Treatment methods

Abstract

5-hydroxytryptamine (HT) 2C Provided herein are therapeutic methods that involve administering a receptor agonist to a patient in need thereof. An exemplary method is the administration of 5-hydroxytryptamine (HT) 2C 5-hydroxytryptamine (HT) receptor-related disorders in patients in need of treatment or prevention 2C and treating or preventing a receptor-associated disorder, the method comprising administering to a patient (R)—N-(2,2-difluoroethyl)-7-methyl-l,2,3,4,6,7-hexahydro-[l,4]diazepino[6,7,l-hi]indole-8-carboxamide (Compound 1) or a pharmaceutically acceptable salt thereof, wherein Compound 1 or a pharmaceutically acceptable salt thereof is administered twice daily.

Description

[Technical Field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS This application claims priority to U.S. Provisional Patent Application No. 63 / 429,755, filed December 2, 2022, and U.S. Provisional Patent Application No. 63 / 589,283, filed October 10, 2023, the disclosures of which are incorporated herein by reference in their entireties.

[0002] This application relates to 5-hydroxytryptamine (HT) 2C Therapeutic and prophylactic methods are provided which involve administering a receptor agonist to a patient in need thereof. [Background technology]

[0003] Developmental and epileptic encephalopathies (DEEs) are a heterogeneous group of rare neurodevelopmental disorders. They are often intractable and characterized by early seizures associated with EEG abnormalities, and developmental delay or regression that may worsen over time. These disorders are generally diagnosed in childhood and adolescence and vary in their etiology, seizure type, EEG patterns, cognitive impairment, and prognosis. The International League Against Epilepsy recently expanded this definition to include disorders that may cause developmental delay before the onset of epilepsy and used the term DEE to encompass this broader population.

[0004] 5-HT2 receptor agonists have been shown to be effective treatments for a variety of motor seizure and seizure disorders. Specifically, low-dose fenfluramine (Fintepla®), mixed 5-HT 2C , 5-HT 2B , and 5-HT 2A Receptor agonists have recently been approved for the treatment of Dravet syndrome and Lennox-Gastaut syndrome. However, Fintepla® is a 5-HT 2B It was given a boxed warning requiring cardiac monitoring due to the association between serotonergic drugs with receptor agonist activity and valvular heart disease.

[0005] 5-HT 2C The receptor agonist (R)-N-(2,2-difluoroethyl)-7-methyl-l,2,3,4,6,7-hexahydro-[l,4]diazepino[6,7,l-hi]indole-8-carboxamide (see U.S. Pat. No. 10,392,390) is in clinical trials for the treatment of DEE and related seizure disorders. U.S. Patent Application Publication No. 2023 / 0293546 reports PK data showing TID dosing regimens (including escalation and tapering) at doses of 3, 6, 12, 18, and 24 mg, including a steady-state half-life ranging from 4.81 to 6.50 hours. Summary of the Invention [Problem to be solved by the invention]

[0006] There is a significant unmet need for safe and effective treatments for DEE and other seizure disorders. The compounds and dosing methods described herein help meet this need and also provide related advantages. [Means for solving the problem]

[0007] 5-hydroxytryptamine (HT) 2C Provided is a method for treating or preventing a 5-hydroxytryptamine (HT)2C receptor-associated disorder in a patient in need thereof, the method comprising administering (R)-N-(2,2-difluoroethyl)-7-methyl-l,2,3,4,6,7-hexahydro-[l,4]diazepino[6,7,l-hi]indole-8-carboxamide (Compound 1) or a pharmaceutically acceptable salt thereof to the patient, wherein Compound 1 or a pharmaceutically acceptable salt thereof is administered twice daily.

[0008] Also provided is a method for treating or preventing epilepsy in a patient in need thereof, the method comprising administering (R)—N-(2,2-difluoroethyl)-7-methyl-1,2,3,4,6,7-hexahydro-[1,4]diazepino[6,7,1-hi]indole-8-carboxamide (Compound 1) or a pharmaceutically acceptable salt thereof to the patient, wherein Compound 1 or a pharmaceutically acceptable salt thereof is administered twice daily.

[0009] Also provided is a method for reducing the severity of epileptic seizures in a patient in need thereof, the method comprising administering (R)—N-(2,2-difluoroethyl)-7-methyl-1,2,3,4,6,7-hexahydro-[1,4]diazepino[6,7,1-hi]indole-8-carboxamide (Compound 1) or a pharmaceutically acceptable salt thereof to the patient, wherein Compound 1 or a pharmaceutically acceptable salt thereof is administered twice daily.

[0010] Also provided is a method for reducing the frequency of epileptic seizures in a patient in need thereof, the method comprising administering to the patient (R)—N-(2,2-difluoroethyl)-7-methyl-1,2,3,4,6,7-hexahydro-[1,4]diazepino[6,7,1-hi]indole-8-carboxamide (Compound 1) or a pharmaceutically acceptable salt thereof, wherein Compound 1 or a pharmaceutically acceptable salt thereof is administered twice daily.

[0011] Also provided is a method for treating or preventing a seizure disorder in a patient in need thereof, the method comprising administering (R)—N-(2,2-difluoroethyl)-7-methyl-l,2,3,4,6,7-hexahydro-[l,4]diazepino[6,7,l-hi]indole-8-carboxamide (Compound 1) or a pharmaceutically acceptable salt thereof to the patient, wherein Compound 1 or a pharmaceutically acceptable salt thereof is administered twice daily.

[0012] Also provided is a method for treating or preventing developmental and epileptic encephalopathy (DEE) in a patient in need thereof, the method comprising administering (R)—N-(2,2-difluoroethyl)-7-methyl-1,2,3,4,6,7-hexahydro-[1,4]diazepino[6,7,1-hi]diazepinoindole-8-carboxamide (Compound 1) or a pharmaceutically acceptable salt thereof to the patient, wherein Compound 1 or a pharmaceutically acceptable salt thereof is administered twice daily.

[0013] Also provided is a method for treating or preventing refractory epilepsy in a patient in need thereof, the method comprising administering (R)—N-(2,2-difluoroethyl)-7-methyl-1,2,3,4,6,7-hexahydro-[1,4]diazepino[6,7,1-hi]indole-8-carboxamide (Compound 1) or a pharmaceutically acceptable salt thereof to the patient, wherein Compound 1 or a pharmaceutically acceptable salt thereof is administered twice daily.

[0014] These and other aspects of the invention disclosed herein will be explained in more detail as the patent disclosure proceeds. [Brief explanation of the drawings]

[0015] [Figure 1] 1 is a graph showing the PK (pharmacokinetic) profile of Compound 1 in plasma and CSF (cerebrospinal fluid) following TID administration of 6 mg / dose of Compound 1. [Figure 2] 1 is a graph showing the PK profile of Compound 1 in plasma and CSF following TID administration of 12 mg / dose of Compound 1. [Figure 3] 1 is a series of plots of Compound 1 concentrations in CSF and plasma following TID administration of Compound 1 at 6 mg / dose (subjects 101-110) or 12 mg / dose (subjects 201-210). [Figure 4] 1 is a plot comparing the Cmax of Compound 1 in CSF and plasma for TID administration of Compound 1. [Figure 5]1 is a plot comparing the AUCtau of Compound 1 in CSF and plasma for TID administration of Compound 1. [Figure 6] 1 is a table showing qEEG results after TID administration of 6 mg / dose of Compound 1. [Figure 7] 1 is a table showing qEEG results after TID administration of 12 mg / dose of Compound 1. [Figure 8] 1 is a table showing the PK profile for Compound 1 when administered with quinidine. [Figure 9] 1 is a series of plots showing the mean concentration profiles of Compound 1 in plasma following BID and TID administration of Compound 1. [Figure 10] 1 is a series of plots showing the mean concentration profiles of Compound 1 in the CSF following BID and TID administration of Compound 1. [Figure 11] 1 is a plot comparing the Cmax of Compound 1 in CSF and plasma for BID administration of Compound 1. [Figure 12] 1 is a plot comparing the AUCtau of Compound 1 in CSF and plasma for BID administration of Compound 1. [Figure 13] 1 is a series of plots comparing mean and maximum plasma concentrations of Compound 1 for 12 mg TID and 18 mg BID administration of Compound 1. [Figure 14] 1 is a series of plots comparing the mean concentrations of Compound 1 in plasma and CSF with the Ki for 5-HT2C agonism. [Figure 15] 1 is a series of plots comparing mean and maximum CSF concentrations of Compound 1 for 12 mg TID and 18 mg BID doses of Compound 1. [Figure 16] 1 is a series of plots comparing the percentage of time above Ki during the dosing interval for BID and TID dosing regimens. [Figure 17] 1 is a graph comparing CSF / P Ctrough for Compound 1 administered at 12 mg TID and 18 mg BID. [Figure 18A]18A-18E: Table showing qEEG results for TID and BID administration of Compound 1. [Figure 18B] (As mentioned above.) [Figure 18C] (As mentioned above.) [Figure 18D] (As mentioned above.) [Figure 18E] (As mentioned above.) [Figure 19A] 19A-19E: Table showing qEEG results for TID and BID administration of Compound 1. [Figure 19B] (As mentioned above.) [Figure 19C] (As mentioned above.) [Figure 19D] (As mentioned above.) [Figure 19E] (As mentioned above.) [Figure 20A] 20A-20E: Table showing qEEG results for TID and BID administration of Compound 1. [Figure 20B] (As mentioned above.) [Figure 20C] (As mentioned above.) [Figure 20D] (As mentioned above.) [Figure 20E] (As mentioned above.) [Figure 21A] 21A-21E: Table showing qEEG results for TID and BID administration of Compound 1. [Figure 21B] (As mentioned above.) [Figure 21C] (As mentioned above.) [Figure 21D] (As mentioned above.) [Figure 21E] (As mentioned above.) DETAILED DESCRIPTION OF THE INVENTION

[0016] As used herein, the following words and phrases are generally intended to have the meanings set forth below, unless the context in which they are used indicates otherwise.

[0017] Compound 1: As used herein, "Compound 1" means (R)-N-(2,2-difluoroethyl)-7-methyl-l,2,3,4,6,7-hexahydro-[l,4]diazepino[6,7,l-hi]indole-8-carboxamide. [ka] Compound 1, or a pharmaceutically acceptable salt thereof, is a potent and selective inhibitor of 5-hydroxytryptamine (HT). 2C receptor agonist, 5-HT 2A and 5-HT 2B 5-HT 2C Compound 1 exhibits increased selectivity for the ligand binding site of the human 5-HT receptor. 2C It exhibits a binding affinity of 44 nM at the 5-HT receptor, in contrast to previously developed agonists such as Fintepla® (low-dose fenfluramine). 2A and 5-HT 2B It shows no activity against

[0018] Methods of using Compound 1 or a pharmaceutically acceptable salt thereof are disclosed in US Pat. No. 10,392,390, which is incorporated herein by reference in its entirety for all purposes.

[0019] Convulsive / Motor Seizures: As used herein, "convulsive / motor seizures" refers to tonic-clonic seizures, tonic seizures, tonic-atonic seizures leading to ataxia, focal motor seizures, epileptic spasms, myoclonic-atonic seizures leading to ataxia and seizures. Non-convulsive seizures include myoclonic, seizure, absence seizure, atypical absence seizure, or atonic seizure, and focal seizures without an observable motor component.

[0020] Seizure / Motor Seizure Free Day: As used herein, a "seizure / motor seizure free day" refers to a day for which diary data is available and no seizures / motor seizures were reported.

[0021] Astatic Seizure: As used herein, the term "astatic seizure" refers to a seizure involving the whole body, trunk, or head that may result in falling, injury, thrashing in a chair, or headbutting, or may result in falling or injury, depending on the subject's position at the time of the attack or hypoxic spell.

[0022] Agonist: As used herein, the term "agonist" refers to an antagonist of a 5-HT 2C A moiety that interacts with and activates a receptor, such as a serotonin receptor, initiating the physiological or pharmacological response characteristic of that receptor.

[0023] Administration: As used herein, "administering" means providing a compound or other therapy, medical treatment, or treatment such that the patient internalizes the compound.

[0024] Oral or Orally: As used herein, "oral" or "orally" refers to the administration of a compound or composition to a patient by a route or mode along the digestive tract. Examples of enteral administration routes include, but are not limited to, oral, such as when swallowing a solid (e.g., tablet) or liquid (e.g., syrup) form; sublingual (sublingual absorption); nasojejunal or gastrostomy tube (intragastric); intraduodenal administration; and rectal administration (e.g., suppository for release and absorption of a compound or composition in the lower intestinal tract).

[0025] Prescribe: As used herein, "prescribe" means to order, authorize, or recommend the use of a drug or other therapy, medical treatment, or treatment. In some embodiments, a healthcare professional may advise, recommend, or authorize the use of a compound, dosage regimen, or other treatment to a patient orally. In this case, the healthcare professional may or may not provide a prescription for the compound, dosage regimen, or treatment. Furthermore, the healthcare professional may or may not provide the recommended compound or treatment. For example, the healthcare professional may advise the patient where to obtain a compound without providing the compound. In some embodiments, the healthcare professional may provide the patient with a prescription for the compound, dosage regimen, or treatment. For example, the healthcare professional may give the patient a written or oral prescription. The prescription may be written on paper or electronic media such as a computer file, e.g., a handheld computing device. For example, the healthcare professional may convert a sheet of paper or electronic media with a prescription for the compound, dosage regimen, or treatment. Additionally, prescriptions may be telephoned (verbally), faxed (in writing), or submitted electronically via the internet to a pharmacy or dispensing pharmacy. In some embodiments, a sample of the compound or treatment may be given to the patient. As used herein, giving a sample of the compound constitutes an implicit prescription of the compound. Different health care systems around the world use different methods for prescribing and / or administering compounds or treatments, and these methods are encompassed by this disclosure.

[0026] A prescription may include identifying information, such as, for example, a patient's name and / or date of birth. Additionally, for example, a prescription may include medication name, dosage strength, dosage amount, frequency of administration, route of administration, number or amount to be dispensed, number of refills, physician name, physician signature, etc. Further, for example, a prescription may include a DEA number and / or state number.

[0027] A healthcare professional can include, for example, a doctor, nurse, nurse practitioner, or other related healthcare professional who can prescribe or administer a compound (drug) to treat a condition described herein. In addition, a healthcare professional can include anyone who can recommend, prescribe, administer, or prevent a patient from receiving a compound or drug, including, for example, an insurance provider.

[0028] Prevent, preventing, or prophylaxis: As used herein, the terms "prevent," "preventing," or "prevention," such as the prevention of a particular disorder or the onset or development of one or more symptoms associated with a particular disorder, do not necessarily refer to complete prevention of the disorder. For example, the terms "prevent," "preventing," and "prevention" refer to the administration of a therapy on a prophylactic or preventative basis to patients who may eventually exhibit at least one symptom of a disease or condition, but have not yet done so. Such individuals can be identified based on risk factors known to correlate with the subsequent development of the disease. Alternatively, prophylactic therapy can be administered without prior identification of risk factors, as a preventative measure. Delaying the onset of at least one symptom can also be considered prevention or prophylaxis.

[0029] Treat, Treating, or Treatment: As used herein, the terms "treat," "treating," or "treatment" refer to the administration of a therapy to a patient who already exhibits at least one symptom of a disease or condition or who has previously exhibited at least one symptom of a disease or condition. For example, "treating" can include alleviating, reducing, or ameliorating the symptoms of a disease or condition, preventing further symptoms, ameliorating the underlying metabolic cause of the symptoms, inhibiting the disease or condition, e.g., arresting the development of the disease or condition, relieving the disease or condition, causing regression of the disease or condition, alleviating a condition caused by the disease or condition, or halting the symptoms of the disease or condition. For example, the term "treating" with respect to a disorder refers to a reduction in the severity of one or more symptoms associated with that particular disorder. Thus, treating a disorder does not necessarily mean a reduction in the severity of all symptoms associated with the disorder, nor necessarily a complete reduction in the severity of one or more symptoms associated with the disorder.

[0030] Tolerance: As used herein, a patient is said to "tolerate" a dose of a compound if that dose does not result in an intolerable adverse event or an intolerable combination of adverse events. Those skilled in the art will understand that tolerance is a subjective measure, and what is tolerable to one individual may not be tolerable to another. For example, one individual may not be able to tolerate a headache, while a second individual may tolerate a headache but not vomit, while a third individual may tolerate either a headache alone or vomit alone, but the patient cannot tolerate the combination of headache and vomit, even if the severity of each is less than when experienced alone.

[0031] Intolerance: As used herein, "intolerance" means significant toxicity and / or tolerability problems that have led to a reduction in dosage or discontinuation of drug therapy. "Intolerance" may be interchanged herein with the term "untolerable."

[0032] Adverse Event: As used herein, an "adverse event" is a troublesome medical event associated with treatment with Compound 1 or a pharmaceutically acceptable salt thereof. 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, e.g., first-degree atrioventricular heart 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 an FEV1 of less than 80% of FVC. In one embodiment, the adverse event is macular edema.

[0033] Needing and in need of treatment: As used herein, "needing treatment" and "in need of it," when referring to treatment, are used interchangeably to mean the judgment made by a caregiver (e.g., a physician, nurse, nurse practitioner, etc.) that a patient needs or will benefit from treatment. This judgment is within the expertise of the caregiver, but is made based on a variety of factors, including knowledge that the patient is ill or will become ill as a result of a disease, condition, or disorder treatable by the compounds of the invention. Thus, the compounds of the invention can be used protectively or prophylactically, or the compounds of the invention can be used to alleviate, inhibit, or ameliorate a disease, condition, or disorder.

[0034] Patient: As used herein, "patient" means any human. In some embodiments, a human individual is referred to as a "subject," "participant," or "individual."

[0035] Dose: As used herein, "dose" means the amount of Compound 1 or a pharmaceutically acceptable salt thereof given to a patient at a particular time to treat or prevent a disease or disorder. As used herein, "administration amount" refers to the amount of Compound 1 or a pharmaceutically acceptable salt thereof in one or more doses.

[0036] Therapeutically effective amount: As used herein, a "therapeutically effective amount" of an agent, compound, drug, composition, or combination is an amount that is non-toxic and effective to produce some desired therapeutic effect upon administration to a subject or patient (e.g., a human subject or patient). The precise therapeutically effective amount for a subject may depend, for example, on the subject's size and health, the nature and extent of the condition, the therapeutic agent or combination of therapeutic agents selected for administration, and other variables known to those of skill 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 dosage.

[0037] Pharmaceutical composition: As used herein, "pharmaceutical composition" means a composition comprising at least one active component, such as Compound 1, including, but not limited to, salts of Compound 1, whereby the composition is suitable for investigation to obtain a particular efficacious result. Those of skill in the art will understand and appreciate the techniques appropriate for determining whether an active component has a desired efficacious result based on the needs of the artisan.

[0038] The compounds according to the present invention may optionally be present as pharmaceutically acceptable salts, including pharmaceutically acceptable acid addition salts prepared from pharmaceutically acceptable non-toxic acids, including inorganic and organic acids. Representative acids include acetic acid, benzenesulfonic acid, benzoic acid, camphorsulfonic acid, citric acid, ethenesulfonic 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, sulfidic acid, tartaric acid, oxalic acid, p-toluenesulfonic acid, and the like, including, but not limited to, the pharmaceutically acceptable salts listed by Berge et al., Journal of Pharmaceutical Sciences, 66:1-19 (1977), the entire contents of which are incorporated herein by reference.

[0039] Steady state: As used herein, "steady state" is reached when the amount of drug excreted in a given unit time equals the amount of drug that reaches the systemic circulation in that unit time. A pharmacokinetic characteristic of "steady state" means that the characteristic can be achieved once steady state is reached.

[0040] Acid addition salts can be obtained as the direct product of compound synthesis. Alternatively, the free base can be dissolved in a suitable solvent containing the appropriate acid, and the salt can be isolated by evaporating the solvent or otherwise separating the salt and solvent. The compounds of the present invention can form solvates with standard low molecular weight solvents using methods known to those skilled in the art.

[0041] It will be apparent to those skilled in the art that the dosage forms described herein may contain, as the active ingredient, either Compound 1 or a pharmaceutically acceptable salt thereof, or a solvate or hydrate thereof. Furthermore, various hydrates and solvates of Compound 1 and its salts will find use as intermediates in the preparation of pharmaceutical compositions. Exemplary procedures for making and identifying suitable hydrates and solvates, in addition to those described herein, are well known to those skilled in the art; see, for example, K. J. 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, pp. 202-209. Accordingly, one aspect of the present disclosure relates to methods of formulating and / or administering hydrates and solvates of Compound 1 and / or its pharmaceutically 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. Several commercial entities offer fast and efficient services for the routine identification of solvates and hydrates. Exemplary companies offering these services include Wilmington PharmaTech (Wilmington, DE), Avantium Technologies (Amsterdam), and Aptuit (Greenwich, CT).

[0042] When integers are used in the methods disclosed herein, the term "about" may be inserted before the integer.

[0043] Throughout this specification, unless the context requires otherwise, the word "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 any other step or element or integer or group of elements or integers.

[0044] Throughout this specification, unless otherwise stated or the context requires otherwise, references to a single step, composition of matter, group of steps, or group of compositions of matter should be interpreted as encompassing one and more (i.e., one or more) of that step, composition of matter, group of steps, or group of compositions of matter.

[0045] Each embodiment described herein applies mutatis mutandis to each and every other embodiment unless otherwise stated.

[0046] Those skilled in the art will understand that the invention described herein is susceptible to variations and modifications other than those specifically described. The invention is to be understood to include all such variations and modifications. The invention also includes all steps, features, compositions, and compounds referred to or indicated herein, individually or collectively, and includes any and all combinations of any two or more of said steps or features, unless otherwise specified.

[0047] The present invention is not to be limited in scope by the specific embodiments described herein, which are intended for purposes of illustration only. Functionally equivalent products, compositions, and methods are clearly within the scope of the invention as described herein.

[0048] It is understood that certain features of the invention that are described in the context of separate embodiments for clarity may also be provided in combination in a single embodiment. Conversely, various features of the invention that are described in the context of a single embodiment for brevity may also be provided separately or in any suitable subcombination. For example, a method describing formulating and / or administering Compound 1 or a pharmaceutically acceptable salt thereof can be separated into two methods: one method describing formulating Compound 1 or a pharmaceutically acceptable salt thereof and another method describing administering Compound 1 or a pharmaceutically acceptable salt thereof. In addition, for example, separate methods of the invention that describe formulating Compound 1 or a pharmaceutically acceptable salt thereof and administering Compound 1 or a pharmaceutically acceptable salt thereof can be combined into a single method describing formulating and / or administering Compound 1 or a pharmaceutically acceptable salt thereof.

[0049] method 5-hydroxytryptamine (HT) 2C Provided are methods for treating or preventing a 5-hydroxytryptamine (HT) receptor-associated disorder in a patient in need thereof, comprising administering (R)—N-(2,2-difluoroethyl)-7-methyl-1,2,3,4,6,7-hexahydro-[1,4]diazepino[6,7,1-hi]indole-8-carboxamide (Compound 1) or a pharmaceutically acceptable salt thereof to the patient. In some embodiments, Compound 1 or a pharmaceutically acceptable salt thereof is administered twice daily.

[0050] Also provided is a method for treating or preventing epilepsy in a patient in need thereof, comprising administering to the patient (R)—N-(2,2-difluoroethyl)-7-methyl-l,2,3,4,6,7-hexahydro-[l,4]diazepino[6,7,l-hi]indole-8-carboxamide (Compound 1) or a pharmaceutically acceptable salt thereof, wherein Compound 1 or a pharmaceutically acceptable salt thereof is administered twice daily. In some embodiments, Compound 1 or a pharmaceutically acceptable salt thereof is administered twice daily.

[0051] In some embodiments, the epilepsy is focal epilepsy, generalized epilepsy, or a combination of generalized and focal epilepsy, hi some embodiments, the epilepsy has one or more of a structural etiology, a genetic etiology, an infectious etiology, a metabolic etiology, and an immune etiology.

[0052] Also provided is a method for reducing the severity of epileptic seizures in a patient in need thereof, comprising administering to the patient (R)—N-(2,2-difluoroethyl)-7-methyl-1,2,3,4,6,7-hexahydro-[1,4]diazepino[6,7,1-hi]indole-8-carboxamide (Compound 1) or a pharmaceutically acceptable salt thereof, wherein Compound 1 or a pharmaceutically acceptable salt thereof is administered twice daily. In some embodiments, Compound 1 or a pharmaceutically acceptable salt thereof is administered twice daily.

[0053] Also provided is a method for reducing the frequency of epileptic seizures in a patient in need thereof, comprising administering to the patient (R)—N-(2,2-difluoroethyl)-7-methyl-1,2,3,4,6,7-hexahydro-[1,4]diazepino[6,7,1-hi]indole-8-carboxamide (Compound 1) or a pharmaceutically acceptable salt thereof, wherein Compound 1 or a pharmaceutically acceptable salt thereof is administered twice daily. In some embodiments, Compound 1 or a pharmaceutically acceptable salt thereof is administered twice daily.

[0054] In some embodiments, the epileptic seizures are focal or generalized seizures. In some embodiments, the epileptic seizures have one or more of a structural etiology, a genetic etiology, an infectious etiology, a metabolic etiology, and an immune etiology.

[0055] Also provided is a method for treating or preventing a seizure disorder in a patient in need thereof, comprising administering to the patient (R)—N-(2,2-difluoroethyl)-7-methyl-l,2,3,4,6,7-hexahydro-[l,4]diazepino[6,7,l-hi]indole-8-carboxamide (Compound 1) or a pharmaceutically acceptable salt thereof, wherein Compound 1 or a pharmaceutically acceptable salt thereof is administered twice daily. In some embodiments, Compound 1 or a pharmaceutically acceptable salt thereof is administered twice daily.

[0056] In some embodiments, the seizure disorder is a focal seizure disorder, a generalized seizure disorder, or a combined generalized and focal seizure disorder, hi some embodiments, the seizure disorder has one or more of a structural etiology, a genetic etiology, an infectious etiology, a metabolic etiology, and an immune etiology.

[0057] In some embodiments, the seizure disorder is epilepsy, epilepsy with generalized tonic-clonic seizures, epilepsy with myoclonic atonic seizures, frontal lobe epilepsy, temporal lobe epilepsy, Landau-Kleffner syndrome, Rasmussen syndrome, Dravet syndrome, Douze syndrome (epilepsy with myoclonic atonic seizures (EM)), or other conditions. The condition is selected from: AS), CDKL5 deficiency (CDKL5 encephalopathy, or CDD), infantile spasms (West syndrome), juvenile myoclonic epilepsy (JME), vaccine-associated encephalopathy, refractory childhood epilepsy (ICE), Lennox-Gastaut syndrome (LGS), Rett syndrome, Ohtahara syndrome (early infantile DEE, or EIDEE), 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.

[0058] Also provided is a method for treating or preventing developmental and epileptic encephalopathy (DEE) in a patient in need thereof, comprising administering to the patient (R)—N-(2,2-difluoroethyl)-7-methyl-1,2,3,4,6,7-hexahydro-[1,4]diazepino[6,7,1-hi]diazepinoindole-8-carboxamide (Compound 1) or a pharmaceutically acceptable salt thereof, wherein Compound 1 or a pharmaceutically acceptable salt thereof is administered twice daily. In some embodiments, Compound 1 or a pharmaceutically acceptable salt thereof is administered twice daily.

[0059] In some embodiments, the DEE is selected from epilepsy syndromes involving developmental disorders associated with an underlying etiology (e.g., genetic mutations), frequent epileptiform activity, or both. In some embodiments, the DEE is epileptic. Epileptic encephalopathy (EE) may involve frequent epileptiform activity that contributes to a degree of cognitive and behavioral impairment that is more severe than would be expected based on the underlying etiology alone. In some embodiments, the DEE is developmental. Developmental encephalopathy (DE) may involve developmental consequences (e.g., developmental delay or regression) that result directly from the underlying etiology and may not involve frequent epileptic activity. In some embodiments, the DEE is both epileptic and developmental, where both developmental and epileptiform factors contribute to the encephalopathy.

[0060] In some embodiments, the DEE is early infantile DEE (EIDEE, or Ohtahara syndrome). In some embodiments, EIDEE is an encephalopathy associated with mutations in one or more of ARHGEF9, ARX, BRAT1, CASK, CDKL5, CYFIP2, DMXL2, GNAO1, KCNQ2, KCNT1, NECAP1, NSF, PCDH19, PIGA, PLCB1, PNKP, SCN2A, SCN8A, SIK1, SLC13A5, SLC25A22, SPTAN1, ST3GAL3, STXBP1, TBC1D24, WWOX, GLDC, AMT, GCSH, ALDH7A1, and PNPO. In some embodiments, EIDEE is an encephalopathy associated with nonketotic hyperglycinemia (NKH; e.g., associated with mutations in one or more of GLDC, AMT, GCSH), cortical dysplasia, and mitochondrial disorders.

[0061] In some embodiments, the EIDEE is KCNQ2 encephalopathy, SCN2A encephalopathy, SCN8A encephalopathy, or pyridoxine-dependent epilepsy (PDE).

[0062] In some embodiments, the DEE is infantile epileptic spasms syndrome (IESS), which includes infants who exhibit epileptic spasms and do not meet the criteria for West syndrome. In some embodiments, the IESS is selected from the group consisting of AARS, ACADS ALG1, ALG13, ALPL, AMT, ARX, ATP2A2, ATP7A, CACNA1A, CACNA1C, CDKL5, CD99L2, CLCN4, CLCN6, CYFIP1, CYFIP2, DCX, DNM1, EEF1A2, FLNA, FOXG1, GABRE, GCSH, GLDC, GNAO1, GNB1, GPT2, GRIN2A, GRIN2B, HCN1, HEXA, IRF2BPL, KCNB1, KCNJ11, KCNQ2, KCNT1, KIF1A, KMT2D, LIS1 (also referred to as PAFAH1B1), MAGI2, MECP2, MED12, MEF2C, MMACHC Encephalopathy associated with mutations in one or more of MT-ND1, MYO18A, NEDD4L, NF1, NPRL3, NTRK2, PNKP, SCN2A, SCN8A, SCN10A, SETBP1, SETD5, SLC25A22, SLC35A2, SMARCA2, SPTAN1, STXBP1, TAF1, TBL1XR1, TCF4, TCF20, TSC1, TSC2, TUBA1A, UFC1, and WDR45. In some embodiments, the EISS is an encephalopathy associated with a 17p13.3 microdeletion, an Xp22.13 microdeletion, a 20q13.33 microdeletion, a 9q33.3-34.11 microdeletion, a 9p24.3-22.3 microdeletion, a 5p12-11 microduplication, a 3p25.3 microdeletion, a 1p36.33 microdeletion, an Xp22.11-21.3 microduplication, or a 15q11.2 microduplication.

[0063] In some embodiments, the IESS is encephalopathy associated with a chromosomal syndrome (e.g., 1p36 deletion syndrome, tetrasomy 12p, dup15q syndrome, trisomy 21 (Down syndrome)), NKH, organic acidemia, hypoxic-ischemic encephalopathy (HIE), neurofibromatosis, intracranial infection, brain injury secondary to neonatal hypoglycemia, intracranial hemorrhage (ICH), encephalomalacia, glioma, focal brain lesion, pachygyria-lissencephaly, focal cortical dysplasia, heterotopia, polymicrogyria, schizencephaly, agenesis of the corpus callosum, intracranial hemangioma, Menkes disease, neurodegeneration with brain iron accumulation, methylmalonic acidemia (MMA), short-chain acyl-CoA dehydrogenase (SCAD) deficiency, lysosomal storage disease, mitochondrial disorders, intrauterine infection, GLUT-1 deficiency syndrome (cerebrospinal fluid glycemia), leukoencephalopathy, and hypophosphatasia.

[0064] In some embodiments, the IESS is tuberous sclerosis complex (TSC; associated with mutations in TSC1 or TSC2), ARX encephalopathy, CDKL5 encephalopathy (CDK5L deficiency), or STXBP1 encephalopathy.

[0065] In some embodiments, the DEE is selected from Lennox-Gastaut syndrome, Dravet syndrome, Douze syndrome (EMAS), West syndrome (infantile spasms), Landau-Kleffner syndrome, and a genetic disorder, such as CDKL5 encephalopathy (CDK5L deficiency) or CHD2 encephalopathy.

[0066] In some embodiments, the DEE is selected from Ohtahara syndrome (EIDEE), Lennox-Gastaut syndrome, Dravet syndrome, Does syndrome (EM AS), West syndrome (infantile spasms), Landau-Kleffner syndrome, tuberous sclerosis complex, CDKL5 encephalopathy (CDKL5 deficiency), dup15q syndrome, SCN2A-associated epilepsy, SCN8A-associated epilepsy, KCNQ2-associated epilepsy, KCNQ3-associated epilepsy, Angelman syndrome, KCNT1-associated epilepsy, SynGAP1-associated epilepsy, Rett syndrome, PCDH19 epilepsy, ring chromosome 14 syndrome, ring chromosome 20 syndrome, CHD2 encephalopathy, early myoclonic encephalopathy, infantile epilepsy with transitional focal seizures, and epileptic encephalopathy with persistent spike waves.

[0067]

[0009] Provided is a method for treating or preventing intractable epilepsy in a patient in need thereof, comprising administering to the patient (R)-N-(2,2-difluoroethyl)-7-methyl-l,2,3,4,6,7-hexahydro-[l,4]diazepino[6,7,l-hi]indole-8-carboxamide (Compound 1) or a pharmaceutically acceptable salt thereof. In some embodiments, Compound 1 or a pharmaceutically acceptable salt thereof is administered twice daily.

[0068] In some embodiments, the patient has a co-morbid condition, such as intellectual disability, autism spectrum disorder, and / or behavioral problems.

[0069] In some embodiments, the method provides improvement in at least one symptom selected from ataxia, gait disturbance, speech disturbance, phonation, cognitive impairment, abnormal motor activity, clinical seizures, subclinical seizures, hypotonia, hypertonia, salivation, oral behavior, aura, convulsions, repetitive movements, abnormal sensations, seizure frequency, and seizure severity.

[0070] In some embodiments, administration results in an improvement in the frequency of convulsive / motor seizures and other seizure types. In some embodiments, administration results in an improvement in one or more of the following: the frequency of countable motor seizures observed, total number of seizures, frequency of non-convulsive seizures, Number of episodes of status epilepticus, Frequency of rescue medication use, and / or Number of days without countable motor seizures.

[0071] In some embodiments, administration results in improvement in subject / caregiver and investigator's Clinical Global Impression-Improvement (CGI-I), investigator's Clinical Global Impression-Severity (CGI-S), and / or the 55-item Quality of Life for Children 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.

[0072] In some embodiments, prior to administration, the patient had treatment-resistant countable motor seizures with an average of ≥ 4 observed / countable motor seizures per 4 weeks while on stable ASM treatment.

[0073] In some embodiments, the patient has DEE but does not have Dravet syndrome or Lennox-Gastaut syndrome.

[0074] In some embodiments, the patient has DEE but does not have Dravet syndrome or Lennox-Gastaut syndrome, A history of unprovoked seizures before age 5 years history of developmental delay, a history of focal and generalized seizures or multiple generalized seizure types; History of delayed or disorganized EEG, and / or No history of idiopathic generalized seizures had the following characteristics:

[0075] In some embodiments, the patient has Dravet syndrome.

[0076] In some embodiments, where the patient has Dravet syndrome, prior to administration, the patient: Onset of seizures in healthy infants between 3 and 12 months of age, a history of seizures that were either generalized tonic-clonic, unilateral-clonic, or bilateral-clonic; Normal early development, and / or History of developmental delay had the following characteristics:

[0077] In some embodiments, where the patient has Dravet syndrome, prior to administration, the patient: The appearance of a different seizure type prolonged exposure to heat-induced seizures and / or seizures related to heat from illness or vaccines, hot baths, high levels of activity, and sudden temperature changes; and / or Seizures were induced by strong natural and / or fluorescent light.

[0078] In some embodiments in which the patient has Dravet syndrome, prior to administration, the patient had genetic test results consistent with a diagnosis of Dravet syndrome.

[0079] In some embodiments, the patient has Lennox-Gastaut syndrome.

[0080] In some embodiments, the patient has Lennox-Gastaut syndrome prior to administration, and the patient: history of tonic or tonic / atonic seizures, more than one type of generalized seizure, including but not limited to generalized tonic-clonic, tonic-clonic, atonic, tonic, myoclonic, or astatic seizures; history of seizures before age 8, history of developmental delay, A previous EEG reporting diagnostic criteria for Lennox-Gastaut syndrome (abnormal interictal EEG background activity with an interictal slow spike pattern of ≤2.5 Hz or interictal generalized paroxysmal rapid activity), and / or A mean of ≥4 astatic seizures observed every 4 weeks during stable ASM treatment had the following characteristics:

[0081] In some embodiments, the total daily dosage of Compound 1 or a pharmaceutically acceptable salt thereof is equivalent to about 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 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 of Compound 1. In some embodiments, the total daily dosage of Compound 1 or a pharmaceutically acceptable salt thereof is equivalent to about 6, 9, 12, 15, 18, 21, 24, 27, 30, 33, 36, 39, 42, 45, 48, 51, 54, 57, 60, 63, 66, 69, or 72 mg of Compound 1. In some embodiments, the total daily dosage of Compound 1 or a pharmaceutically acceptable salt thereof is equivalent to about 6 mg of Compound 1. In some embodiments, the total daily dosage of Compound 1 or a pharmaceutically acceptable salt thereof is equivalent to about 9 mg of Compound 1. In some embodiments, the total daily dosage of Compound 1 or a pharmaceutically acceptable salt thereof is equivalent to about 12 mg of Compound 1. In some embodiments, the total daily dosage of Compound 1 or a pharmaceutically acceptable salt thereof is equivalent to about 18 mg of Compound 1. In some embodiments, the total daily dosage of Compound 1 or a pharmaceutically acceptable salt thereof is equivalent to about 24 mg of Compound 1. In some embodiments, the total daily dosage of Compound 1, or a pharmaceutically acceptable salt thereof, is equivalent to about 30 mg of Compound 1. In some embodiments, the total daily dosage of Compound 1, or a pharmaceutically acceptable salt thereof, is equivalent to about 36 mg of Compound 1. In some embodiments, the total daily dosage of Compound 1, or a pharmaceutically acceptable salt thereof, is equivalent to about 54 mg of Compound 1. In some embodiments, the total daily dosage of Compound 1, or a pharmaceutically acceptable salt thereof, is equivalent to about 72 mg of Compound 1.

[0082] In some embodiments, Compound 1 or a pharmaceutically acceptable salt thereof is administered three times daily at a dose equivalent to about 3 mg / dose of Compound 1. In some embodiments, Compound 1 or a pharmaceutically acceptable salt thereof is administered three times daily at a dose equivalent to about 6 mg / dose of Compound 1. In some embodiments, Compound 1 or a pharmaceutically acceptable salt thereof is administered three times daily at a dose equivalent to about 9 mg / dose of Compound 1. In some embodiments, Compound 1 or a pharmaceutically acceptable salt thereof is administered three times daily at a dose equivalent to about 12 mg / dose of Compound 1. In some embodiments, Compound 1 or a pharmaceutically acceptable salt thereof is administered three times daily at a dose equivalent to about 18 mg / dose of Compound 1. In some embodiments, Compound 1 or a pharmaceutically acceptable salt thereof is administered three times daily at a dose equivalent to about 24 mg / dose of Compound 1.

[0083] In some embodiments, Compound 1 or a pharmaceutically acceptable salt thereof is administered twice daily at a dose equivalent to about 3 mg / dose of Compound 1. In some embodiments, Compound 1 or a pharmaceutically acceptable salt thereof is administered twice daily at a dose equivalent to about 6 mg / dose of Compound 1. In some embodiments, Compound 1 or a pharmaceutically acceptable salt thereof is administered twice daily at a dose equivalent to about 9 mg / dose of Compound 1. In some embodiments, Compound 1 or a pharmaceutically acceptable salt thereof is administered twice daily at a dose equivalent to about 12 mg / dose of Compound 1. In some embodiments, Compound 1 or a pharmaceutically acceptable salt thereof is administered twice daily at a dose equivalent to about 15 mg / dose of Compound 1. In some embodiments, Compound 1 or a pharmaceutically acceptable salt thereof is administered twice daily at a dose equivalent to about 18 mg / dose of Compound 1. In some embodiments, Compound 1 or a pharmaceutically acceptable salt thereof is administered twice daily at a dosage equivalent to about 24 mg / dose of Compound 1.

[0084] In some embodiments, administration of Compound 1 described herein reduces the geometric mean steady-state C in CSF. trough , geometric mean steady state C in plasma troughIn some embodiments, administration may achieve one or more pharmacokinetic characteristics including a geometric mean steady-state C of Compound 1 in the CSF of at least about 1.4. trough Geometric mean steady-state C of compound 1 in plasma versus trough Ratio of CSF / PC trough In some embodiments, administration results in about 1.4 to about 3, about 1.4 to about 2.5, about 1.4 to about 2, about 1.5 to about 3, about 1.5 to about 2.5, or about 1.5 to about 2 CSF / PC. trough In some embodiments, administration results in a CSF / PC of about 1.5 to 1.7, or about 1.9. trough results.

[0085] In some embodiments, administration provides a geometric mean steady-state C of Compound 1 in CSF of about 3 ng / mL to about 15 ng / mL, e.g., about 3 ng / mL to about 12 ng / mL, about 3 ng / mL to about 10 ng / mL, about 4 ng / mL to about 15 ng / mL, about 4 ng / mL to about 12 ng / mL, about 4 ng / mL to about 10 ng / mL, about 5 ng / mL to about 15 ng / mL, about 5 ng / mL to about 12 ng / mL, or about 5 ng / mL to about 10 ng / mL. trough In some embodiments, administration results in a geometric mean steady-state C of Compound 1 in the CSF of about 6.5 ng / mL, about 7 ng / mL, or about 7.7 ng / mL. trough results.

[0086] In some embodiments, administration achieves a geometric mean steady-state C of Compound 1 in plasma of about 2 ng / mL to about 12 ng / mL, e.g., about 2 ng / mL to about 10 ng / mL, about 2 ng / mL to about 9 ng / mL, about 3 ng / mL to about 12 ng / mL, about 3 ng / mL to about 10 ng / mL, about 3 ng / mL to about 9 ng / mL, about 4 ng / mL to about 12 ng / mL, about 4 ng / mL to about 10 ng / mL, or about 4 ng / mL to about 9 ng / mL. troughIn some embodiments, administration results in a geometric mean steady-state C of Compound 1 in plasma of about 4.0 ng / mL, about 4.4 ng / mL, about 4.9 ng / mL, about 5.2 ng / mL, about 5.6 ng / mL, about 6.5 ng / mL, about 7.1 ng / mL, or about 7.4 ng / mL. trough results.

[0087] In some embodiments, Compound 1 or a pharmaceutically acceptable salt thereof is administered via a titration scheme involving increasing amounts of Compound 1 or a pharmaceutically acceptable salt thereof until an optimized dosage is administered.

[0088] In some embodiments, the total daily dose of Compound 1 or a pharmaceutically acceptable salt thereof is titrated to a dose equivalent to about 9 mg of Compound 1. In some embodiments, the total daily dose of Compound 1 or a pharmaceutically acceptable salt thereof is titrated to a dose equivalent to about 18 mg of Compound 1. In some embodiments, the total daily dose of Compound 1 or a pharmaceutically acceptable salt thereof is titrated to a dose equivalent to about 24 mg of Compound 1. In some embodiments, the total daily dose of Compound 1 or a pharmaceutically acceptable salt thereof is titrated to a dose equivalent to about 30 mg of Compound 1. In some embodiments, the total daily dose of Compound 1 or a pharmaceutically acceptable salt thereof is titrated to a dose equivalent to about 36 mg of Compound 1. In some embodiments, the total daily dose of Compound 1 or a pharmaceutically acceptable salt thereof is titrated to a dose equivalent to about 54 mg of Compound 1. In some embodiments, the total daily dose of Compound 1, or a pharmaceutically acceptable salt thereof, is titrated to a dose equivalent to about 72 mg of Compound 1.

[0089] In some embodiments, the total daily dosage of Compound 1, or a pharmaceutically acceptable salt thereof, is tapered to a dose equivalent to 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, 17, 16, 15, 14, 13, 12, 11, 10, 9, 8, 7, 6, 5, 4, 3, 2, or 1 mg of Compound 1. In some embodiments, the total daily dosage of Compound 1, or a pharmaceutically acceptable salt thereof, is tapered to a dose equivalent to about 54 mg of Compound 1. In some embodiments, the total daily dose of Compound 1 or a pharmaceutically acceptable salt thereof is tapered to a dose equivalent to about 36 mg of Compound 1. In some embodiments, the total daily dose of Compound 1 or a pharmaceutically acceptable salt thereof is tapered to a dose equivalent to about 30 mg of Compound 1. In some embodiments, the total daily dose of Compound 1 or a pharmaceutically acceptable salt thereof is tapered to a dose equivalent to about 24 mg of Compound 1. In some embodiments, the total daily dose of Compound 1 or a pharmaceutically acceptable salt thereof is tapered to a dose equivalent to about 18 mg of Compound 1. In some embodiments, the total daily dose of Compound 1 or a pharmaceutically acceptable salt thereof is tapered to a dose equivalent to about 12 mg of Compound 1. In some embodiments, the total daily dose of Compound 1 or a pharmaceutically acceptable salt thereof is tapered to a dose equivalent to about 9 mg of Compound 1. In some embodiments, the total daily dose of Compound 1, or a pharmaceutically acceptable salt thereof, is tapered to a dose equivalent to about 6 mg of Compound 1. In some embodiments, the total daily dose of Compound 1, or a pharmaceutically acceptable salt thereof, is tapered to a dose equivalent to about 3 mg of Compound 1.

[0090] In some embodiments, the dosage increase of Compound 1 or a pharmaceutically acceptable salt thereof is in increments equivalent to about 1.5 mg / dose of Compound 1 about every 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 days until the optimized dosage is administered. In some embodiments, the dosage increase of Compound 1 or a pharmaceutically acceptable salt thereof is in increments equivalent to about 3 mg / dose of Compound 1 about every 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 days until the optimized dosage is administered. In some embodiments, the optimized dosage is equivalent to about 3 mg / dose of Compound 1. In some embodiments, the optimized dosage is equivalent to about 6 mg / dose of Compound 1. In some embodiments, the optimized dosage is equivalent to about 9 mg / dose of Compound 1. In some embodiments, the optimized dosage is equivalent to about 12 mg / dose of Compound 1. In some embodiments, the optimized dosage is equivalent to about 15 mg / dose of Compound 1. In some embodiments, the optimized dosage is equivalent to about 18 mg / dose of Compound 1.

[0091] In some embodiments, a titration scheme involves prescribing and / or administering Compound 1 or a pharmaceutically acceptable salt thereof at an initial dosage (also referred to as a starting dosage) equivalent to about 1 mg / dose, about 2 mg / dose, about 3 mg / dose, about 4 mg / dose, about 5 mg / dose, or about 6 mg / dose of Compound 1, provided that the initial dosage is tolerated by the patient. In some embodiments, a titration scheme involves prescribing and / or administering Compound 1 or a pharmaceutically acceptable salt thereof at an initial dosage equivalent to about 1 mg / dose, about 2 mg / dose, about 3 mg / dose, about 4 mg / dose, about 5 mg / dose, or about 6 mg / dose of Compound 1, provided that the initial dosage is tolerated by the patient and the patient does not have an adequate response. In some embodiments, the titration scheme involves prescribing and / or administering Compound 1 or a pharmaceutically acceptable salt thereof at an initial dosage equivalent to about 1 mg / dose, about 2 mg / dose, about 3 mg / dose, about 4 mg / dose, about 5 mg / dose, or about 6 mg / dose of Compound 1, two or three times daily for about 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 days, provided that the dosage is increased by the patient if the initial dosage is tolerated. In some embodiments, the titration scheme comprises prescribing and / or administering Compound 1 or a pharmaceutically acceptable salt thereof at an initial dosage equivalent to about 1 mg / dose, about 2 mg / dose, about 3 mg / dose, about 4 mg / dose, about 5 mg / dose, or about 6 mg / dose of Compound 1 twice or three times daily for about 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 days, provided that the dosage is increased if the patient tolerates the initial dosage and the patient does not have an adequate response. In some embodiments, the titration scheme comprises prescribing and / or administering Compound 1 or a pharmaceutically acceptable salt thereof at an initial dosage equivalent to about 6 mg / dose of Compound 1 for about 2 days, provided that the patient tolerates the initial dosage and the patient does not have an adequate response.

[0092] In some embodiments, the increased dose is optimized for further response. In some embodiments, the increased dose is equivalent to about 3 mg / dose of Compound 1. In some embodiments, the increased dose is equivalent to about 6 mg / dose of Compound 1. In some embodiments, the increased dose is equivalent to about 9 mg / dose of Compound 1. In some embodiments, the increased dose is equivalent to about 12 mg / dose of Compound 1. In some embodiments, the increased dose is equivalent to about 15 mg / dose of Compound 1. In some embodiments, the increased dose is equivalent to about 18 mg / dose of Compound 1.

[0093] In some embodiments, the titration scheme further comprises administering Compound 1 or a pharmaceutically acceptable salt thereof at increasing doses for about 2, 3, 4, 5, 6, 7, 8, 9, or 10 days. In some embodiments, the titration scheme further comprises administering Compound 1 or a pharmaceutically acceptable salt thereof at increasing doses for about 2 days. In some embodiments, the titration scheme further comprises administering Compound 1 or a pharmaceutically acceptable salt thereof at increasing doses for about 5 days.

[0094] In some embodiments, if the patient cannot tolerate an increased dose, the optimized dose is the initial dose.

[0095] In some embodiments, the optimized dose is the increased dose if the patient tolerates the increased dose, hi some embodiments, the optimized dose is the increased dose if the patient tolerates the increased dose and if the patient has an adequate response.

[0096] In some embodiments, the titration scheme includes further increasing the dosage, provided that the individual tolerates the increased dosage. In some embodiments, the titration scheme includes further increasing the dosage, provided that the individual tolerates the increased dosage and the individual does not have an adequate response. In some embodiments, the further increased dosage is optimized for a further response. In some embodiments, the further increased dosage is equivalent to about 12 mg / dose of Compound 1. In some embodiments, the further increased dosage is equivalent to about 15 mg / dose of Compound 1. In some embodiments, the further increased dosage is equivalent to about 18 mg / dose of Compound 1.

[0097] In some embodiments, the titration scheme further comprises administering Compound 1 or a pharmaceutically acceptable salt thereof at an increased dose for about 2, 3, 4, 5, 6, 7, 8, 9, or 10 days. In some embodiments, the titration scheme further comprises administering Compound 1 or a pharmaceutically acceptable salt thereof at an increased dose for about 2 days. In some embodiments, the titration scheme further comprises administering Compound 1 or a pharmaceutically acceptable salt thereof at an increased dose for about 5 days.

[0098] In some embodiments, the optimized dose is an increased dose if the patient cannot tolerate a further increased dose.

[0099] In some embodiments, the optimized dose is a further increased dose if the patient tolerates a further increased dose, hi some embodiments, the optimized dose is a further increased dose if the patient tolerates a further increased dose and if the patient has an adequate response.

[0100] In some embodiments, the titration scheme further comprises administering an optimized dose of Compound 1, or a pharmaceutically acceptable salt thereof, to the patient.

[0101] In some embodiments, if the patient tolerates the increased dosage, and if the patient does not have an adequate response, the method further comprises increasing the dosage.

[0102] In some embodiments, the titration scheme further comprises administering an optimized dose of Compound 1, or a pharmaceutically acceptable salt thereof, to the patient.

[0103] In some embodiments, the titration scheme further comprises tapering of Compound 1 or a pharmaceutically acceptable salt thereof, for example, if the patient does not tolerate increased doses of Compound 1 or a pharmaceutically acceptable salt thereof. In some embodiments, the tapering comprises decreasing the dose of Compound 1 or a pharmaceutically acceptable salt thereof administered to the patient by increments equal to about 1, 2, 3, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12 mg / dose of Compound 1. In some embodiments, the tapering scheme comprises decreasing the dose of Compound 1 or a pharmaceutically acceptable salt thereof administered to the patient in a single dose. In some embodiments, the tapering scheme comprises decreasing the dose of Compound 1 or a pharmaceutically acceptable salt thereof administered to the patient two or more times. In some embodiments, the tapering scheme involves decreasing the dosage of Compound 1 or a pharmaceutically acceptable salt thereof administered to the patient in increments equivalent to about 3 mg / dose of Compound 1 about every 1, 2, 3, 4, or 5 days until the patient is no longer receiving Compound 1 or a pharmaceutically acceptable salt thereof.

[0104] In some embodiments, the dosage of Compound 1 or a pharmaceutically acceptable salt thereof is tapered to address observed side effects, hi some embodiments, the dosage of Compound 1 or a pharmaceutically acceptable salt thereof is tapered to minimize the risk of withdrawal-induced side effects.

[0105] In some embodiments, the patient is also receiving an antiepileptic or antiseizure drug. In some embodiments, the patient is also receiving an antiepileptic drug effective to suppress interictal epileptic discharges (e.g., benzodiazepines, valproic acid, and lamotrigine). In some embodiments, the patient is also receiving immunomodulatory therapy (e.g., corticosteroids, intravenous immunoglobulin [IVIG], plasma deposition). In some embodiments, the patient is also receiving a ketogenic diet. In some embodiments, the patient is also receiving vagus nerve stimulation (VNS) or deep brain stimulation (DBS).

[0106] In some embodiments, the patient is also receiving a CYP enzyme inhibitor, and no adjustment is made to the dosage of Compound 1 or a pharmaceutically acceptable salt thereof compared to a corresponding patient not receiving a CYP enzyme inhibitor. In some embodiments, the CYP enzyme inhibitor is a moderate or strong CYP enzyme inhibitor. In some embodiments, the CYP enzyme inhibitor is an anti-seizure drug. In some embodiments, the CYP enzyme inhibitor is fenfluramine, carbamazepine, clobazam, cannabidiol, felbamate, phenobarbital, or phenytoin. In some embodiments, the CYP enzyme inhibitor is a substrate for CYP2D6, CYP3A4, CYP2C19, or CYP2C9.

[0107] In some embodiments, the patient is also receiving a P-glycoprotein (P-gp) inhibitor and no dose adjustment is made to the dosage of Compound 1 or a pharmaceutically acceptable salt thereof compared to a corresponding patient not receiving a P-gp inhibitor. In some embodiments, the P-gp inhibitor is a P-gp-mediated efflux or renal transporter.

[0108] In some embodiments, Compound 1 or a pharmaceutically acceptable salt thereof is administered as the neat or pure chemical, for example, as a powder in a capsule formulation.

[0109] In some embodiments, Compound 1, or a pharmaceutically acceptable salt thereof, is formulated as a pharmaceutical composition further comprising one or more pharmaceutically acceptable carriers.

[0110] 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.

[0111] Conventional excipients such as binders, fillers, acceptable wetting agents, tableting lubricants, and disintegrants can be used in tablets and capsules for oral administration.The compounds described herein can be formulated into pharmaceutical compositions using techniques well known to those skilled in the art.Suitable pharmaceutically acceptable carriers are known in the art except those mentioned herein; for example, see Remington, The Science and Practice of Pharmacy, 2004. th Edition, 2000, Lippincott Williams & Wilkins, (Editors: Gennaro et al.).

[0112] In some embodiments, Compound 1 or a pharmaceutically acceptable salt thereof is formulated in a manner suitable for oral administration.

[0113] For oral administration, pharmaceutical compositions can be in the form of tablets or capsules, for example.Pharmaceutical compositions are preferably prepared in the form of dosage units containing a specific amount of active ingredients.Examples of such dosage units are capsules, 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 gelatin; disintegrants such as cornstarch, potato starch, or sodium carboxymethylcellulose; and lubricants such as talc or magnesium stearate.Solid preparations include powders, tablets, pills, capsules, cachets, suppositories, and dispersible granules.Solid carriers can be one or more substances that can also act as diluents, flavoring agents, solubilizers, lubricants, suspending agents, binders, preservatives, tablet disintegrating agents, or encapsulating materials.

[0114] In powders, the carrier is a finely divided solid that is in a mixture with the finely divided active ingredient.

[0115] In tablets, the active component is mixed with the carrier having the necessary binding capacity in suitable proportions and compacted to the desire shape and size.

[0116] Powders and tablets may contain varying percentage amounts of the active compound. A typical amount in a powder or tablet can range from 0.5 to about 90 percent of the active compound. However, one of ordinary skill in the art will recognize 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 waxes, cocoa butter, and the like. The term "formulation" includes formulations of the active compound with an encapsulating material as a carrier, providing capsules in which the active ingredient is surrounded by, and thus associated with, the carrier, with or without a carrier. Cachets and lozenges are also included. Tablets, powders, capsules, pills, cachets, and lozenges can be used as solid forms suitable for oral administration.

[0117] For oral administration, the pharmaceutical composition may be in a form suitable for administration via a gastrostomy tube or a percutaneous endoscopic gastrostomy tube.

[0118] Pharmaceutical preparations are preferably in unit dosage form.In such form, the preparation is subdivided into unit doses containing appropriate amounts of active ingredients.The unit dosage form can be a packaged preparation, and the package contains individual amounts of preparations, such as packaged tablets or capsules.Also, the unit dosage form can be a capsule or tablet itself, or it can be the appropriate number of any of these in packaged form.

[0119] Further embodiments include those disclosed in the examples below, which should not be construed as limiting in any way. [Example]

[0120] Example 1: Multiple-dose study in healthy adult subjects Cohorts 1 and 2 were part of a Phase 1, open-label, four-cohort, multiple-dose study in healthy adult male and female subjects. Approximately 20 subjects were aged 18-55 years and had a mean dose of 18.5-30.0 kg / m 2Healthy subjects with a body mass index of 1.0 (gender balanced in each cohort) were enrolled to ensure that at least six subjects completed qEEG (quantitative electroencephalogram) and CSF (cerebrospinal fluid) PK (pharmacokinetic) assessments in each cohort.

[0121] Subjects were enrolled in one of two dosing regimens. Subject enrollment was stratified by gender to ensure approximate gender balance in each cohort. All dosing regimens included an escalation phase and a tapering phase. Compound 1 was administered according to the dosing regimen in Table 1.

[0122] [Table 1]

[0123] Subjects received all doses of Compound 1 (Table 2 below) as a liquid formulation for oral administration, immediately followed by ingesting approximately 240 mL of water.

[0124] [Table 2]

[0125] The morning dose was administered every day after a standard light breakfast (e.g., milk and cereal, toast, and fruit). TID dosing (three times daily) was approximately 8 hours apart. Subjects fasted from midnight each day until breakfast in the morning. There were no fluid restrictions during the study, but subjects were not allowed to consume excessive amounts of fluid on any day.

[0126] For Cohorts 1 and 2, the study consisted of a screening period (days -28 to -2), an on-site period from days -1 to 16, and a 10-day post-dose follow-up visit (day 25). Subjects were admitted to the clinic on day -1 of the evaluation period and remained confined to the clinic until the completion of the evaluation period (or longer if the investigator deemed it clinically necessary for safety follow-up). Safety was assessed continuously from the time of signing the informed consent form until the follow-up visit. Safety assessments, including cardiac troponin, vital signs, and 12-lead ECGs, were performed at screening and daily from days -1 to 16, as well as at follow-up. The Columbia-Suicide Severity Rating Scale (C-SSRS) was assessed at screening, days -1, 11, 16, and 25.

[0127] Study evaluations related to PK and PD (pharmacodynamic) endpoints were as follows: Serial CSF samples: Day 11 Serial sampling for plasma protein binding: Day 11 Serial EEG: Days 1, 3, and 10 Trough qEEG: Day 16 Serial serum prolactin samples: Days 1 and 10 Serial plasma PK samples: Days 1, 3, 10, and 11 Trough plasma PK samples: Day 2, Days 4-9, and Days 12-16 Bladder ultrasound was performed on days -1, 1, 8, and 9 Sampling for Pharmacogenomics: Day 1

[0128] Pharmacokinetics Pharmacokinetic parameters for Compound 1 and its metabolites were determined from CSF and plasma concentration-time profiles for all evaluable subjects and are shown in Table 3 below.

[0129] [Table 3]

[0130] C for Compound 1 max , T max , and AUC tau The CSF to free drug plasma ratio was also determined.

[0131] Plasma and CSF concentration-time data were tabulated by cohort and time point for all subjects and summarized using descriptive statistics (n, arithmetic mean, SD, median, and range [min-max]). Mean (SD) and individual concentration-time profiles for plasma and CSF PK were plotted by cohort.

[0132] Plasma and CSF PK parameters were estimated using noncompartmental methods using actual dosing and sampling times. Data were tabulated by cohort and subject and summarized using descriptive statistics (n, arithmetic mean, SD, coefficient of variation [%CV] for the arithmetic mean, median, geometric mean, and range [min-max]). PK parameters were plotted using box plots or scatter plots and mean plots to assess their relationship to dose / dosing regimen.

[0133] Representative Compound 1 plasma and CSF profiles for Cohort 1 (6 mg TID) and Cohort 2 (12 mg TID) at steady state are shown in Figures 1 and 2, respectively. 2C The associated inhibition constant (K i ) are also shown in Figures 1 and 2. As shown in Figure 2, the majority of participants in Cohort 2 experienced a significant decrease in the associated K throughout the medication period. i Plasma and CSF levels of >100 were achieved.

[0134] Figure 3 shows the CSF and plasma profiles of Compound 1 for individual subjects within Cohort 1 (subjects 101-110) and Cohort 2 (subjects 201-210). max ) and Figure 5 (AUC tau ) C of Compound 1 in plasma and CSF max and AUC tauPlots comparing the parameters showed a strong correlation between plasma and CSF PK parameters.

[0135] Pharmacodynamics After eligibility assessment, a screening EEG was performed as part of the screening evaluation to exclude subjects with clinically significant abnormalities. The screening EEG was 20 minutes in duration and included hyperventilation and photic stimulation. They were scored as either within the normal range (0) or abnormal and excluded (1).

[0136] All qEEG assessments were performed by registered EEG technicians using individually applied gold cup electrodes and a state-of-the-art EEG recording system. All tests were performed with participants comfortably seated in a sound-attenuating room. In addition to the standard 19 EEG leads of the International 10 / 20 system, the left and right earlobes were recorded as active leads, and vertical and horizontal electro-oculograms were recorded as bipolar pairs. The reference electrode was amplifier-dependent but was usually placed over a bony scalp region near the location of the FCz or FC3 electrode.

[0137] A 5-minute resting qEEG with eyes closed (EC) and a 5-minute resting EEG with eyes open (EO) were performed with participants comfortably seated in a sound-attenuating room. Participants were instructed to view a fixation cross on a video monitor while keeping their eyes open and to avoid excessive eye movement or blinking. Resting qEEG was assessed by spectral and coherence analysis, including spectral amplitude and coherence in clinical frequency bands (delta, theta, alpha1, alpha2, beta1, beta2, beta2, beta3, high beta, gamma) and derived frequency measures (theta-beta ratio (TBR), beta-alpha ratio (BAR), alpha-low frequency index (ASI), dominant frequency, 1 / f slope). qEEG was measured within 45 minutes of the scheduled dose time and again at 1, 2, 4, and 8 hours after the morning dose.

[0138] Representative qEEG results for Cohort 1 are shown in Figure 6, and representative qEEG results for Cohort 2 are shown in Figure 7. Figures 6 and 7 show changes in EC oscillatory band parameters detected by qEEG. Significant contrasts (≥10%, ≥15%) between large and small are indicated by thin and bold arrows, respectively (downward = decrease, upward = increase). Significant Cohen's d values ​​(≥0.5, ≥0.8) between large and small are indicated by dotted and solid boxes, respectively. Days and time points are located in the columns and bands. qEEG results for Cohorts 1 and 2, including those shown in Figures 6 and 7, showed a progressive (with multiple dosing) significant increase in EC and EO delta band amplitude. In Cohort 2, significant decreases in EC and EO theta band amplitude on days 10 and 16, as well as a transient EC theta increase on day 3, were observed. A progressive and significantly reduced EC alpha 1 band amplitude was observed in Cohorts 1 and 2.

[0139] A progressive and significant decrease in EC (Cohorts 1 and 2) and EO (Cohort 2) alpha2 band amplitude was observed, with a consistent corresponding decrease in EO alpha2 band amplitude observed in Cohort 1. Cohort 1 showed transiently increased EO alpha2 and beta1 band amplitudes after dosing, and Cohort 2 showed transiently increased late (8 h) EO alpha1 band amplitude after dosing.

[0140] Cohorts 1 and 2 each showed a progressive and significant decrease in EO beta 3 band amplitude and a progressive increase in EC and EO BAR, partially reflecting the decrease seen in the alpha band. A transient decrease in occipital EO TBR was observed in Cohort 1, and a transient decrease in frontal TBR was observed in Cohort 2. These decreases directly reflected the transient increase in EO beta amplitude in Cohort 1, and the late (day 10) increase in beta 3 band amplitude and decrease in theta band amplitude in Cohort 2.

[0141] A prominent feature of the fractal changes observed by qEEG for Cohorts 1 and 2 was an early (D1-3, +1 to +4 h) increase in EC gamma-band amplitude, which translated into a late (D10, -1 h / +8 h) decrease with continued dosing. This increase / decrease was supported by a parallel decrease in TGR and 1 / f slope and area. Results demonstrated an early effect on EEG activity within the first three doses, and a sustained dose-dependent effect on EEG activity after continued dosing, indicating receptor engagement.

[0142] Pharmacodynamic parameters estimated from EEG and ultrasound were summarized by subject, cohort, and time point. Absolute and percent changes from baseline were calculated, with the baseline value defined as the last estimated value before the first dose of study drug. All parameters were summarized using descriptive statistics (n, arithmetic mean, SD, median, and range [min-max]).

[0143] Results from Cohorts 1 and 2 showed that plasma and CSF concentrations of Compound 1 increased dose-dependently and continuously, suggesting that Compound 1 engaged the neurotransmitter system and altered the EEG spectra of subjects. Favorable safety and tolerability results were also observed in Cohorts 1 and 2.

[0144] Example 2: Multiple-dose study in healthy adult subjects A Phase 1, open-label, four-cohort, multiple-dose study of Example 1 will be conducted for Cohorts 3 and 4.

[0145] Twenty additional subjects will be enrolled in one of two dosing regimens. Enrollment will be stratified by gender to ensure approximate gender balance in each cohort. All dosing regimens will include an escalation phase and a tapering phase. Compound 1 will be administered according to the dosing regimen in Table 4.

[0146] [Table 4]

[0147] Subjects will receive all doses of Compound 1 (Table 2 above) as a liquid formulation for oral administration, followed immediately by approximately 240 mL of water. The morning dose will be administered every day after a standard light breakfast (e.g., milk and cereal, toast, and fruit). BID dosing (twice daily) will be 12 hours apart. Subjects will fast from midnight each day until breakfast in the morning. There will be no fluid restrictions during the study, but subjects should not consume excessive amounts of fluid on any day.

[0148] For Cohorts 3 and 4, the study consists of a screening period (Days -28 to -2), an on-site period from Days -1 to 16, and a 10-day post-dose follow-up visit (Day 25). Subjects will be admitted to the clinic on Day -1 of the evaluation period and remain confined to the clinic until the evaluation period is completed (or longer if the investigator deems clinically necessary for safety follow-up). Safety will be assessed continuously from the time of signing the informed consent form until the follow-up visit. Safety assessments, including cardiac troponin, vital signs, and 12-lead ECGs, will be performed at screening and daily from Days -1 to 16, as well as at follow-up. The Columbia-Suicide Severity Rating Scale (C-SSRS) will be assessed at screening, Days -1, 11, 16, and 25.

[0149] Study evaluations related to PK and PD (pharmacodynamic) endpoints include: Serial CSF samples: Day 11 Serial sampling for plasma protein binding: Day 11 Serial EEG: Days 1, 3, and 10 Trough qEEG: Day 16 Serial serum prolactin samples: Days 1 and 10 Serial plasma PK samples: Days 1, 3, 10, and 11 Trough plasma PK samples: Day 2, Days 4-9, and Days 12-16 Bladder ultrasound performed on days -1, 1, 8, and 9 Sampling for Pharmacogenomics: Day 1

[0150] Pharmacokinetics Pharmacokinetic parameters for Compound 1 and its metabolites are determined from CSF and plasma concentration-time profiles for all evaluable subjects and are shown in Table 5 below.

[0151] [Table 5]

[0152] C for Compound 1 max , T max , and AUC tau The CSF to free drug plasma ratio is also determined.

[0153] Plasma and CSF concentration-time data will be tabulated by cohort and time point for all subjects and summarized using descriptive statistics (n, arithmetic mean, SD, median, and range [min-max]). Mean (SD) and individual concentration-time profiles for plasma and CSF PK will be plotted by cohort.

[0154] Plasma and CSF PK parameters will be estimated using noncompartmental methods using actual dosing and sampling times. They will be tabulated by cohort and subject and summarized using descriptive statistics (n, arithmetic mean, SD, coefficient of variation [%CV] for the arithmetic mean, median, geometric mean, and range [min-max]). PK parameters will be plotted using box plots or scatter plots and mean plots to assess their relationship to dose / dosing regimen.

[0155] Pharmacodynamics Prolactin serum concentrations are summarized by subject, cohort, and time point. Plasma and CSF exposure of Compound 1 versus metabolites and prolactin are plotted.

[0156] After eligibility assessment, a screening EEG is performed as part of the screening assessment to exclude subjects with clinically significant abnormalities. The screening EEG is 20 minutes in duration and includes hyperventilation and photic stimulation. It is scored as either within the normal range (0) or abnormal and excluded (1).

[0157] All qEEG assessments are performed by registered EEG technicians using individually applied gold cup electrodes and a state-of-the-art EEG recording system. All tests are performed with participants seated comfortably in a sound-attenuating room. In addition to the standard 19 EEG leads of the International 10 / 20 system, the left and right earlobes are recorded as active leads, and vertical and horizontal electro-oculograms are recorded as bipolar pairs. The reference electrode is amplifier-dependent, but is usually placed over a bony scalp area near the location of the FCz or FC3 electrode.

[0158] A 5-minute resting qEEG with eyes closed (EC) and a 5-minute resting EEG with eyes open (EO) are performed with participants comfortably seated in a sound-attenuating room. Participants are instructed to view a fixation cross on a video monitor while keeping their eyes open and to avoid excessive eye movement or blinking. Resting qEEG is assessed by spectral and coherence analysis, including spectral amplitude and coherence in clinical frequency bands (delta, theta, alpha 1, alpha 2, beta 1, beta 2, beta 2, beta 3, high beta, gamma) and derived frequency measures (theta-beta ratio (TBR), beta-alpha ratio (BAR), alpha-low frequency index (ASI), dominant frequency, 1 / f slope). qEEG is measured within 45 minutes of the scheduled dose time and again at 1, 2, 4, and 8 hours after the morning dose.

[0159] Example 3: CYP and P-glycoprotein interaction potential Rationale Complex polypharmacy is common in patients with developmental and epileptic encephalopathies (DEEs), and therefore avoiding drug-drug interactions (DDIs) is particularly important in this population. Many antiseizure medications (ASMs) are CYP enzyme inhibitors, particularly CYP2D6 (fenfluramine, carbamazepine), CYP3A4 (clobazam, cannabidiol, felbamate, carbamazepine), and CYP2C19 (fenfluramine, cannabidiol, phenobarbital, phenytoin). In addition, many patients use three or more ASMs simultaneously, some of which are CYP inhibitors themselves. P-glycoprotein (P-gp)-mediated efflux and renal transporters can also cause undesirable pharmacokinetic (PK) effects. Therefore, the favorable PK profile of Compound 1 involves avoidance of CYP metabolism, P-gp excretion, and renal transporters, and instead relies on the propensity of UDP-glucuronosyltransferase (UGT).

[0160] method The study was designed to (a) confirm the metabolism of Compound 1 via glucuronidation by UGTs, (b) evaluate the disposition of Compound 1 and its potential to be affected by renal transporters, and (c) characterize the potential for Compound 1 to be affected by P-gp efflux or DDIs through CYP metabolic pathways. This open-label study in 19 healthy volunteers was conducted in two parts. Part 1 evaluated the role of the UGT metabolic pathway and renal transporters using a single 12 mg dose of Compound 1 (administered as a liquid formulation; Table 2 above) in the presence of a UGT inhibitor (probenecid) and a renal transport inhibitor (cimetidine) compared to Compound 1 alone. Part 2 evaluated the PK of a 12 mg TID Compound 1 (administered as a liquid formulation; Table 2 above) at steady state with a CYP and P-gp inhibitor (quinidine) compared to Compound 1 alone. Serial plasma samples were collected during both parts of the study. Safety parameters were monitored throughout.

[0161] result Part 1: C for Compound 1 maxand AUC values ​​were higher in the presence of probenecid / cimetidine compared to Compound 1 alone. The observed approximately 80% increase in Compound 1 exposure is consistent with and supports in vitro data indicating that Compound 1 is displaced via UGTs and is unlikely to be affected by renal transport inhibitors.

[0162] Part 2: C for Compound 1 max The RI and AUC values ​​were 33.6 ng / mL and 167.4 h.ng / mL in the presence of quinidine, and 30.8 ng / mL and 148.9 h.ng / mL for Compound 1 alone. The lack of effect of quinidine on exposure indicates that Compound 1 is not a substrate for CYP3A4, CYP2D6, or P-gp. Figure 8 shows the geometric least squares mean ratios comparing administration of Compound 1 alone with administration of quinidine. The possibility that Compound 1 is affected by inhibition of CYP219 and CYP2C9 was not evaluated, as in vitro data indicated that these are unlikely metabolic pathways for Compound 1. Compound 1, alone or in combination with other probe substrates, was safe and generally well tolerated.

[0163] The results indicate that Compound 1 is unlikely to be subject to clinically significant CYP-mediated DDIs. Furthermore, these results support the low potential for P-gp or renal transporter interactions in Compound 1's configuration.

[0164] Example 4: Antiepileptic activity in preclinical seizure models Rationale 5-HT2 receptor agonists have demonstrated efficacy against a variety of seizure types and seizure disorders. Compound 1 is a potent and selective 5-HT 2CCompound 1 is a superagonist. Proof of concept for its utility across various seizure etiologies has been established in zebrafish and mouse model systems. Due to their rapid reproductive capacity and ease of genetic manipulation, both zebrafish and mice are highly useful model systems for studying many human diseases. Both have been validated as experimental models of seizures and epilepsy and demonstrate sensitivity to many classes of anti-seizure medications.

[0165] method For zebrafish experiments, the locomotor activity of individual larvae in 96-well plates was tracked with an automated tracker. Local field potentials were recorded by noninvasive surface recording from the skin over the optic tectum, and epileptic activity was quantified.

[0166] Experiment 1: Mutations in the human SCN1A gene, which encodes the α-subunit of the voltage-gated sodium channel, are associated with a genetic epilepsy known as Dravet syndrome. - / - Zebrafish larvae containing mutations in the α-gamma gene were treated with Compound 1 or vehicle, and motor behavior and brain epileptiform activity were measured.

[0167] Experiment 2: Wild-type zebrafish larvae were treated with ethyl ketopentenoate (EKP), which reduces the synthesis of the inhibitory neurotransmitter GABA, to induce generalized seizures. EKP-treated larvae were then exposed to compound 1, and brain epileptiform activity was recorded.

[0168] Experiment 3: Wild-type zebrafish larvae were treated with kainic acid (KA), a cyclic analog of L-glutamate that binds to and activates excitatory glutamate receptors, to induce acute and chronic seizures in zebrafish in a model of temporal lobe epilepsy. KA-treated larvae were exposed to compound 1, and brain epileptiform activity was recorded.

[0169] Experiment 4: Mice were administered intravenous pentylenetetrazole (PTZ), a GABA-A receptor antagonist, to induce myoclonic and tonic-clonic seizures in a generalized epilepsy model. Compound 1 was administered orally before PTZ administration, and the time to the onset of the first myoclonic twitch or generalized clonus was recorded.

[0170] result Experiment 1: Compound 1 treatment reduced locomotor activity and both the frequency and mean cumulative duration of epileptiform events (84% and 85%, respectively).

[0171] Experiment 2: Compound 1 treatment reduced cerebral seizure activity by an average of 69.1%.

[0172] Experiment 3: Compound 1 treatment resulted in an 82.4% reduction in cerebral seizure activity.

[0173] Experiment 4: Administration of Compound 1 resulted in a dose-dependent increase in the time to the first myoclonic twitch and the time to onset of generalized clonus.

[0174] The results show that Compound 1 broadly reduces a wide variety of seizure activity resulting from multiple underlying causes, including genetic mutations in neuronal sodium channels, reduced GABAergic signaling, and excessive glutamatergic excitation. These data support the utility of Compound 1 in treating heterogeneous seizure disorders, for example, in patients with DEE, who have heterogeneous underlying pathologies.

[0175] Example 5: Multiple-dose study in healthy adult subjects A Phase 1, open-label, multiple-dose study of Example 1 was conducted on Cohorts 1-3, 4A, and 4B.

[0176] 18 to 55 years old, 18.5 to 30.0 kg / m 2Forty-eight healthy subjects with a body mass index of 0.05 and a body weight of at least 50 kg were enrolled. Subjects were enrolled in one of five dosing regimens. All dosing regimens included an escalation phase and a tapering phase. Compound 1 was administered according to the dosing regimen in Table 6.

[0177] [Table 6]

[0178] Subjects received all doses of Compound 1 (Table 2 above) as a liquid formulation for oral administration, followed immediately by approximately 240 mL of water. The morning dose was administered every day after a standard light breakfast (e.g., milk and cereal, toast, and fruit). TID dosing (three times a day) was approximately 8 hours apart, and BID dosing (twice a day) was 12 hours apart. Subjects fasted from midnight each day until breakfast in the morning. There was no fluid restriction during the study, but subjects did not consume excessive amounts of fluid on any day.

[0179] For all cohorts, the study consisted of a screening period (days -28 to -2), an on-site period from days -1 to 16, and a 10-day post-dose follow-up visit (day 25). Subjects were admitted to the clinic on day -1 of the evaluation period and remained confined to the clinic until the completion of the evaluation period (or longer if the investigator deemed it clinically necessary for safety follow-up). Safety was assessed continuously from the signing of the informed consent form until the follow-up visit. Safety assessments, including cardiac troponin, vital signs, and 12-lead ECGs, were performed at screening and daily from days -1 to 16, as well as at follow-up. The Columbia-Suicide Severity Rating Scale (C-SSRS) was assessed at screening, days -1, 11, 16, and 25.

[0180] Study evaluations related to PK and PD endpoints were as follows: Serial CSF samples: Day 11 Serial sampling for plasma protein binding: Day 11 Continuous qEEG: Day 1, Day 1, Day 3 (Cohorts 1-3), Day 5 (Cohorts 4A, 4B), and Day 10 Trough qEEG: Day 16 Serial serum prolactin samples: Days 1 and 10 Serial plasma PK samples: Days 1, 3, 5 (Cohorts 4A and 4B), and 8-11 Trough plasma PK samples: Day 2, Days 4-7, and Days 12-16 Bladder ultrasound was performed on days -1, 2, 8, and 9 Sampling for Pharmacogenomics: Day 1

[0181] Pharmacokinetics Pharmacokinetic parameters for Compound 1 and its metabolites were determined from CSF and plasma concentration-time profiles for all evaluable subjects and are shown in Table 7 below.

[0182] [Table 7]

[0183] C for Compound 1 max , C trough , and AUC tau The CSF to free drug plasma ratio (CSF / P) was also determined.

[0184] Plasma PK of Compound 1 Plasma PK parameters were obtained for Compound 1 on the above days.

[0185] Pre-dose concentrations of Compound 1 in plasma were below the limit of quantitation (BLQ) across all five cohorts on Day 1, and quantifiable Compound 1 concentrations were observed 1 hour after dosing. On Day 1, after a single 3 mg dose of Compound 1 (Cohort 1), the geometric mean C of 4.7 ng / mL was observed. max had a median elimination time of 1.00 h, an apparent terminal half-life of 3.1 h, and a geometric mean AUC of 21.3 h*ng / mL.0-inf After a single 6 mg dose of Compound 1 (Cohorts 2, 3, 4A, and 4B), the geometric mean C max ranged from 7.8 to 12.4 ng / mL, which was reached in a median time of 0.98 to 1.14 hours, with an apparent terminal half-life of 3.1 to 3.3 hours, and a geometric mean AUC of 36.5 to 51.9 h*ng / mL across the four cohorts. 0-inf Comparing Cohorts 2, 3, 4A, and 4B after a single 6 mg dose of Compound 1, Cohort 4A appeared to exhibit lower exposure PK parameters compared to the other three cohorts.

[0186] On Day 3, Cohort 1 was titrated to 6 mg TID, Cohort 2 was titrated to 12 mg BID, and Cohorts 3, 4A, and 4B were titrated to 12 mg TID. On Day 5, Cohort 4A was titrated to 15 mg TID and Cohort 4B was titrated to 18 mg TID. Due to the dose escalation, steady state had not yet been reached.

[0187] All cohorts reached steady-state exposure to Compound 1 by Day 8. A summary of the plasma PK parameters of Compound 1 on Days 8-10 is provided in Tables 8-10, respectively.

[0188] [Table 8]

[0189] [Table 9]

[0190] [Table 10]

[0191] The mean concentration profile of Compound 1 in plasma is shown in Figure 9. The results demonstrated a linear increase in plasma concentrations over the daily dose and consistent pharmacokinetics at steady state.

[0192] Exposure PK parameters appeared dose-proportional between 6 mg TID and 12 mg TID and between 12 mg BID and 18 mg BID. At steady state, the half-life of Compound 1 was approximately 5 hours.

[0193] Plasma PK of Compound 1 (excluding subject 208) One subject (Subject 208) from Cohort 2 (12 mg TID) had an unexpected PK profile (high plasma concentrations for all PK days and CSF). At steady state, after visual inspection of the concentration-time curves, the plasma concentrations of the 12 mg TID cohort, excluding Subject 208, showed similar maximum concentrations compared to the 12 mg BID cohort and similar concentrations to the 15 mg BID cohort at terminal stage.

[0194] Plasma PK of Compound 1 metabolites Plasma PK parameters were obtained for Compound 1 metabolites M9, M12, and M20 on the days indicated above.

[0195] At steady state, M9 AUC and C max did not increase proportionally between cohort 1 and cohort 2. In the BID cohort, AUC and C max was higher in cohort 3 compared with cohort 4A, and T max The MPR AUC was approximately 4 hours. tau and MPR C max tended to be higher at lower doses within a given regimen, BID or TID.

[0196] At steady state, M12 AUC and C max did not increase proportionally between cohort 1 and cohort 2. In the BID cohort, AUC and C max was higher in cohort 3 compared with cohort 4A, and T max The MPR AUC was approximately 2 hours. tau and MPR C max tended to be higher at lower doses within a given regimen, BID or TID.

[0197] At steady state, M20 AUC and C max increased dose-proportionally between cohort 1 and cohort 2. In the BID cohort, AUC and C max also increased dose-proportionally between cohort 3 and cohort 4B, and T max was approximately 1 hour. MPR AUC tau and MPR C max were similar between dosing regimens. M20 levels were comparable between cohorts 2 (12 mg TID) and 4B (18 mg BID).

[0198] CSF PK of Compound 1 CSF PK parameters were obtained for Compound 1 on Day 11. A summary of the CSF PK parameters for Compound 1 is shown in Table 11.

[0199] [Table 11]

[0200] The mean concentration profile of Compound 1 in CSF is shown in Figure 10. The results demonstrated a linear increase in plasma concentrations over the daily dose and consistent pharmacokinetics at steady state.

[0201] Lower CSF C compared to plasma PK parameters of Compound 1 on day 10 max reached at a later time, and CSF T max The CSF C of Compound 1 ranged from 2.52 hours to 3.06 hours. max is plasma C max and CSF / PC across all cohorts. max The ratio was 0.6630 to 0.7640. trough is plasma C trough and CSF / PC across all cohorts. trough The ratios were 1.263 to 1.917, suggesting a slower elimination half-life in CSF compared with plasma.

[0202] Across cohorts 3, 4A, and 4B (BID dosing regimen), PK observed in both plasma and CSF was dose-linear, with CSF / P AUC tau was generally >0.84. max ) and AUC tau There was a strong correlation between plasma and CSF PK parameters, including CSF / PC (Figures 11 and 12). max was lower for Cohorts 3, 4A, and 4B (BID dosing regimens) compared to Cohorts 1 and 2 (TID dosing regimens). As shown in Figure 13, mean plasma concentrations over the dosing interval were similar (approximately 28%) between Cohort 2 (12 mg TID) and Cohort 4B (18 mg BID).

[0203] The mean concentration profiles of Compound 1 in CSF and plasma were compared with those of 5-HT in Figure 14. 2C Agonism-related K i The results demonstrate a linear increase in plasma concentrations over the daily dose and consistent pharmacokinetics at steady state. In CSF, Compound 1 concentrations were generally higher than 5-HT in Cohort 2 (12 mg TID) and Cohort 4B (18 mg BID). 2C Agonism-related K i As shown in Figure 16, the K i The percentage of time above 0.05 was comparable, with cohort 2 showing greater spread and higher variability (subject 208 excluded).

[0204] Furthermore, CSF / PC trough were generally higher in the BID regimen compared to the TID regimen. For example, Figure 17 shows that CSF / PC Ctrough in Cohort 4B (18 mg BID) was significantly higher than CSF / PC Ctrough in Cohort 3 (12 mg TID), even though both cohorts received a total daily dose of 36 mg Compound 1. trough This higher ratio indicates that for the same total daily dose of Compound 1, BID administration may result in increased levels of Compound 1 in the CSF, and thus increased levels of 5-HT expressed in the brain. 2C This suggests that this may result in increased exposure of Compound 1 to the receptor.

[0205] Plasma protein binding Plasma protein binding of Compound 1 was assessed at three different time points on day 11. For each individual time point, the average of the three values ​​was used to derive the mean free drug concentration, which was compared or correlated with CSF concentrations. As shown in Table 12, the mean unbound Compound 1 plasma fraction ranged from 91.3% to 96.9% across all cohorts.

[0206] [Table 12]

[0207] Pharmacodynamics Serum prolactin The PD parameters listed in Table 13 were derived for serum prolactin based on actual time and calculated using non-compartmental analysis (NCA) methods where data allowed.

[0208] [Table 13]

[0209] Prolactin serum PD parameters on days 1 and 10 are summarized in Tables 14 and 15, respectively.

[0210] [Table 14]

[0211] [Table 15]

[0212] Similar E across all cohorts max values ​​were observed, ranging from 14.7 to 18.2 ng / mL on day 10. In general, higher Compound 1 exposure (C max and AUC tau ) for BID dose cohorts 3, 4A, and 4B. max While TID-treated cohorts 1 and 2 were associated with a greater change from baseline in CI, TID-treated cohorts 1 and 2 showed the opposite correlation.

[0213] EEG After eligibility assessment, a screening EEG was performed as part of the screening evaluation to exclude subjects with clinically significant abnormalities. The screening EEG was 20 minutes in duration and included hyperventilation and photic stimulation. They were scored as either within the normal range (0) or abnormal and excluded (1).

[0214] All qEEG assessments were performed by registered EEG technicians using individually applied gold cup electrodes and a state-of-the-art EEG recording system. All tests were performed with participants comfortably seated in a sound-attenuating room. In addition to the standard 19 EEG leads of the International 10 / 20 system, the left and right earlobes were recorded as active leads, and vertical and horizontal electro-oculograms were recorded as bipolar pairs. The reference electrode was amplifier-dependent but was usually placed over a bony scalp region near the location of the FCz or FC3 electrode.

[0215] A 5-minute resting qEEG with eyes closed (EC) and a 5-minute resting EEG with eyes open (EO) were performed with participants comfortably seated in a sound-attenuating room. Participants were instructed to view a fixation cross on a video monitor while keeping their eyes open and to avoid excessive eye movement or blinking. Resting qEEG was assessed by spectral and coherence analysis, including spectral amplitude and coherence in clinical frequency bands (delta, theta, alpha1, alpha2, beta1, beta2, beta2, beta3, high beta, gamma) and derived frequency measures (theta-beta ratio (TBR), beta-alpha ratio (BAR), alpha-low frequency index (ASI), dominant frequency, 1 / f slope). Continuous qEEG was measured within 45 minutes of the scheduled dosing time and again 1, 2, 4, and 8 hours after the morning dose.

[0216] Representative qEEG results for all cohorts are shown in Figures 18-21. Figures 18 and 19 show the changes in EC and EO oscillatory band parameters, respectively, detected by qEEG. Figures 20 and 21 show the changes in EC and EO fractal band parameters, respectively, detected by qEEG. Significant contrasts (≥10%, ≥15%) are indicated by thin and bold arrows, respectively (downward = decrease, upward = increase). Significant Cohen's d values ​​(≥0.5, ≥0.8) are indicated by dotted and solid boxes, respectively. Dates and time points are located in the columns and bands.

[0217] Results from the qEEG oscillatory band showed that Compound 1 administration resulted in an immediate, limited decrease in delta amplitude, followed by a more prolonged rebound increase that appeared to accumulate with repeated dosing, resulting in a significant increase in delta amplitude with a brief, transient normalization after each additional dose. The delta increase appeared to be more pronounced on the right and posterior sides. Carryover effects on day 16 suggest that accumulation was strongest in Cohort 4A for EO and Cohort 2 for EC.

[0218] After repeated dosing, a sustained overall decrease in EO and EC theta band amplitude was consistently observed from pre-dose. Alpha 1 band amplitude decreased after single and repeated dosing of Compound 1 in Cohorts 1 and 3, but a trend toward a posterior increase in alpha 1 band amplitude developed for EO in Cohorts 2 and 4A and EC in Cohort 4B. The pattern of change in alpha 2 band amplitude aligned with the effect of alpha 1 band amplitude, with a progressive decrease in alpha 2 over several days.

[0219] Cohorts 2 and 4B showed a significant increase in EO beta 2 band amplitude that accumulated over the 10 treatment days. An overall decrease in EC beta 3 band amplitude was observed, except in the temporal region of Cohort 4B. Findings for EO beta 3 band amplitude were similar, but less consistent.

[0220] Cohort 2 showed a decrease in EC ASI (alpha slow wave index) over time. Cohorts 2 and 4A showed a decrease in EO ASI with multiple dosing, while an increase was observed in Cohort 4B. An increase in EC TBR (theta / beta ratio) was observed across posterior regions for Cohort 2, but a decrease was observed at later time points. EC BAR (beta / alpha ratio) tended to increase transiently after dosing in Cohorts 2 and 4A, with a sustained increase observed at day 16; rostral increases in EO BAR were observed at days 3 and 10.

[0221] A notable feature of the fractal changes observed by qEEG was an early post-dose (D1-5, +1-4 h) increase in EC gamma-band amplitude, which diminished or was replaced by a late (+8 h) decrease, which also manifested as a rostral decrease pre-dose on day 10 for all cohorts. qEEG results on day 16 still showed a rostral decrease in gamma-band amplitude (most evident in cohort 2), often combined with a caudal increase. TBR and 1 / f were observed to change in parallel with gamma-band amplitude.

[0222] The results demonstrated an initial effect of Compound 1 on EEG activity and a sustained dose-dependent effect on EEG activity after successive dosing, indicating successful receptor engagement in the brain.

[0223] Genotyping Blood samples were collected to investigate genetic polymorphisms in drug-metabolizing enzymes and drug transporter proteins that may affect the PK of Compound 1 and its metabolites.

[0224] bladder ultrasound Bladder ultrasound was performed within 10 minutes of bladder emptying, and post-cavity residual (PVR) urine volume was recorded.

[0225] Safety and Tolerability Favorable safety and tolerability results were observed in all cohorts.

[0226] While the present disclosure has been described with reference to the above examples, it will be understood that modifications and variations are encompassed within the spirit and scope of the present disclosure. The various embodiments described above can 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 Sheets are incorporated herein by reference in their entirety. Aspects of the embodiments can be modified, if necessary, to use concepts from the various patents, applications, and publications to provide still further embodiments.

[0227] These and other changes can 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 to limit the claims to the specific embodiments disclosed in the specification and the claims, but should be construed to include all possible embodiments, along with the full range of equivalents to which such claims are entitled. Accordingly, the claims are not limited by this disclosure.

Claims

1. 5-hydroxytryptamine (HT) ２Ｃ In patients in need of treatment or prevention of a 5-hydroxytryptamine (HT) receptor-associated disorder, ２Ｃ 1. A method for treating or preventing a receptor-associated disorder, said method comprising administering to said patient (R)—N-(2,2-difluoroethyl)-7-methyl-1,2,3,4,6,7-hexahydro-[1,4]diazepino[6,7,1-hi]indole-8-carboxamide (Compound 1) or a pharmaceutically acceptable salt thereof; The method, wherein Compound 1 or a pharmaceutically acceptable salt thereof is administered twice daily.

2. 1. A method of treating or preventing epilepsy in a patient in need thereof, said method comprising administering to said patient (R)—N-(2,2-difluoroethyl)-7-methyl-1,2,3,4,6,7-hexahydro-[1,4]diazepino[6,7,1-hi]indole-8-carboxamide (Compound 1) or a pharmaceutically acceptable salt thereof; The method, wherein Compound 1 or a pharmaceutically acceptable salt thereof is administered twice daily.

3. 1. A method of reducing the severity of epileptic seizures in a patient in need thereof, said method comprising administering to said patient (R)—N-(2,2-difluoroethyl)-7-methyl-1,2,3,4,6,7-hexahydro-[1,4]diazepino[6,7,1-hi]indole-8-carboxamide (Compound 1) or a pharmaceutically acceptable salt thereof; The method, wherein Compound 1 or a pharmaceutically acceptable salt thereof is administered twice daily.

4. 1. A method for reducing the frequency of epileptic seizures in a patient in need thereof, said method comprising administering to said patient (R)—N-(2,2-difluoroethyl)-7-methyl-1,2,3,4,6,7-hexahydro-[1,4]diazepino[6,7,1-hi]indole-8-carboxamide (Compound 1) or a pharmaceutically acceptable salt thereof; The method, wherein Compound 1 or a pharmaceutically acceptable salt thereof is administered twice daily.

5. 1. A method of treating or preventing a seizure disorder in a patient in need thereof, said method comprising administering to said patient (R)—N-(2,2-difluoroethyl)-7-methyl-1,2,3,4,6,7-hexahydro-[1,4]diazepino[6,7,1-hi]indole-8-carboxamide (Compound 1) or a pharmaceutically acceptable salt thereof; The method, wherein Compound 1 or a pharmaceutically acceptable salt thereof is administered twice daily.

6. The seizure disorder is selected from the group consisting of epilepsy, epilepsy with generalized tonic-clonic seizures, epilepsy with myoclonic atonic seizures, frontal lobe epilepsy, temporal lobe epilepsy, Landau-Kleffner syndrome, Rasmussen syndrome, Dravet syndrome, Douze syndrome, epilepsy with myoclonic atonic seizures (EM), 6. The method of claim 5, wherein the condition is selected from: CDKL5 deficiency (CDKL5 encephalopathy, or CDD), infantile spasms (West syndrome), juvenile myoclonic epilepsy (JME), vaccine-associated encephalopathy, intractable childhood epilepsy (ICE), Lennox-Gastaut syndrome (LGS), Rett syndrome, Ohtahara syndrome (early infantile DEE, or EIDEE), 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.

7. 1. A method of treating or preventing developmental and epileptic encephalopathy (DEE) in a patient in need thereof, said method comprising administering to said patient (R)—N-(2,2-difluoroethyl)-7-methyl-1,2,3,4,6,7-hexahydro-[1,4]diazepino[6,7,1-hi]indole-8-carboxamide (Compound 1) or a pharmaceutically acceptable salt thereof; The method, wherein Compound 1 or a pharmaceutically acceptable salt thereof is administered twice daily.

8. 8. The method of claim 7, wherein the DEE is selected from Lennox-Gastaut syndrome, Dravet syndrome, Does syndrome (EM AS), West syndrome (infantile spasms), Landau-Kleffner syndrome, and a genetic disorder such as CDKL5 encephalopathy (CDK5L deficiency), or CHD2 encephalopathy.

9. 8. The method of claim 7, wherein the DEE is selected from Ohtahara syndrome (EIDEE), Lennox-Gastaut syndrome, Dravet syndrome, Does syndrome (EM AS), West syndrome (infantile spasms), Landau-Kleffner syndrome, tuberous sclerosis complex, CDKL5 encephalopathy (CDKL5 deficiency), dup15q syndrome, SCN2A-associated epilepsy, SCN8A-associated epilepsy, KCNQ2-associated epilepsy, KCNQ3-associated epilepsy, Angelman syndrome, KCNT1-associated epilepsy, SynGAP1-associated epilepsy, Rett syndrome, PCDH19 epilepsy, ring chromosome 14 syndrome, ring chromosome 20 syndrome, CHD2 encephalopathy, early myoclonic encephalopathy, infantile epilepsy with transitional focal seizures, and epileptic encephalopathy with persistent spike waves.

10. 1. A method of treating or preventing refractory epilepsy in a patient in need thereof, said method comprising administering to said patient (R)—N-(2,2-difluoroethyl)-7-methyl-1,2,3,4,6,7-hexahydro-[1,4]diazepino[6,7,1-hi]indole-8-carboxamide (Compound 1) or a pharmaceutically acceptable salt thereof; The method, wherein Compound 1 or a pharmaceutically acceptable salt thereof is administered twice daily.

11. 11. The method of any one of claims 1 to 10, wherein Compound 1 or a pharmaceutically acceptable salt thereof is administered at a dosage equivalent to about 3 mg / dose of Compound 1.

12. 11. The method of any one of claims 1 to 10, wherein Compound 1 or a pharmaceutically acceptable salt thereof is administered at a dosage equivalent to about 6 mg / dose of Compound 1.

13. 11. The method of any one of claims 1 to 10, wherein Compound 1 or a pharmaceutically acceptable salt thereof is administered at a dosage equivalent to about 12 mg / dose of Compound 1.

14. 11. The method of any one of claims 1 to 10, wherein Compound 1 or a pharmaceutically acceptable salt thereof is administered at a dosage equivalent to about 15 mg / dose of Compound 1.

15. 11. The method of any one of claims 1 to 10, wherein Compound 1 or a pharmaceutically acceptable salt thereof is administered at a dosage equivalent to about 18 mg / dose of Compound 1.

16. 11. The method of any one of claims 1 to 10, wherein Compound 1 or a pharmaceutically acceptable salt thereof is administered via a titration scheme involving increasing amounts of Compound 1 or a pharmaceutically acceptable salt thereof until an optimized dosage is administered.

17. 17. The method of claim 16, wherein the titration scheme comprises administering Compound 1 or a pharmaceutically acceptable salt thereof at an initial dosage equivalent to about 3 mg / dose of Compound 1, provided that the individual tolerates the initial dosage and the dosage is increased if the individual does not have an adequate response.

18. 17. The method of claim 16, wherein the titration scheme comprises administering Compound 1 or a pharmaceutically acceptable salt thereof at an initial dosage equivalent to about 3 mg / dose of Compound 1 for about 2 days, provided that the individual tolerates the initial dosage and the dosage is increased if the individual does not have an adequate response.

19. 17. The method of claim 16, wherein the titration scheme comprises administering Compound 1 or a pharmaceutically acceptable salt thereof at an initial dosage equivalent to about 6 mg / dose of Compound 1, provided that the individual tolerates the initial dosage and the dosage is increased if the individual does not have an adequate response.

20. 17. The method of claim 16, wherein the titration scheme comprises administering Compound 1 or a pharmaceutically acceptable salt thereof at an initial dosage equivalent to about 6 mg / dose of Compound 1 for about 2 days, provided that the individual tolerates the initial dosage and the dosage is increased if the individual does not have an adequate response.

21. 21. The method of claim 19 or claim 20, wherein the increased dosage is equivalent to about 12 mg / dose of Compound 1.

22. 22. The method of any one of claims 19-21, wherein the titration scheme further comprises administering Compound 1 or a pharmaceutically acceptable salt thereof at the increased doses for about 2 days.

23. 22. The method of any one of claims 19-21, wherein the titration scheme further comprises administering Compound 1, or a pharmaceutically acceptable salt thereof, at the increased doses for about 5 days.

24. 24. The method of any one of claims 19 to 23, wherein the optimized dose is the initial dose if the individual does not tolerate the increased dose.

25. 24. The method of any one of claims 19 to 23, wherein the optimized dose is the increased dose if the individual tolerates the increased dose and if the individual has a sufficient response.

26. 24. The method of any one of claims 19 to 23, wherein the titration scheme comprises further escalating the dosage, provided that the individual tolerates the increased dosage and the individual does not have an adequate response.

27. 27. The method of claim 26, wherein the further increased dosage is equivalent to about 15 mg / dose of Compound 1.

28. 27. The method of claim 26, wherein the further increased dosage is equivalent to about 18 mg / dose of Compound 1.

29. 29. The method of any one of claims 26-28, wherein the titration scheme further comprises administering Compound 1 or a pharmaceutically acceptable salt thereof at increasing doses for about 5 days.

30. 30. The method of any one of claims 26 to 29, wherein the optimized dose is the increased dose if the individual does not tolerate the further increased dose.

31. 30. The method of any one of claims 26 to 29, wherein if the individual tolerates the further increased dose, and if the individual has a sufficient response, the optimized dose is the further increased dose.

32. 32. The method of any one of claims 24, 25, 30, and 31, further comprising administering the optimized dose of Compound 1 or a pharmaceutically acceptable salt thereof to the individual.

33. 33. The method of any one of claims 16 to 32, wherein the titration scheme further comprises tapering off Compound 1 or a pharmaceutically acceptable salt thereof.

34. 34. The method of any one of claims 1 to 33, wherein said administration results in an improvement in the frequency of convulsions / motor seizures.

35. wherein the administering the frequency of countable motor seizures observed, total number of seizures, frequency of non-convulsive seizures, Number of episodes of status epilepticus, Frequency of rescue medication use, and Number of days without countable motor seizures 35. The method of claim 34, wherein the method results in one or more improvements in:

36. 36. The method of any one of claims 1-35, wherein said administering 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 Questionnaire-55 item Quality of Life (QOLCE-55).

37. 37. The method of claim 36, wherein said administering results in at least a 1 point change from baseline in CGI-I and / or CGI-S.

38. 38. The method of any one of claims 1-37, wherein prior to administration, the patient had treatment-resistant countable motor seizures with an average of ≥ 4 observed / countable motor seizures per 4 weeks during stable ASM treatment.

39. 39. The method of any one of claims 1 to 38, wherein the patient has DEE but does not have Dravet syndrome or Lennox-Gastaut syndrome.

40. Prior to administration, the patient: A history of unprovoked seizures before age 5 years history of developmental delay, a history of focal and generalized seizures or multiple generalized seizure types; History of delayed or disorganized EEG, and / or No history of idiopathic generalized seizures 40. The method of claim 39, wherein

41. The method of any one of claims 1 to 38, wherein the patient has Dravet syndrome.

42. Prior to administration, the patient: Onset of seizures between 3 and 12 months of age in healthy infants, a history of seizures that were either generalized tonic-clonic, unilateral-clonic, or bilateral-clonic; normal early development, and / or History of developmental delay 42. The method of claim 41 , wherein

43. Prior to administration, the patient: The appearance of a different seizure type prolonged exposure to heat-induced seizures and / or seizures related to heat from illness or vaccines, hot baths, high levels of activity, and sudden temperature changes; and / or 43. The method of claim 41 or 42, wherein the seizures are induced by strong natural and / or fluorescent lighting.

44. 44. The method of any one of claims 41 to 43, wherein prior to administration, the patient had genetic testing results consistent with a diagnosis of Dravet syndrome.

45. 39. The method of any one of claims 1 to 38, wherein the patient has Lennox-Gastaut syndrome.

46. Prior to administration, the patient: history of tonic or tonic / atonic seizures, more than one type of generalized seizure, including but not limited to generalized tonic-clonic, tonic-clonic, atonic, tonic, myoclonic, or astatic seizures; History of seizures before age 8 years history of developmental delay, A previous electroencephalogram reporting diagnostic criteria for Lennox-Gastaut syndrome (abnormal interictal EEG background activity with an interictal slow spike pattern of ≦2.5 Hz or interictal generalized paroxysmal rapid activity), and / or A mean of ≥ 4 astatic seizures observed every 4 weeks during stable ASM treatment 46. ​​The method of claim 45, wherein

47. 47. The method of any one of claims 1-46, wherein the method provides improvement in at least one symptom selected from ataxia, gait disturbance, speech disturbance, phonation, cognitive impairment, abnormal motor activity, clinical seizures, subclinical seizures, hypotonia, hypertonia, salivation, oral behavior, aura, convulsions, repetitive movements, abnormal sensations, seizure frequency, and seizure severity.

48. 48. The method of any one of claims 1 to 47, wherein the compound 1 or a pharmaceutically acceptable salt thereof is the HCl salt of compound 1.

49. said administration results in a geometric mean steady-state C of Compound 1 in the CSF of at least about 1.4 ｔｒｏｕｇｈ Geometric mean steady state C of Compound 1 in plasma ｔｒｏｕｇｈ The ratio of CSF / PC ｔｒｏｕｇｈ 49. The method of any one of claims 1 to 48, wherein

50. The administration of about 1.4 to about 2.5 CSF / PC ｔｒｏｕｇｈ 50. The method of claim 49, wherein

51. The administration of about 1.5 to about 2 CSF / PC ｔｒｏｕｇｈ 50. The method of claim 49, wherein

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