg and 12 mg doses. By 24 hours post-dose, prolactin levels had returned to baseline only at the 6 mg dose level. In the placebo and 1 mg dose groups, there was an initial decrease at 2 hours, followed by higher prolactin concentrations at 24 hours, which may be the result of diurnal variation and data variability.

[0102] The most common treatment-emergent adverse events were headache, postural dizziness, and nausea, which were mild to moderate in severity.

[0103] In summary, the study drug was rapidly absorbed into the systemic circulation after administration of a single oral dose of the study drug PIC formulation. Peak plasma concentrations occurred with a median T of 1.02 to 1.54 hours after administration of 1 to 24 mg as a single oral dose. max A range was observed. The mean half-life of the study drug ranged from 4.67 to 6.66 hours in the 1- to 24-mg dose groups. Less than 5% of the dose was excreted via the renal route, so most of the elimination appears to have occurred via metabolism.

[0104] Example 2: Multiple ascending dose study in healthy subjects A randomized, double-blind, placebo-controlled, multiple ascending dose study of the study drug in healthy subjects was conducted to evaluate the PK, PD, safety, and tolerability of multiple doses of the study drug.

[0105] In this study, participants were aged 18-55 years and had a BMI of 18.5-30.0 kg / m 2Healthy adults were enrolled in two groups. Subjects in one group received the powder in capsules three times daily (every 8 hours) for 14 days without dose adjustment, while subjects in the other group received the maximum dose with 3-day dose adjustment. On the PK sampling day, subjects fasted overnight before the morning dose. Serial plasma and prolactin samples were collected on days 1 and 14, and a urine sample was collected on day 14. Safety was assessed continuously from signed informed consent until follow-up visits.

[0106] Plasma and urinary concentration-time data were analyzed using non-compartmental methods to demonstrate the following key PK parameters: max , T max , AUC tau , C trough , C av , Vss / F, CL / F, Racc,C max ,Racc,AUC,T 1 / 2 Concentration-time data and PK parameters were summarized using descriptive metrics. Trough plasma concentrations were plotted and steady state was visually assessed.

[0107] Prolactin serum concentrations were summarized by time point, dose, and site. Absolute and percent change from baseline in prolactin values ​​were calculated, with pre-dose values ​​on Day 1 considered as baseline values. Observed prolactin data, absolute and percent change from baseline versus time were plotted.

[0108] Forty-three subjects (16M, 27F) were enrolled. The study drug was rapidly absorbed. Multiple doses TID resulted in significant accumulation. At doses up to 18 mg TID, steady state was achieved in most cases by day 10. At steady state, approximately 30% of the dose was excreted via the renally route at 48 hours (non-escalating group).

[0109] A summary of pharmacokinetic parameters by cohort is shown below. [Table 2-1] [Table 2-2]

[0110] Prolactin increased in a dose- and concentration-dependent manner, with greater increases seen after the first dose.

[0111] Three subjects discontinued due to adverse events. The majority of treatment-emergent adverse events (TEAEs) were mild to moderate in severity. The most common were headache, somnolence, dizziness, postural dizziness, urgency, and orthostatic hypotension. Five TEAEs (all after discontinuation of study drug) occurred in three subjects and were serious. One serious adverse event was reported after discontinuing treatment with study drug 24 mg TID, consistent with abrupt discontinuation of serotonergic medication. This subject accounted for three serious TEAEs. The data support further development of developmental and epileptic encephalopathies, and other seizure disorders.

[0112] In summary, the test drug was rapidly absorbed into the systemic circulation after administration of the first dose of the capsule formulation of the test drug powder and after administration of multiple oral doses. Peak plasma concentrations after the first and last doses were T max The median time occurred between 1.00 and 2.00 hours.

[0113] Most subjects reached steady state after 10 days of treatment in the non-titration portion.

[0114] Multiple dosing in a TID regimen resulted in dose-dependent accumulation. AUC tau The cumulative fraction of β increased from 1.75 to 3.79 from 3 mg to 18 mg in Part C and was 3.25 in the 12 / 24 mg titration regimen. max The cumulative fraction of β-blockers increased from 1.55 to 3.37 from 3 mg to 18 mg in Part C and decreased slightly to 2.79 with the 12 / 24 mg titration regimen.

[0115] The mean half-life of study drug at steady state was consistent across all dose groups, ranging from 4.81 to 6.50 hours.

[0116] At steady state, across the 3-18 mg TID dosing regimens, 20.9%-32.3% of the dose was excreted via the renal route over 48 hours. With the 12 / 24 mg TID titration regimen, only 12.3% of the dose was excreted via the renal route over 48 hours.

[0117] The mean percent change from baseline prolactin levels at 2 hours increased as the dose increased from 3 mg to 12 mg and then plateaued. The data were highly variable.

[0118] Example 3: A Phase 1b / 2a randomized, double-blind, placebo-controlled, parallel-group, dose-escalation study will be conducted to investigate the safety, tolerability, pharmacokinetics, pharmacodynamics, and exploratory efficacy of the study medication in subjects with developmental epileptic encephalopathy.

[0119] Study objectives and endpoints may include: [Table 3-1] [Table 3-2]

[0120] The study consisted of the following periods: Screening (7 days) / Baseline (28 days) Part 1: Randomization and Titration (15 days) Part 2: Maintenance (60 days) Part 3: Tapering (up to 15 days) Follow-up (30 days after completion of tapering)

[0121] If tolerated, a target maximum dose of 12 mg TID will be reached after a 15-day titration period. The double-blind treatment period consists of randomization and titration in Part 1 (15 days) and maintenance in Part 2 (60 days).

[0122] Part 1: Titration (Days 1-15) During the titration period, subjects will be titrated to 12 mg TID or maximum tolerated dose. Planned dose escalation steps of study drug or placebo during the titration period are 6 mg TID (days 1-5), 9 mg TID (days 6-10) and 12 mg TID (days 11-15) or matching placebo TID. Subjects who do not tolerate escalation to 12 mg TID may have their dose reduced to 9 mg TID. Subjects who do not tolerate escalation to 9 mg TID D may have their dose reduced to 6 mg TID.

[0123] Part 2: Maintenance (Days 16-75) After completing titration to either dose of study drug at 6 mg TID, 9 mg TID, or 12 mg TID, or placebo TID, subjects will be maintained at these doses for a 60-day maintenance period. During the maintenance period, if a subject does not tolerate their assigned dose level from the titration period, they will be discontinued.

[0124] Part 3: Tapering (Days 76-80 / 85 / 90) During the taper / reduction period, the study drug will be reduced by 3 mg TID every 5 days until the subject is no longer taking study drug or placebo as follows: 12 mg dose: 15-day taper / reduction period Days 76-80 (first 5-day taper) = 9 mg study drug TID or placebo TID Days 81-85 (second 5-day dose reduction) = 6 mg study drug TID or placebo TID Days 86-90 (third 5-day dose reduction) = 3mg TID or placebo TID 9 mg dose: 10 day taper / reduction period Days 76-80 (first 5-day taper) = 6 mg of study drug TID or placebo Days 81-85 (second 5-day taper) = 3 mg study drug TID or placebo TID 6 mg dose: 5-day taper / reduction period Days 76-80 = 3 mg study drug TID or placebo TID

[0125] The total daily dose is not to exceed 36 mg.

[0126] Subjects who meet all of the following inclusion criteria and none of the exclusion criteria are eligible to participate in this study.

[0127] Inclusion criteria may include: Age >18 to <65 years at screening with a body mass index (BMI) of 35 kg / m 2 Less than 18kg / m 2 Super adult male or female. Diagnosis of DEE, including Dravet syndrome, Lennox-Gastaut syndrome, and other DEE, and based on subject / caregiver report and investigator assessment, demonstrating an average of 4 or more treatment-resistant countable motor seizures per 4 weeks during the 12 weeks prior to screening while receiving stable antiseizure medication (ASM) treatment. a. Subjects characterized as having DEE, but not having Dravet or Lennox-Gastaut syndrome, have all of the following, based on subject / caregiver history and investigator assessment: i. History of unprovoked seizures before age 5 years. ii. History of developmental delay. iii. History of generalized focal combined epilepsy type or multiple generalized epilepsy types. iv. History of slow or disorganized EEG. v. No history of idiopathic generalized epilepsy. vi. An average of 4 or more countable motor seizures observed while receiving stable ASM treatment during the 12 weeks prior to screening based on subject / caregiver report and investigator assessment. b. A subject characterized as having Dravet Syndrome must meet all of the following: i. Onset of seizures in an otherwise healthy infant between 3 and 12 months of age. ii. History of seizures, either generalized tonic-clonic or unilateral-clonic or bilateral-clonic. iii. Early development was normal. iv. History of developmental delay. v. Lack of an alternative diagnosis. vi. An average of 4 or more countable motor seizures observed while receiving stable ASM treatment during the 12 weeks prior to screening based on subject / caregiver report and investigator assessment. And at least one of the following: vii. The occurrence of another seizure type after the first one, including myoclonic, generalized tonic-clonic, tonic, atonic, absence and / or focal developmental. viii. Seizures triggered by warm temperatures and / or prolonged exposure to fever due to illness or vaccination, hot baths, seizures associated with high levels of activity and sudden temperature changes, and / or seizures triggered by strong natural and / or fluorescent lighting and certain visual patterns. ix. Genetic test results consistent with a diagnosis of Dravet syndrome (pathogenic, likely pathogenic, variant of uncertain significance, or inconclusive but unlikely to support an alternative diagnosis). c. Subjects characterized as having Lennox-Gastaut Syndrome must meet the following: i. History of tonic or tonic / atonic seizures. ii. 2 or more types of generalized epilepsy, including but not limited to generalized tonic-clonic, tonic-atonic, atonic, tonic, myoclonic or drop attacks, within 6 months prior to screening. A drop attack is defined as a seizure involving the whole body, trunk or head that may result in a fall, injury, slumping in a chair or striking the head on the ground, or that may result in a fall or injury depending on the position of the subject's body at the time of the seizure or convulsion. iii. History of seizures before age 8 years. iv. History of developmental delay. v. Previous EEG documentation reporting diagnostic criteria for Lennox-Gastaut syndrome (abnormal interictal EEG background activity with interictal slow spike-and-wave pattern below 2.5 Hz, or generalized interictal episodic fast activity). vi. An average of 4 or more drop attacks observed per 4 weeks during the 12 weeks prior to screening while on stable ASM treatment based on subject / caregiver report and investigator assessment. -Taking a stable dose of 1-4 ASMs for at least 4 weeks prior to screening and the subject or the subject's legal representative is willing to maintain a stable regimen for the duration of the study. All medications or interventions for epilepsy (including ketogenic diet and vagus nerve stimulation) must be stable for 4 weeks prior to screening and are expected to remain stable for the duration of the study. G-tube / PEG tube (if present) must be in place and functioning for at least 3 months prior to screening. Nasogastric tubes are not permitted.

[0128] Randomization inclusion criteria may include: 4 or more observed and countable motor seizures during a 28-day baseline period, with a minimum of 2 in the first 14 days and 2 in the next 14 days, and a stable baseline with no seizures for more than 21 consecutive days during the 28-day baseline period. The subject, parent or guardian, in the opinion of the investigator, is compliant with completing the diary during the baseline period (i.e., at least 80% compliant but with no more than 5 days missed in total). ·Subjects, parents or caregivers responsible for administering the study medication demonstrate an understanding of how to administer the study medication correctly.

[0129] A subject may be excluded from the study if any of the following criteria are met: - Admission to a medical institution for treatment of status epilepticus requiring mechanical ventilation within 3 months prior to screening. Current or previous idiopathic generalized epilepsy. ·Has had a vagus nerve stimulator implanted within 6 months prior to screening, and / or its settings have been changed within 1 month prior to screening, and / or are expected to be changed during the study. -Has started a ketogenic diet within 6 months of the screening visit, changed within 1 month of the screening visit, or is expected to change during the study period. -Subjects with Dravet syndrome who have used sodium channel blockers, phenytoin, fosphenytoin, carbamazepine, oxcarbazepine, eslicarbazepine, lamotrigine, lacosamide, rufinamide, vigabatrin, tiagabine, pregabalin, or gabapentin within the past month (30 days) prior to screening. · Current felbamate use (unless subject had been taking a stable dose of felbamate for at least 12 months prior to screening, with stable liver function and hematological laboratory tests). · Current topiramate use (unless subject had been taking a stable dose of topiramate for at least 12 months prior to screening and was weight stable). -Fenfluramine was used. There is a clear pattern of perimenstrual exacerbation. · Deemed at risk for suicidal behavior based on the C-SSRS. If the subject has had suicidal intent (ideation items 4 or 5) in the past 6 months prior to randomization or has had suicidal behavior or attempts in the past year, the subject will be excluded and a risk assessment must be performed by a licensed mental health professional (MHP). If the subject is unable to complete the C-SSRS due to their developmental status, an authorized representative may complete the C-SSRS. The investigator may also use clinical judgment, which must be documented in the source documentation. · PHQ-9 score greater than 9 or an affirmative response to question 9. Current or recent history of moderate or severe depression according to the Diagnostic and Statistical Manual of Mental Disorders, 5th Edition, anorexia nervosa, or bulimia nervosa within the past year. Positive for human immunodeficiency virus (HIV), hepatitis B, or hepatitis C infection, including subjects who have received the hepatitis B vaccine (hepatitis B surface antibody positive) and who are negative for other markers of past hepatitis B infection (e.g., hepatitis B core antibody negative). Hepatitis C antibody positive subjects are also eligible as long as their hepatitis C viral load by quantitative polymerase chain reaction is negative. ·An abnormal and clinically significant 12-lead ECG at screening, in the opinion of the Investigator (e.g., second or third degree heart block, or a corrected QT interval (QTc) greater than 450 milliseconds for men and greater than 470 milliseconds for women). Inclusion of subjects with an abnormal but not clinically significant ECG must be approved and documented by signature of the Investigator or an appropriately qualified representative. - Supine or sitting blood pressure greater than 140mmHg systolic or 90mmHg diastolic, or less than 90mmHg systolic or 60mmHg diastolic. - Have signs or a history of orthostatic hypotension. A sustained increase in heart rate of more than 30 beats per minute within 3 minutes of standing from a supine or sitting position. History of progressive neurodegeneration demonstrated by magnetic resonance imaging. -Having moderate or severe renal dysfunction. History of glaucoma. History of significant lower urinary tract pathology, including bladder outflow obstruction, urinary retention, urethral stricture, bladder neck contracture, bladder diverticulum or bladder stones. · History of recurrent urinary tract infections (UTIs) (2 or more documented UTIs in the past 12 months) or currently presenting with a UTI. Abnormal laboratory results suggestive of clinically significant underlying liver disease at screening. Medical monitoring should be consulted if the subject has alanine aminotransferase (ALT) and / or aspartate aminotransferase (AST) >2.5 times the upper limit of normal (ULN) and / or bilirubin elevation >2 times the ULN. - centrally acting appetite suppressants; monoamine oxidase inhibitors; centrally acting compounds with clinically significant serotonergic or antagonist properties, including serotonin and norepinephrine reuptake inhibitors, serotonin reuptake inhibitors; receiving concomitant treatment with atomoxetine, vortioxetine, or other centrally acting noradrenergic agonists or drugs intended to promote weight loss. · Use of narrow therapeutic index substrates of CYP1A2 during the study. ·Concomitant use of strong or moderate inhibitors of CYP1A2 and other prohibited drugs / drug classes. Concomitant use of medications whose exposure may be altered by the study drug from the first dose to follow-up. See current Investigator Brochure for guidance. Use of grapefruit juice, grapefruit, Seville oranges, St. John's wort, or products containing these within 30 days prior to the first dose of study drug and until the follow-up visit. Use of cannabidiol preparations other than Epidiolex. · A positive urine drug test for any substance that contains tetrahydrocannabinol, but excludes any other controlled substance taken as prescribed. · Unstable clinically significant neurological (other than the disease being studied), psychiatric, cardiovascular, pulmonary, hepatic, renal, metabolic, gastrointestinal, urinary, immune, hematopoietic or endocrine disease, or other abnormality that may affect the subject's ability to participate or potentially confound the results of the study. - Have a current or past medical history of pulmonary arterial hypertension, cardiovascular disease or cerebrovascular disease, e.g. valvular heart disease, myocardial infarction or stroke.

[0130] Study drug and placebo doses should be administered TID, with each dose washed down with 120 mL of noncarbonated water. Doses may be administered without regard to food. Subjects on a ketogenic diet should maintain stable eating habits, and diet should not be altered during the study unless medically necessary and documented. Subjects receiving study drug via G-tube / PEG tube should not receive other medications or enteral nutrition concomitantly.

[0131] If possible, on the PK sampling day, subjects are encouraged to remain upright (sitting, standing or walking) for approximately 1 hour after administration of study drug.

[0132] The following drugs and preparations will be excluded from the screening visit (Visit 1) through the end of the follow-up visit (Visit 10): Fenfluramine Lorcaserin Medications that may worsen seizures in subjects with known or suspected Dravet syndrome, such as sodium blockers, phenytoin, fosphenytoin, carbamazepine, oxcarbazepine, eslicarbazepine, lamotrigine, lacosamide, rufinamide, vigabatrin, tiagabine, pregabalin, and gabapentin · Centrally acting appetite suppressants; monoamine oxidase inhibitors; centrally acting compounds with clinically significant serotonergic or antagonist properties, including serotonin and norepinephrine reuptake inhibitors, serotonin reuptake inhibitors; atomoxetine, vortioxetine, or other centrally acting noradrenergic agonists or drugs intended to promote weight loss

[0133] Subjects should be instructed not to consume alcohol or drugs, e.g., cannabis, during the study. Subjects should be instructed not to take any medication, including over-the-counter products, without first consulting the investigator.

[0134] Study drug or placebo will be administered as a liquid orally or via G-tube / PEG tube. Detailed instructions will be provided to subjects / caregivers in a separate document.

[0135] Each subject and / or caregiver will be instructed to administer the study drug TID orally or via G-tube / PEG tube, washing down with 120 mL of non-carbonated water each time. The three daily doses should be administered at least 6 hours apart. For example, a recommended dosing schedule would be a morning dose upon awakening no later than 8:00 AM, a midday dose at approximately 3:00 PM, and an evening dose at bedtime after 10:00 PM. Doses may be administered with or without food. Subjects receiving study drug via G-tube / PEG tube should not be receiving other medications or enteral feedings at the same time.

[0136] Efficacy evaluation Attack frequency Seizure frequency is quantified as an exploratory measure of the anti-seizure activity of the study drug versus placebo. When used as a continuous variable, seizure frequency is considered a sensitive measure of efficacy.

[0137] During the pretreatment phase, existing therapy is stable and baseline seizure frequency and seizure type are recorded in a 24-hourly diary for 28 days.

[0138] During the double-blind treatment period (Parts 1 and 2), seizure frequency and seizure type will be recorded in an electronic diary (e-diary) every 24 hours per day throughout the 75-day double-blind treatment period.

[0139] Throughout the study, either the primary caregiver or the subject, but not both, may enter seizure information into the electronic diary. The electronic diary is expected to be completed at the beginning of each day, including the previous day, although if necessary, seizure diary completion may be completed within 3 days after the onset of a seizure.

[0140] Clinical overall impression - improvement level The overall level of improvement from treatment will be assessed using the Clinical Global Impression-Improvement (CGI-I). This scale will be completed by the parent / caregiver and the investigator at the visits listed in the SoA. The CGI-I has a 7-point scale: "extremely improved" (1); "much improved" (2); "slightly improved" (3); "no change" (4); "slightly worse" (5); "much worse" (6); "extremely worse" (7). Whenever possible, the same assessors should complete each scale throughout the study.

[0141] Clinical Global Impression - Severity The Clinical Global Impression-Severity (CGI-S) will be assessed by the investigator at the visits listed in the SoA. The CGI-S involves the clinician asking the question: "Considering your overall clinical experience with this particular population, how sick is the patient at the moment?" This is rated on a 7-point scale: 1=normal, not ill at all, 2=borderline ill, 3=mildly ill, 4=moderately ill, 5=markedly ill, 6=severely ill, 7=one of the most seriously ill patients. Whenever possible, the same assessors should complete each scale throughout the study.

[0142] Quality of Life Questionnaire in Pediatric Epilepsy The 55-item Quality of Life Questionnaire in Pediatric Epilepsy (QOLCE-55) is a 55-item questionnaire that measures the impact of epilepsy on functioning and well-being in children; however, this scale has been used in young adults with DEE-related cognitive impairment who may not be able to complete a patient-reported quality of life scale. The QOLCE-55 includes four domains: cognitive functioning (22 items), emotional functioning (17 items), social functioning (7 items) and physical functioning (9 items). The questionnaire should be completed by the subject's parent / caregiver. Higher scores indicate better quality of life and / or greater well-being. Whenever possible, the same assessor should complete each scale throughout the study.

[0143] Although the present disclosure has been described with reference to the above examples, it is understood that modifications and variations are encompassed within the spirit and scope of the present disclosure. The various embodiments described above may be combined to provide further embodiments. All U.S. patents, U.S. patent application publications, U.S. patent applications, foreign patents, foreign patent applications, and non-patent publications mentioned herein and / or listed in the Application Data Sheet are hereby incorporated by reference in their entirety. Aspects of the embodiments may be modified, if necessary, to employ concepts from various patents, applications, and publications to provide further embodiments.

[0144] These and other changes may be made to the embodiments in light of the above detailed description. In general, in the following claims, the terms used should not be construed as limiting the claims to the specific embodiments disclosed in the specification and claims, but should be construed as including all possible embodiments along with the full scope of equivalents to which such claims are entitled. Thus, the claims are not limited by this disclosure.

Claims

1. 5-hydroxytryptamine (HT), comprising prescribing and / or administering to an individual in need thereof (R)-N-(2,2-difluoroethyl)-7-methyl-1,2,3,4,6,7-hexahydro-[1,4]diazepino[6,7,l-hi]indole-8-carboxamide (Compound 1), or a pharma- ceutical acceptable salt, hydrate, or solvate thereof. 2C A method for treating a receptor-associated disorder, wherein compound 1, or a pharma- ceutically acceptable salt, hydrate or solvate thereof, is administered by a dose titration scheme involving titrating compound 1, or a pharma- ceutically acceptable salt, hydrate or solvate thereof, until an optimized dose is administered.

2. 1. A method of treating epilepsy comprising prescribing and / or administering (R)-N-(2,2-difluoroethyl)-7-methyl-1,2,3,4,6,7-hexahydro-[1,4]diazepino[6,7,l-hi]indole-8-carboxamide (Compound 1), or a pharma- ceutically acceptable salt, hydrate or solvate thereof, to an individual in need of treatment, wherein Compound 1, or a pharma- ceutically acceptable salt, hydrate or solvate thereof, is administered by a dose titration scheme comprising titrating Compound 1, or a pharma- ceutically acceptable salt, hydrate or solvate thereof, until an optimized dose is administered.

3. 1. A method of reducing the severity of epileptic seizures comprising prescribing and / or administering (R)-N-(2,2-difluoroethyl)-7-methyl-1,2,3,4,6,7-hexahydro-[1,4]diazepino[6,7,l-hi]indole-8-carboxamide (Compound 1), or a pharma- ceutically acceptable salt, hydrate or solvate thereof, to an individual in need thereof, wherein Compound 1, or a pharma- ceutically acceptable salt, hydrate or solvate thereof, is administered by a dose titration scheme comprising titrating Compound 1, or a pharma- ceutically acceptable salt, hydrate or solvate thereof, until an optimized dose is administered.

4. 1. A method of treating a seizure disorder comprising prescribing and / or administering (R)-N-(2,2-difluoroethyl)-7-methyl-1,2,3,4,6,7-hexahydro-[1,4]diazepino[6,7,l-hi]indole-8-carboxamide (Compound 1), or a pharma- ceutically acceptable salt, hydrate or solvate thereof, to an individual in need of treatment, wherein Compound 1, or a pharma- ceutically acceptable salt, hydrate or solvate thereof, is administered by a dose titration scheme comprising titrating Compound 1, or a pharma- ceutically acceptable salt, hydrate or solvate thereof, until an optimized dose is administered.

5. 5. The method of claim 4, wherein the seizure disorder is selected from epilepsy, epilepsy with generalized tonic-clonic seizures, epilepsy with myoclonic absence, frontal lobe epilepsy, temporal lobe epilepsy, Landau-Kleffner syndrome, Rasmussen syndrome, Dravet syndrome, Douzet syndrome, CDKL5 disorder, infantile spasms (West syndrome), juvenile myoclonic epilepsy (JME), vaccine-associated encephalopathy, refractory childhood epilepsy (ICE), Lennox-Gastaut syndrome (LGS), Rett syndrome, Ohtahara syndrome, CDKL5 disorder, childhood absence epilepsy, essential tremor, acute repetitive seizures, benign rolandic epilepsy, status epilepticus, refractory status epilepticus, very refractory status epilepticus (SRSE), PCDH19 childhood epilepsy, drug withdrawal induced seizures, alcohol withdrawal induced seizures, increased seizure activity, and breakthrough seizures.

6. 1. A method of treating developmental epileptic encephalopathy (DEE) and other refractory epilepsies comprising prescribing and / or administering (R)-N-(2,2-difluoroethyl)-7-methyl-1,2,3,4,6,7-hexahydro-[1,4]diazepino[6,7,l-hi]indole-8-carboxamide (Compound 1), or a pharma- ceutically acceptable salt, hydrate or solvate thereof, to an individual in need of treatment, wherein Compound 1, or a pharma- ceutically acceptable salt, hydrate or solvate thereof, is administered via a dose titration scheme comprising titrating Compound 1, or a pharma- ceutically acceptable salt, hydrate or solvate thereof, until an optimized dose is administered.

7. 7. The method of claim 6, wherein the DEE is selected from Lennox-Gastaut syndrome, Dravet syndrome, Douzet syndrome (epilepsy with myoclonic atonic seizures (EM AS)), West syndrome (infantile spasms), Landau-Kleffner syndrome, and a predisposing disorder, such as CDKL5 encephalopathy or CHD2 encephalopathy.

8. 8. The method of claim 7, wherein the DEE is selected from Ohtahara syndrome, Lennox-Gastaut syndrome, Dravet syndrome, Douzet syndrome, West syndrome, Landau-Kleffner syndrome, tuberous sclerosis, CDKL5 encephalopathy, CHD2 encephalopathy, early myoclonic encephalopathy, infantile epilepsy with migratory focal seizures, epilepsy with myoclonic atonic seizures, and epileptic encephalopathy with continuous spike-and-wave pattern during sleep.

9. 1. A method of treating a seizure disorder comprising prescribing and / or administering a therapeutically effective amount of (R)-N-(2,2-difluoroethyl)-7-methyl-1,2,3,4,6,7-hexahydro-[1,4]diazepino[6,7,l-hi]indole-8-carboxamide (Compound 1), or a pharma- ceutically acceptable salt, hydrate or solvate thereof, to an individual in need of treatment, wherein the therapeutically effective amount of Compound 1, or a pharma- ceutically acceptable salt, hydrate or solvate thereof, is about 6 to 12 mg.

10. 10. The method of claim 9, wherein the seizure disorder is selected from epilepsy, epilepsy with generalized tonic-clonic seizures, epilepsy with myoclonic absence, frontal lobe epilepsy, temporal lobe epilepsy, Landau-Kleffner syndrome, Rasmussen syndrome, Dravet syndrome, Douse syndrome, CDKL5 disorder, infantile spasms (West syndrome), juvenile myoclonic epilepsy (JME), vaccine-associated encephalopathy, refractory childhood epilepsy (ICE), Lennox-Gastaut syndrome (LGS), Rett syndrome, Ohtahara syndrome, CDKL5 disorder, childhood absence epilepsy, essential tremor, acute repetitive seizures, benign rolandic epilepsy, status epilepticus, refractory status epilepticus, very refractory status epilepticus (SRSE), PCDH19 childhood epilepsy, drug withdrawal induced seizures, alcohol withdrawal induced seizures, increased seizure activity and breakthrough seizures.

11. 11. The method of any one of claims 1 to 10, wherein administration results in an improvement in the frequency of convulsive / motor seizures and other seizure types.

12. The administration comprises: the frequency of countable motor seizures observed; total number of seizures; frequency of nonconvulsive seizures; number of episodes of status epilepticus; Frequency of rescue medication use; and / or Number of days without countable motor seizures The method of claim 11 , wherein the method results in one or more improvements in:

13. 13. The method of any one of claims 1-12, wherein administration results in improvement in subject / caregiver and investigator Clinical Global Impression-Improvement (CGI-I), investigator Clinical Global Impression-Severity (CGI-S), and / or Pediatric Epilepsy 55-item Quality of Life Questionnaire (QOLCE-55).

14. 14. The method of claim 13, wherein administration results in at least a 1 point change from baseline in CGI-I and / or CGI-S.

15. 15. The method of any one of claims 1-14, wherein prior to administration, the individual has treatment-resistant countable motor seizures with an average of 4 or more observed / countable motor seizures per 4 weeks while receiving stable ASM treatment.

16. 16. The method of any one of claims 1 to 15, wherein the individual has DEE but does not have Dravet syndrome or Lennox-Gastaut syndrome.

17. Prior to administration, the individual: A history of unprovoked seizures before age 5 years; History of developmental delay; a history of generalized focal combined epilepsy type or multiple generalized epilepsy types; History of slow or disorganized EEG; and / or No history of idiopathic generalized epilepsy 17. The method of claim 16, comprising:

18. The method of any one of claims 1 to 15, wherein the individual has Dravet Syndrome.

19. Prior to administration, the individual: Onset of seizures in an otherwise healthy infant between 3 and 12 months of age; History of seizures, either generalized tonic-clonic or unilateral-clonic or bilateral-clonic; Normal early development; and / or History of developmental delay 20. The method of claim 18, comprising:

20. Prior to administration, the individual: The appearance of a different seizure type; Seizures triggered by warm temperatures and / or prolonged exposure to heat due to illness or vaccination, hot baths, high levels of activity and seizures associated with sudden temperature changes; and / or Seizures triggered by bright natural light and / or fluorescent lighting 20. The method of claim 18 or 19, comprising the steps of:

21. The method of any one of claims 18 to 20, wherein prior to administration, the individual has a genetic test result consistent with a diagnosis of Dravet Syndrome.

22. 16. The method of any one of claims 1 to 15, wherein the individual has Lennox-Gastaut syndrome.

23. Prior to administration, the individual: History of tonic or tonic / atonic seizures; Two or more types of generalized epilepsy, including but not limited to generalized tonic-clonic, tonic-atonic, atonic, tonic, myoclonic, or drop seizures; History of seizures before age 8 years; History of developmental delay; Previous electroencephalogram reporting diagnostic criteria for Lennox-Gastaut syndrome (abnormal interictal EEG background activity with interictal slow spike-and-wave pattern of 2.5 Hertz or less, or generalized interictal episodic fast activity); and / or Observation of an average of 4 or more drop attacks per 4 weeks while receiving stable ASM treatment 23. The method of claim 22, comprising:

24. 24. The method of any one of claims 1 to 23, wherein the dose titration scheme comprises prescribing and / or administering Compound 1, or a pharma- ceutically acceptable salt, hydrate or solvate thereof, at an initial dose equivalent to 6 mg of Compound 1 three times a day for about 5 days, and increasing the dose if the individual tolerates the initial dose and if the individual does not respond adequately.

25. 25. The method of claim 24, wherein the increased dose corresponds to 9 mg of Compound 1 three times a day.

26. 26. The method of claim 24 or 25, wherein the dose titration scheme further comprises administering Compound 1, or a pharma- ceutically acceptable salt, hydrate or solvate thereof, at increasing doses for about 5 days.

27. 27. The method of any one of claims 24 to 26, wherein the optimized dose is the initial dose if the individual does not tolerate the increased dose.

28. 27. The method of any one of claims 24 to 26, wherein the optimized dose is the increased dose if the individual tolerates the increased dose and if the individual shows an adequate response.

29. 29. The method of claim 27 or 28, further comprising administering to the individual an optimized dose of Compound 1, or a pharma- ceutically acceptable salt, hydrate or solvate thereof.

30. 27. The method of claim 26, wherein if the individual tolerates the increased dose, but the individual does not respond adequately, the method further comprises increasing the dose.

31. 31. The method of claim 30, wherein the further increased dose corresponds to about 12 mg of Compound 1 three times a day.

32. 32. The method of claim 30 or 31, wherein the optimized dose is an increased dose if the individual does not tolerate a further increased dose.

33. 32. The method of claim 30 or 31, wherein the optimized dose is the further increased dose if the individual tolerates the further increased dose and if the individual shows a sufficient response.

34. 34. The method of claim 32 or 33, further comprising administering to the individual an optimized dose of Compound 1, or a pharma- ceutically acceptable salt, hydrate or solvate thereof.

35. 35. The method of any one of claims 1 to 34, wherein the method provides improvement in at least one symptom selected from ataxia, gait disturbance, speech disorder, vocalization, cognitive impairment, abnormal motor activity, clinical seizures, subclinical seizures, hypotonia, hypertonia, drooling, mouthing behavior, aura, convulsions, repetitive movements, abnormal sensations, seizure frequency, and seizure severity.

36. 36. The method of any one of claims 1 to 35, further comprising tapering off Compound 1, or a pharma- ceutically acceptable salt, hydrate or solvate thereof.

37. The method of any one of claims 1 to 36, wherein compound 1, or a pharma- ceutically acceptable salt, hydrate or solvate thereof, is an HCl salt of compound 1.

Images