Bexicaserin for use in a method of treatment of seizure-induced sudden unexpected death in epilepsy

Abstract

Provided herein are treatment methods including administering a 5-hydroxytryptamine (HT)2C receptor agonist to a patient in need thereof. An exemplary method includes preventing, controlling, treating or reducing likelihood of seizure-induced sudden unexpected death in epilepsy (SUDEP) in a patient in need thereof, wherein the method comprises 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.

Description

51896-0040 WO 1 1318-WO-PCTMETHODS OF TREATMENTFIELD OF INVENTIONThe present invention relates to a method of treating seizures with which SUDEP can occur, as well as treating, controlling, preventing, or reducing the likelihood of SUDEP in a human patient by administering to said patient a therapeutically effective amount of Bexicaserin (LP352, Compound 1) or a pharmaceutically acceptable salt thereof.BACKGROUND

[0001] Sudden unexpected death in epilepsy (SUDEP) is characterized as the death of an individual with epilepsy that occurs without any apparent cause and represents a leading cause of death in patients with epilepsy. This excludes death due to known causes such as trauma, drowning or status epilepticus. A study on childhood-onset epilepsy long-term mortality showed that out of 60 deaths, 33 (55%) were related to epilepsy, including sudden, unexplained death in 18 subjects (30%). The risk of sudden, unexplained death was 7% at 40 years. As SUDEP is often unwitnessed, diagnosis is typically made post-mortem.

[0002] SUDEP has a reported incidence of 1 to 2 per 1,000 patient years and represents the most common epilepsy-related cause of death. The major risk factor for SUDEP is the occurrence of generalized tonic-clonic seizures (GTCS); SUDEP risk increases in association with increasing frequency of GTCS occurrence. The exact pathophysiology of SUDEP is currently unknown, although GTCS-induced cardiac, respiratory, and brainstem dysfunction appears likely (Maguire 2016 Cochrane Database Syst Rev 7(7):CD011792; Harden 2017 Neurology 88(17): 1674-1680).

[0003] Seizures associated with SUDEP typically occur in certain diseases. Among them are Dravet syndrome, Ohtahara syndrome, tuberous sclerosis complex (TSC), Angelman syndrome, myoclonic astatic epilepsy, and Lennox-Gastaut syndrome. Patients with developmental and epileptic encephalopathies (DEEs) have a higher risk of SUDEP (Donan 2023, Neurology 100(16):el712-el722).

[0004] Bexicaserin (also known as LP352), a potent and highly selective 5-HT2C receptor agonist, is currently in development for the treatment of seizures in patients with developmental and epileptic encephalopathies. US Pat. App. Pub. 2023 / 0293546 sets out TID dosing regimens51896-0040 WO1 1318-WO-PCT(including up-titration and down -titration) at dosage amounts of 3, 6, 9, 12, 18, and 24 mg and reports pharmacokinetic data including a half-life at steady state ranging from 4.81 to 6.50 hours.

[0005] There is a significant unmet need for safe and effective treatments for SUDEP. The compound and dosing methods described herein help satisfy this need and provide related advantages as well.SUMMARY

[0006] Provided is a method of reducing likelihood of seizure-induced sudden unexpected death in epilepsy (SUDEP) in a patient in need thereof, wherein the method comprises administering to the patient in need thereof a therapeutically effective amount of (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.

[0007] Also provided is a method of treating seizures in a patient suffering from a disease with which sudden unexpected death in epilepsy (SUDEP) can occur, wherein the method comprises administering to the patient in need thereof a therapeutically effective amount of (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.

[0008] Also provided is a method of treating seizure-induced sudden unexpected death in epilepsy (SUDEP) in a patient suffering from a disease with which SUDEP can occur, wherein the method comprises administering to the patient in need thereof a therapeutically effective amount of (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.

[0009] Also provided is a method of preventing or controlling seizure-induced sudden unexpected death in epilepsy (SUDEP) in a patient in need thereof, wherein the method comprises administering to the patient in need thereof a therapeutically effective amount of (R)- N-(2,2-difhioroethyl)-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.

[0010] These and other aspects of the invention disclosed herein will be set forth in greater detail as the patent disclosure proceeds.51896-0040 WO 1 1318-WO-PCTBRIEF DESCRIPTION OF THE DRAWINGS

[0011] FIGURE 1 shows the testing data and specifically that Compound 1 (LP352), or a pharmaceutically acceptable salt thereof, reduced seizure and respiratory arrest incidence in DBA / 1 mice. In the figure LP352 is depicted. However, throughout the text, LP352 may also be referred to as Compound 1 or Bexicaserin. In the figure, vehicle is denoted by •, 1 mg / kg LP352 is denoted by ■, and 10 mg / kg LP352 is denoted by ▼. In the figure, # are used for 1 mg / kg vs. vehicle; * are used for 10 mg / kg vs. vehicle.#p<0.05,#ffp<0.01,ff##p<0.001 , *p<0.05, **p<0.01, ***p<0.001 compared to vehicle (Fisher’s Exact test).

[0012] FIGURE 2 shows testing data and specifically that Compound 1 (LP352), or a pharmaceutically acceptable salt thereof, increased latency to the incidence of seizure and respiratory arrest in DBA / 1 mice. In the figure LP352 is depicted. However, throughout the text, LP352 may also be referred to as Compound 1 or Bexicaserin. In the figure, vehicle is denoted by •, 1 mg / kg LP352 is denoted by ■, and 10 mg / kg LP352 is denoted by ▼ . In the figure, # are used for 1 mg / kg vs. vehicle; * are used for 10 mg / kg vs. vehicle.ffp<0.05,ff#p<0.01,###p<0.001, *p<0.05, *^<0.01,<**p<0.001 compared to vehicle (Mann-Whitney U test).DETAILED DESCRIPTION

[0013] As used in the present specification, the following words and phrases are generally intended to have the meanings as set forth below, except to the extent that the context in which they are used indicates otherwise.

[0014] COMPOUND 1 : As used herein, “Compound 1” means (7?)-N-(2,2-difluoroethyl)-7- methyl-l,2,3,4,6,7-hexahydro-[l,4]diazepino[6,7,l-hi]indole-8-carboxamide (also known as bexicaserin or LP352).Compound 151896-0040 WO1 1318-WO-PCTCompound 1 , or a pharmaceutically acceptable salt thereof, is a potent and selective 5- hydroxytryptamine (HT)2c receptor agonist and exhibits increased selectivity for the ligand binding site of 5-HT2C receptors versus those of 5-HT2A and 5-HT2B. Compound 1 displays a binding affinity of 44 nM at the human 5-HT2C receptor and shows no activity for 5-HT2A and 5- HT2B, in contrast, for example, to previously developed agonists such as Fintepla® (low dose fenfluramine). Methods of use of Compound 1, or a pharmaceutically acceptable salt thereof, are disclosed in US Patent 10,392,390, which is incorporated herein by reference in its entirety for all purposes. In some embodiments, Compound 1 is in the form of a HCl-salt.

[0015] DEVELOPMENTAL AND EPILEPTIC ENCEPHALOPATHIES As used here, “developmental and epileptic encephalopathies” (DEE) are a heterogeneous group of rare neurodevelopmental disorders. They are characterized by early-onset seizures that are often intractable and are associated with electroencephalographic abnormalities, and developmental delay or regression that can worsen over time. These disorders are generally diagnosed in childhood and adolescence; they vary in their etiologies, seizure types, electroencephalographic patterns, cognitive deficits, and prognosis. The International League Against Epilepsy recently expanded this definition to include disorders that may result in developmental delay before epilepsy onset and used the term of DEE to encompass this broader population.

[0016] CONVULSIVE / MOTOR SEIZURES As used here, a “convulsive / motor seizure” refers to a tonic-clonic, tonic, tonic-atonic leading to drop, focal motor, epileptic spasms, myoclonic-atonic leading to drop and seizures. Non-convulsive seizures include myoclonic, absence, atypical absence, or atonic seizures and focal seizures without an observable motor component.

[0017] CONVULSIVE / MOTOR SEIZURE-FREE DAY As used herein, a “convulsive / motor seizure-free day” refers to a day for which diary data are available and no convulsive / motor seizures were reported.

[0018] DROP SEIZURE: As used herein, the term “drop seizure” refers to a seizure involving the entire body, trunk or head that leads to a fall, injury, slumping in a chair, or head hitting the surface, or could have led to a fall or injury, depending on the position of the subject at the time of the attack or spell.51896-0040 WO1 1318-WO-PCT

[0019] AGONIST: As used herein, the term "agonist" refers to a moiety that interacts with and activates a receptor, such as the 5-HT2C serotonin receptor, and initiates a physiological or pharmacological response characteristic of that receptor.

[0020] ADMINISTERING: As used herein, “administering” means to provide a compound or other therapy, remedy, or treatment such that a patient internalizes a compound.

[0021] ORAL or ORALLY: As used herein, “oral” or “orally” refers to administration of a compound or composition to a patient by a route or mode along the alimentary canal. Examples of enteral routes of administration include, without, limitation, oral, as in swallowing solid (e.g., tablet) or liquid (e.g., syrup) forms; sub-lingual (absorption under the tongue); nasojejunal or gastrostomy tubes (into stomach); intraduodenal administration; as well as rectal administration (e.g., suppositories for release and absorption of a compound or composition by in the lower intestinal tract of the alimentary canal).

[0022] PRESCRIBING: As used herein, “prescribing” means to order, authorize, or recommend the use of a drug or other therapy, remedy, or treatment. In some embodiments, a health care practitioner can orally advise, recommend, or authorize the use of a compound, dosage regimen or other treatment to a patient. In this case the health care practitioner may or may not provide a prescription for the compound, dosage regimen, or treatment. Further, the health care practitioner may or may not provide the recommended compound or treatment. For example, the health care practitioner can advise the patient where to obtain the compound without providing the compound. In some embodiments, a health care practitioner can provide a prescription for the compound, dosage regimen, or treatment to the patient. For example, a health care practitioner can give a written or oral prescription to a patient. A prescription can be written on paper or on electronic media such as a computer file, for example, on a hand-held computer device. For example, a health care practitioner can transform a piece of paper or electronic media with a prescription for a compound, dosage regimen, or treatment. In addition, a prescription can be called in (oral), faxed in (written), or submitted electronically via the internet to a pharmacy or a dispensary. In some embodiments, a sample of the compound or treatment can be given to the patient. As used herein, giving a sample of a compound constitutes an implicit prescription for 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 the disclosure.51896-0040 WO1 1318-WO-PCT

[0023] A prescription can include, for example, a patient’s name and / or identifying information such as date of birth. In addition, for example, a prescription can include: the medication name, medication strength, dosage, frequency of administration, route of administration, number or amount to be dispensed, number of refills, physician name, physician signature, and the like. Further, for example, a prescription can include a DEA number and / or state number.

[0024] A healthcare practitioner can include, for example, a physician, nurse, nurse practitioner, or other related health care professional who can prescribe or administer compounds (drugs) for the treatment of a condition described herein. In addition, a healthcare practitioner can include anyone who can recommend, prescribe, administer, or prevent a patient from receiving a compound or drug including, for example, an insurance provider.

[0025] PREVENT, PREVENTING, OR PREVENTION: As used herein, the term “prevent,” “preventing”, or “prevention,” such as prevention of a particular disorder or the occurrence or onset of one or more symptoms associated with the particular disorder and does not necessarily mean the complete prevention of the disorder. For example, the term “prevent,” “preventing” and “prevention” means the administration of therapy on a prophylactic or preventative basis to a patient who may ultimately manifest at least one symptom of a disease or condition but who has not yet done so. Such individuals can be identified on the basis of risk factors that are known to correlate with the subsequent occurrence of the disease. Alternatively, prevention therapy can be administered without prior identification of a risk factor, as a prophylactic measure. Delaying the onset of at least one symptom can also be considered prevention or prophylaxis.

[0026] REDUCE, REDUCING, OR REDUCTION: As used herein, e.g. in the reference to “likelihood of SUDEP”, the term “reduce, “reducing” or “reduction” is intended to mean to reduce the risk of SUDEP, wherein the reduction in risk is to be compared with the risk in patients not undergoing epilepsy treatment or not being treated with Compound 1 (LP352 or bexicaserin)

[0027] TREAT, TREATING, OR TREATMENT: As used herein, the term “treat,” “treating”, or “treatment” means the administration of therapy to a patient who already manifests at least one symptom of a disease or condition or who has previously manifested at least one symptom of a disease or condition. For example, “treating” can include alleviating, abating or ameliorating a disease or condition symptoms, preventing additional symptoms, ameliorating the underlying metabolic causes of symptoms, inhibiting the disease or condition, e.g., arresting the51896-0040 WO1 1318-WO-PCT development of the disease or condition, relieving the disease or condition, causing regression of the disease or condition, relieving a condition caused by the disease or condition, or stopping the symptoms of the disease or condition. For example, the term “treating” in reference to a disorder means a reduction in severity of one or more symptoms associated with that particular disorder. Therefore, treating a disorder does not necessarily mean a reduction in severity of all symptoms associated with a disorder and does not necessarily mean a complete reduction in the severity of one or more symptoms associated with a disorder.

[0028] TOLERATE: As used herein, a patient is said to “tolerate” a dosage of a compound if administration of that dosage to that individual does not result in an unacceptable adverse event or an unacceptable combination of adverse events. One of skill in the art will appreciate that tolerance is a subjective measure and that what may be tolerable to one individual may not be tolerable to a different individual. For example, one individual may not be able to tolerate headache, whereas a second individual may find headache tolerable but is not able to tolerate vomiting, whereas for a third individual, either headache alone or vomiting alone is tolerable, but the patient is not able to tolerate the combination of headache and vomiting, even if the severity of each is less than when experienced alone.

[0029] INTOLERANCE As used herein, “intolerance” means significant toxicities and / or tolerability issues that led to a reduction in dosage or discontinuation of the medication. “Intolerance” can be replaced herein with the term “unable to tolerate.”

[0030] ADVERSE EVENT: As used herein, an “adverse event” is an untoward medical occurrence that is associated with treatment with Compound, 1, or a pharmaceutically acceptable salt thereof. In one embodiment, an adverse event is selected from: leukopenia, constipation, diarrhea, nausea, abdominal pain, neutropenia, vomiting, back pain, and menstrual disorder. In one embodiment, an adverse event is heart block, for example, a first-degree atrioventricular heart block. In one embodiment, an adverse event is an acute heart rate reduction. In one embodiment, an adverse event is an abnormal pulmonary function test finding, such as an FEV1 below 80%, FVC. In one embodiment, an adverse event is macular edema.

[0031] IN NEED OF TREATMENT and IN NEED THEREOF As used herein, in need of treatment” and “in need thereof’ when referring to treatment are used interchangeably to mean a judgment made by a caregiver (e. ., physician, nurse, nurse practitioner, etc.) that a patient requires or will benefit from treatment. This judgment is made based on a variety of factors that51896-0040 WO1 1318-WO-PCT are in the realm of a caregiver’s expertise, but that includes the knowledge that the patient is ill, or will become ill, as the result of a disease, condition or disorder that is treatable by the compounds of the invention. Accordingly, the compounds of the invention can be used in a protective or preventive manner; or compounds of the invention can be used to alleviate, inhibit or ameliorate the disease, condition or disorder.

[0032] PATIENT: As used herein, “patient” means any human. In some embodiments, a human individual is referred to a “subject,” “participant,” or “individual.”

[0033] DOSE: As used herein, “dose” means a quantity of Compound 1, or a pharmaceutically acceptable salt thereof, given to the patient for treating or preventing the disease or disorder at one specific time. As used herein, “dosage” refers to the amount of Compound 1, or a pharmaceutically acceptable salt thereof, in one or more doses.

[0034] THERAPEUTICALLY EFFECTIVE AMOUNT As used herein, “therapeutically effective amount” of an agent, compound, drug, composition or combination is an amount which is nontoxic and effective for producing 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 upon, e.g., the subject’s size and health, the nature and extent of the condition, the therapeutics or combination of therapeutics 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 the standard dosage.

[0035] PHARMACEUTICAL COMPOSITION: As used herein, “pharmaceutical composition” means a composition comprising at least one active ingredient, such as Compound 1, including but not limited to, salts of Compound 1, whereby the composition is amenable to investigation for a specified, efficacious outcome. Those of ordinary skill in the art will understand and appreciate the techniques appropriate for determining whether an active ingredient has a desired efficacious outcome based upon the needs of the artisan.

[0036] The compounds according to the invention may optionally exist 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, but are not limited to, acetic, benzenesulfonic, benzoic, camphorsulfonic, citric, ethenesulfonic, dichloroacetic, formic, fumaric, gluconic, glutamic,51896-0040 WO1 1318-WO-PCT hippuric, hydrobromic, hydrochloric, isethionic, lactic, maleic, malic, mandelic, methanesulfonic, mucic, nitric, oxalic, pamoic, pantothenic, phosphoric, succinic, sulfiric, tartaric, oxalic, / ?-toluenesulfonic and the like, such as those pharmaceutically acceptable salts listed by Berge et al., Journal of Pharmaceutical Sciences, 66:1-19 (1977), incorporated herein by reference in its entirety.

[0037] The acid addition salts may be obtained as the direct products of compound synthesis. In the alternative, the free base may be dissolved in a suitable solvent containing the appropriate acid and the salt isolated by evaporating the solvent or otherwise separating the salt and solvent. The compounds of this invention may form solvates with standard low molecular weight solvents using methods known to the skilled artisan.

[0038] It will be apparent to those skilled in the art that the dosage forms described herein may comprise, as the active component, either Compound 1, or a pharmaceutically acceptable salt thereof. Moreover, various hydrates and solvates of Compound 1 and their salts will find use as intermediates in the manufacture of pharmaceutical compositions. Typical procedures for making and identifying suitable hydrates and solvates, outside those mentioned herein, are well known to those in the art; see for example, pages 202-209 of 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. Accordingly, one aspect of the present disclosure pertains to methods of prescribing and / or administering hydrates and solvates of Compound 1 and / or its pharmaceutical acceptable salts, that can be isolated and characterized by methods known in the art, such as, thermogravimetric analysis (TGA), TGA- mass spectroscopy, TGA-Infrared spectroscopy, powder X-ray diffraction (XRPD), Karl Fisher titration, high resolution X-ray diffraction, and the like. There are several commercial entities that provide quick and efficient services for identifying solvates and hydrates on a routine basis. Example companies offering these services include Wilmington PharmaTech (Wilmington, DE), Avantium Technologies (Amsterdam) and Aptuit (Greenwich, CT).

[0039] When an integer is used in a method disclosed herein, the term “about” can be inserted before the integer.

[0040] Throughout this specification, unless the context requires otherwise, the word “comprise”, or variations such as “comprises” or “comprising” will be understood to imply the51896-0040 WO1 1318-WO-PCT 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.

[0041] Throughout this specification, unless specifically stated otherwise or the context requires otherwise, reference to a single step, composition of matter, group of steps, or group of compositions of matter shall be taken to encompass one and a plurality (i.e., one or more) of those steps, compositions of matter, groups of steps, or groups of compositions of matter.

[0042] Each embodiment described herein is to be applied mutatis mutandis to each and every other embodiment unless specifically stated otherwise.

[0043] Those skilled in the art will appreciate that the invention(s) described herein is susceptible to variations and modifications other than those specifically described. It is to be understood that the invention(s) includes all such variations and modifications. The invention(s) also includes all the steps, features, compositions and compounds referred to or indicated in this specification, individually or collectively, and any and all combinations or any two or more of said steps or features unless specifically stated otherwise.

[0044] The present invention(s) is not to be limited in scope by the specific embodiments described herein, which are intended for the purpose of exemplification only. Functionally equivalent products, compositions, and methods are clearly within the scope of the invention(s), as described herein.

[0045] It is appreciated that certain features of the invention(s), which are, for clarity, described in the context of separate embodiments, can also be provided in combination in a single embodiment. Conversely, various features of the invention(s), which are, for brevity, described in the context of a single embodiment, can also be provided separately or in any suitable subcombination. For example, a method that recites prescribing and / or administering Compound 1, or a pharmaceutically acceptable salt thereof can be separated into two methods; one method reciting prescribing Compound 1, or a pharmaceutically acceptable salt thereof and the other method reciting administering Compound 1, or a pharmaceutically acceptable salt thereof. In addition, for example, a method that recites prescribing Compound 1, or a pharmaceutically acceptable salt thereof and a separate method of the invention reciting administering Compound 1, or a pharmaceutically acceptable salt thereof can be combined into a single method reciting prescribing and / or administering Compound 1, or a pharmaceutically acceptable salt thereof.51896-0040 WO1 1318-WO-PCT

[0046] ANTIEPILEPTIC DRUG (AED): As used herein, “antiepileptic drug” refers to any pharmaceutical drug, both alone and in combination with another drug used for treating epilepsy and seizures. Such AEDs could be ethosuximide, lamotrigine, topiramate, valproate, zonisamide, phenytoin, carbamazepine, gabapentin or levetiracetam. An AED could also be a drug having effect on Ca2+-channels, Na+-channels, or influencing GABA or the AMPA / kainate receptor.

[0047] SEIZURE: As used herein, “seizure” is intended to have its ordinary meaning in the art. Usually it is defined as an abnormal electrical activity in the brain where several changes can occur such as movement and / or consciousness.

[0048] CONTROL and CONTROLLING: As used herein, “control” and “controlling” are intended to mean controlling the progression of DEE or other epilepsy types and thereby reducing the risk of SUDEP. In some embodiments controlling SUDEP may encompass a reduction in SUDEP risk and / or maintaining the treatment effect of Compound 1.METHODS

[0049] Provided is a method of reducing likelihood of seizure-induced sudden unexpected death in epilepsy (SUDEP) in a patient in need thereof, wherein the method comprises administering to the patient in need thereof a therapeutically effective amount of (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.

[0050] Also provided is a method of treating seizures in a patient suffering from a disease with which sudden unexpected death in epilepsy (SUDEP) can occur, wherein the method comprises administering to the patient in need thereof a therapeutically effective amount of (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.

[0051] Also provided is a method of treating seizure-induced sudden unexpected death in epilepsy (SUDEP) in a patient suffering from a disease with which SUDEP can occur, wherein the method comprises administering to the patient in need thereof a therapeutically effective amount of (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.51896-0040 WO 1 1318-WO-PCT

[0052] Also provided is a method of preventing or controlling seizure-induced sudden unexpected death in epilepsy (SUDEP) in a patient in need thereof, wherein the method comprises administering to the patient in need thereof a therapeutically effective amount of (R)- N-(2,2-difh oroethyl)-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.

[0053] In some embodiments the disease with which sudden unexpected death in epilepsy (SUDEP) can occur or wherein it is known to occur is a developmental and epileptic encephalopathy (DEE). In some embodiments, the disease with which sudden unexpected death in epilepsy (SUDEP) can occur or is known to occur is Dravet syndrome, Ohtahara syndrome (EIDEE), tuberous sclerosis complex (TSC), Angelman syndrome, myoclonic astatic epilepsy, or Lennox-Gastaut syndrome, Doose syndrome (EM AS), West syndrome (infantile spasms), Prader-Willi, Landau-Kleffner syndrome, CDKL5 encephalopathy (CDKL5 deficiency disorder), dup!5q syndrome, SCN2A related epilepsies, SCN8A related epilepsies, KCNQ2 related epilepsies, KCNQ3 related epilepsies, KCNT1 related epilepsies, SynGAPl related epilepsies, Rett syndrome, PCDH19 epilepsy, ring 14 syndrome, ring 20 syndrome, CHD2 encephalopathy, early myoclonic encephalopathy, epilepsy of infancy with migrating focal seizures, or epileptic encephalopathy with continuous spike-wave. In some embodiments, the disease with which sudden unexpected death in epilepsy (SUDEP) can occur or is known to occur is Dravet syndrome. In some embodiments, the disease with which sudden unexpected death in epilepsy (SUDEP) can occur or is known to occur is Lennox-Gastaut syndrome.

[0054] In some embodiments, the patient is having more than three generalized tonic-clonic seizures per year.

[0055] In some embodiments, the patient is not taking medications as prescribed.

[0056] In some embodiments, the patient had an early age of epilepsy onset.

[0057] In some embodiments, the patient has uncontrolled or frequent seizures.

[0058] In some embodiments, administration results in a decreased incidence of seizures. In some embodiments, administration results in increased latency to seizures.

[0059] 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, 69,51896-0040 WO1 1318-WO-PCT70, 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.

[0060] In some embodiments, Compound 1, or a pharmaceutically acceptable salt thereof, is administered via a titration scheme that comprises the up-titration of Compound 1, or a pharmaceutically acceptable salt thereof, until an optimized dosage is administered.

[0061] In some embodiments, the dose of Compound 1, or a pharmaceutically acceptable salt thereof, is titrated to an amount equivalent to about 9 mg of Compound 1 daily. In some embodiments, the dose of Compound 1, or a pharmaceutically acceptable salt thereof, is titrated to an amount equivalent to about 18 mg of Compound 1 daily. In some embodiments, the dose of Compound 1, or a pharmaceutically acceptable salt thereof, is titrated to an amount equivalent to about 36 mg of Compound 1 daily. In some embodiments, the dose of Compound 1, or a pharmaceutically acceptable salt thereof, is titrated to an amount equivalent to about 54 mg of Compound 1 daily. In some embodiments, the dose of Compound 1, or a pharmaceutically acceptable salt thereof, is titrated to an amount equivalent to about 72 mg of Compound 1 daily.51896-0040 WO1 1318-WO-PCT

[0062] In some embodiments, the dose of Compound 1, or a pharmaceutically acceptable salt thereof, is down-titrated to, or to an amount 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 daily. In some embodiments, the dose of Compound 1, or a pharmaceutically acceptable salt thereof, is down-titrated to an amount equivalent to about 54 mg of Compound 1 daily. In some embodiments, the dose of Compound 1, or a pharmaceutically acceptable salt thereof, is downtitrated to an amount equivalent to about 36 mg of Compound 1 daily. In some embodiments, the dose of Compound 1, or a pharmaceutically acceptable salt thereof, is down-titrated to an amount equivalent to about 18 mg of Compound 1 daily. In some embodiments, the dose of Compound 1, or a pharmaceutically acceptable salt thereof, is down-titrated to an amount equivalent to about 9 mg of Compound 1 daily. In some embodiments, the total daily dosage of Compound 1, or a pharmaceutically acceptable salt thereof, is down-titrated to a dosage 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 down-titrated to a dosage equivalent to about 3 mg of Compound 1.

[0063] In some embodiments, the increasing of the dosage of Compound 1, or a pharmaceutically acceptable salt thereof, 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 increasing of the dosage of Compound 1, or a pharmaceutically acceptable salt thereof, 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.

[0064] In some embodiments, the titration scheme comprises prescribing and / or administering Compound 1, or a pharmaceutically acceptable salt thereof, at an initial dosage (also referred to51896-0040 WO1 1318-WO-PCT 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 and, provided that the patient tolerates the initial dosage, increasing the dosage. 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 and, provided that the patient tolerates the initial dosage and that the patient has not had an adequate response, increasing the dosage. In some embodiments, the titration scheme comprises prescribing and / or administering Compound 1, or a pharmaceutically acceptable salt thereof, two or three times daily 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 for about 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 days and, provided that the patient tolerates the initial dosage, increasing the dosage. In some embodiments, the titration scheme comprises prescribing and / or administering Compound 1, or a pharmaceutically acceptable salt thereof, two or three times daily 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 for about 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 days and, provided that the patient tolerates the initial dosage and that the patient has not had an adequate response, increasing the dosage. 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 and, provided that the patient tolerates the initial dosage and that the patient has not had an adequate response, increasing the dosage.

[0065] In some embodiments, the increased dosage is optimized for further response. In some embodiments, the increased dosage is equivalent to about 3 mg / dose of Compound 1. In some embodiments, the increased dosage is equivalent to about 6 mg / dose of Compound 1. In some embodiments, the increased dosage is equivalent to about 9 mg / dose of Compound 1. In some embodiments, the increased dosage is equivalent to about 12 mg / dose of Compound 1. In some embodiments, the increased dosage is equivalent to about 15 mg / dose of Compound 1. In some embodiments, the increased dosage is equivalent to about 18 mg / dose of Compound 1.

[0066] In some embodiments, the titration scheme further comprises administering Compound 1, or a pharmaceutically acceptable salt thereof, at the increased dosage for about 2, 3, 4, 5, 6, 7, 8,51896-0040 WO1 1318-WO-PCT9, or 10 days. In some embodiments, the titration scheme further comprises administering Compound 1, or a pharmaceutically acceptable salt thereof, at the increased dosage for about two days. In some embodiments, the titration scheme further comprises administering Compound 1, or a pharmaceutically acceptable salt thereof, at the increased dosage for about five days.

[0067] In some embodiments, if the patient does not tolerate the increased dosage, the optimized dosage is the initial dosage.

[0068] In some embodiments, if the patient tolerates the increased dosage, the optimized dosage is the increased dosage. In some embodiments, if the patient tolerates the increased dosage and if the patient has had an adequate response, the optimized dosage is the increased dosage.

[0069] In some embodiments, the titration scheme comprises further increasing the dosage, provided that the patient tolerates the increased dosage. In some embodiments, the titration scheme comprises further increasing the dosage, provided that the patient tolerates the increased dosage and that the patient has not had an adequate response. In some embodiments, the further increased dosage is optimized for 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.

[0070] In some embodiments, the titration scheme further comprises administering Compound 1, or a pharmaceutically acceptable salt thereof, at the further increased dosage 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 the further increased dosage for about two days. In some embodiments, the titration scheme further comprises administering Compound 1, or a pharmaceutically acceptable salt thereof, at the further increased dosage for about five days.

[0071] In some embodiments, if the patient does not tolerate the further increased dosage, the optimized dosage is the increased dosage.

[0072] In some embodiments, if the patient tolerates the further increased dosage, the optimized dosage is the further increased dosage. In some embodiments, if the patient tolerates the further increased dosage and if the patient has had an adequate response, the optimized dosage is the further increased dosage.51896-0040 WO1 1318-WO-PCT

[0073] In some embodiments, the titration scheme further comprises administering the optimized dosage of Compound 1, or a pharmaceutically acceptable salt thereof, to the patient.

[0074] In some embodiments, if the patient tolerates the increased dosage and if the patient has not had an adequate response, the method further comprises increasing the dosage.

[0075] In some embodiments, the titration scheme further comprises administering the optimized dosage of Compound 1, or a pharmaceutically acceptable salt thereof, to the patient.

[0076] In some embodiments, for example, when the patient does not tolerate the increased dosage of Compound 1, or a pharmaceutically acceptable salt thereof, the titration scheme further comprises down-titration of Compound 1, or a pharmaceutically acceptable salt thereof. In some embodiments, the down-titration comprises reducing the dosage of Compound 1, or a pharmaceutically acceptable salt thereof, being administered to the patient by an increment equivalent 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 down-titration scheme comprises reducing the dosage of Compound 1, or a pharmaceutically acceptable salt thereof, being administered to the patient once. In some embodiments, the down-titration scheme comprises reducing the dosage of Compound 1, or a pharmaceutically acceptable salt thereof, being administered to the patient more than once. In some embodiments, the down-titration scheme comprises reducing the dosage of Compound 1, or a pharmaceutically acceptable salt thereof, being 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 being administered Compound 1, or a pharmaceutically acceptable salt thereof.

[0077] In some embodiments, the dosage of Compound 1, or a pharmaceutically acceptable salt thereof, is down-titrated to address an observed side effect. In some embodiments, the dosage of Compound 1, or a pharmaceutically acceptable salt thereof, is down-titrated to minimize the risk of a withdrawal induced side effect.

[0078] In some embodiments, the patient is also being administered an antiepileptic drug or antiseizure medicine. In some embodiments, the patient is also being administered an antiepileptic drug effective in suppressing interictal epileptiform discharges (e.g., benzodiazepines, valproic acid, and lamotrigine). In some embodiments, the patient is also being administered an immunomodulatory therapy (e.g., corticosteroids, intravenous immunoglobulin [IVIG], plasmapheresis). In some embodiments, the patient is also being administered a51896-0040 WO 1 1318-WO-PCT ketogenic diet. In some embodiments, the patient is also being administered vagal nerve stimulation (VNS) or deep brain stimulation (DBS).TID Dosing

[0079] In some embodiments, Compound 1, or a pharmaceutically acceptable salt thereof, is administered three times daily (TID).

[0080] In some embodiments, the dose of Compound 1, or a pharmaceutically acceptable salt thereof, is equivalent to about 3 mg of Compound 1 TID. In some embodiments, the dose of Compound 1, or a pharmaceutically acceptable salt thereof, is equivalent to about 6 mg of Compound 1 TID. In some embodiments, the dose of Compound 1, or a pharmaceutically acceptable salt thereof, is equivalent to about 9 mg of Compound 1 TID. In some embodiments, the dose of Compound 1, or a pharmaceutically acceptable salt thereof, is equivalent to about 12 mg of Compound 1 TID. In some embodiments, the dose of Compound 1, or a pharmaceutically acceptable salt thereof, is equivalent to about 24 mg of Compound 1 TID.

[0081] In some embodiments, Compound 1, or a pharmaceutically acceptable salt thereof, is administered via a titration scheme that comprises the up-titration of Compound 1, or a pharmaceutically acceptable salt thereof, until an optimized dosage is administered TID.

[0082] In some embodiments, the increasing the dose of Compound 1, or a pharmaceutically acceptable salt thereof, in increments equivalent to about 3 mg Compound 1 TID every 5 days until the optimized dose is administered. In some embodiments, the optimized dose is equivalent to about 3 mg Compound 1 TID. In some embodiments, the optimized dose is equivalent to about 6 mg Compound 1 TID. In some embodiments, the optimized dose is 9 mg TID. In some embodiments, the optimized dose is equivalent to about 12 mg Compound 1 TID.

[0083] In some embodiments, the titration scheme comprises prescribing and / or administering Compound 1, or a pharmaceutically acceptable salt thereof, at an initial dose equivalent to 6 mg of Compound 1 three time daily for about five days and, provided that the patient tolerates the initial dose and that the patient has not had an adequate response, increasing the dose.

[0084] In some embodiments, the increased dose is equivalent to 9 mg of Compound 1 three time daily.

[0085] In some embodiments, the titration scheme further comprises administering Compound 1, or a pharmaceutically acceptable salt thereof, at the increased dose for about five days.51896-0040 WO1 1318-WO-PCT

[0086] In some embodiments, if the patient does not tolerate the increased dose, the optimized dose is the initial dose.

[0087] In some embodiments, if the patient tolerates the increased dose and if the patient has had an adequate response, the optimized dose is the increased dose.

[0088] In some embodiments, the titration scheme further comprises administering the optimized dose of Compound 1, or a pharmaceutically acceptable salt thereof, to the patient.

[0089] In some embodiments, if the patient tolerates the increased dose and if the patient has not had an adequate response, the method further comprises increasing the dose.

[0090] In some embodiments, the further increased dose is equivalent to about 12 mg of Compound 1 three times daily.

[0091] In some embodiments, if the patient does not tolerate the further increased dose, the optimized dose is the increased dose.

[0092] In some embodiments, if the patient tolerates the further increased dose and if the patient has had an adequate response, the optimized dose is the further increased dose.

[0093] In some embodiments, the titration scheme further comprises administering the optimized dose of Compound 1, or a pharmaceutically acceptable salt thereof, to the patient.

[0094] In some embodiments, for example, when the patient does not tolerate the optimized dose of Compound 1, or a pharmaceutically acceptable salt thereof, the method further comprises a down-titration scheme. In some embodiments, the down-titration scheme comprises reducing the dose of Compound 1, or a pharmaceutically acceptable salt thereof, being administered to the patient in an amount equivalent to about, 1, 2, 3, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12 mg Compound 1 per day. In some embodiments, the down-titration scheme comprises reducing the dose of Compound 1, or a pharmaceutically acceptable salt thereof, being administered to the patient once. In some embodiments, the down-titration scheme comprises reducing the dose of Compound 1, or a pharmaceutically acceptable salt thereof, being administered to the patient more than once. In some embodiments, the down-titration scheme comprises reducing the dose of Compound 1, or a pharmaceutically acceptable salt thereof, being administered to the patient in increments equivalent to about 3 mg Compound 1 TID every 5 days until the patient is no longer being administered Compound 1, or a pharmaceutically acceptable salt thereof.

[0095] In some embodiments, the dose of Compound 1, or a pharmaceutically acceptable salt thereof, is down-titrated to address an observed side effect. In some embodiments, the dose of51896-0040 WO1 1318-WO-PCTCompound 1 , or a pharmaceutically acceptable salt thereof, is down-titrated to minimize the risk of a withdrawal induced side effect.Body-Weight Dosing

[0096] In some embodiments, Compound 1, or a pharmaceutically acceptable salt thereof, is administered in an amount based on the body weight of the patient.

[0097] In some embodiments, Compound 1, or a pharmaceutically acceptable salt thereof, is administered via a titration scheme that comprises the up-titration of Compound 1, or a pharmaceutically acceptable salt thereof, until an optimized dosage is administered.

[0098] In some embodiments, the titration scheme comprises administering Compound 1, or a pharmaceutically acceptable salt thereof, at an initial dosage equivalent to about 0.11 mg / kg of Compound 1 TID and, provided that the patient tolerates the initial dosage and that the patient has not had an adequate response, increasing the dosage.

[0099] In some embodiments, the patient is more than 2 years of age and is administered Compound 1, or a pharmaceutically acceptable salt thereof, at an initial dosage equivalent to about 0.11 mg / kg of Compound 1 TID.

[0100] In some embodiments, the increased dosage is equivalent to about 0.17 mg / kg of Compound 1 TID.

[0101] In some embodiments, if the patient does not tolerate the increased dosage, the optimized dosage is the initial dosage.

[0102] In some embodiments, if the patient tolerates the increased dosage and if the patient has had an adequate response, the optimized dosage is the increased dosage.

[0103] In some embodiments, the titration scheme comprises further increasing the dosage, provided that the patient tolerates the increased dosage and that the patient has not had an adequate response.

[0104] In some embodiments, the further increased dosage is equivalent to about 0.24 mg / kg Compound 1 free base three times daily (TID).

[0105] In some embodiments, if the patient tolerates the further increased dosage and if the patient has had an adequate response, the optimized dosage is the further increased dosage.

[0106] In some embodiments, the method further comprises administering the optimized dosage of Compound 1, or a pharmaceutically acceptable salt thereof, to the patient.51896-0040 WO 1 1318-WO-PCT

[0107] In some embodiments, the dosage of Compound 1, or a pharmaceutically acceptable salt thereof, is down-titrated to address an observed side effect. In some embodiments, the dosage of Compound 1, or a pharmaceutically acceptable salt thereof, is down-titrated to minimize the risk of a withdrawal induced side effect.

[0108] In some embodiments, the dosage of Compound 1, or a pharmaceutically acceptable salt thereof, is gradually increased, i.e., up-titrated, to achieve the highest maintenance dose based on tolerability.

[0109] In some embodiments, the patient is less than 2 years of age. In some embodiments, the patient is less than 2 years of age and the maintenance dose is equivalent to up to about 0.3 mg / kg TID Compound 1 free base three times daily.

[0110] In some embodiments, the patient is an infant (29 days to less than 2 years). In some embodiments, the patient is an infant (29 days to less than 2 years) and is administered Compound 1, or a pharmaceutically acceptable salt thereof, at a dosage equivalent to from about 0.03 to about 0.05 mg / kg Compound 1 free base three times daily (TID) as the initial dose.

[0111] In some embodiments, the patient is less than 2 years of age and is administered Compound 1, or a pharmaceutically acceptable salt thereof, at a dosage equivalent to about 0.03 mg / kg Compound 1 free base three times daily (TID). In some embodiments, the patient is less than 2 years of age and is administered Compound 1, or a pharmaceutically acceptable salt thereof, at a dosage equivalent to about 0.05 mg / kg Compound 1 free base three times daily (TID) as the initial dose.

[0112] In some embodiments, the patient is an infant (29 days to less than 2 years) and has body weight of approximately 3 to 10 kg. In some embodiments, the patient is an infant boy and has a body weight between about 10.6 kg and about 15.2 kg. In some embodiments, the patient is an infant female and has a body weight between about and 10.2 kg and 14.6 kg.

[0113] In some embodiments, the patient is a child (2 years to less than 12 years).

[0114] In some embodiments, the patient is an adolescent (12 years to 21 years (up to but not including the 22ndbirthday).

[0115] In some embodiments, the patient is an adult (22 years or older).

[0116] In some embodiments, the patient is < 40 kg and Compound 1, or a pharmaceutically acceptable salt thereof, is administered at a dose equivalent to Compound 1 free base TID according to the following schedule:51896-0040 WO1 1318-WO-PCT• Bodyweight based dosing for < 40 kg and fixed dosing if >40 kg bodyweightBID Dosing

[0117] In some embodiments, Compound 1, or a pharmaceutically acceptable salt thereof, is administered twice daily.

[0118] In some embodiments, Compound 1, or a pharmaceutically acceptable salt thereof, is administered via a titration scheme that comprises the up-titration of Compound 1, or a pharmaceutically acceptable salt thereof, until an optimized dosage is administered.

[0119] In some embodiments, Compound 1, or a pharmaceutically acceptable salt thereof, is administered twice daily in a dosage equivalent to about 3 mg / dose of Compound 1. In some embodiments, the Compound 1, or a pharmaceutically acceptable salt thereof, is administered twice daily in a dosage equivalent to about 6 mg / dose of Compound 1. In some embodiments, Compound 1, or a pharmaceutically acceptable salt thereof, is administered twice daily in a dosage equivalent to about 9 mg / dose of Compound 1. In some embodiments, Compound 1, or a pharmaceutically acceptable salt thereof, is administered twice daily in a dosage equivalent to about 12 mg / dose of Compound 1. In some embodiments, Compound 1, or a pharmaceutically acceptable salt thereof, is administered twice daily in a dosage equivalent to about 18 mg / dose of Compound 1. In some embodiments, Compound 1, or a pharmaceutically acceptable salt thereof, is administered twice daily in a dosage equivalent to about 24 mg / dose of Compound 1.

[0120] In some embodiments, Compound 1, or a pharmaceutically acceptable salt thereof, is administered twice daily in a dosage equivalent to about 3 mg / dose of Compound 1. In some embodiments, the Compound 1, or a pharmaceutically acceptable salt thereof, is administered twice daily in a dosage equivalent to about 6 mg / dose of Compound 1. In some embodiments, Compound 1, or a pharmaceutically acceptable salt thereof, is administered twice daily in a dosage equivalent to about 9 mg / dose of Compound 1. In some embodiments, Compound 1, or a51896-0040 wot 1318-WO-PCT pharmaceutically acceptable salt thereof, is administered twice daily in a dosage equivalent to about 12 mg / dose of Compound 1. In some embodiments, Compound 1, or a pharmaceutically acceptable salt thereof, is administered twice daily in a dosage equivalent to about 15 mg / dose of Compound 1. In some embodiments, Compound 1, or a pharmaceutically acceptable salt thereof, is administered twice daily in a dosage equivalent to about 18 mg / dose of Compound 1. In some embodiments, Compound 1, or a pharmaceutically acceptable salt thereof, is administered twice daily in a dosage equivalent to about 24 mg / dose of Compound 1.

[0121] In some embodiments, Compound 1, or a pharmaceutically acceptable salt thereof, is administered via a titration scheme that includes the up-titration of Compound 1, or a pharmaceutically acceptable salt thereof, until an optimized dosage is administered.

[0122] In some embodiments, the total daily dosage of Compound 1, or a pharmaceutically acceptable salt thereof, is titrated to a dosage 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 titrated to a dosage 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 titrated to a dosage 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 titrated to a dosage 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 titrated to a dosage 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 titrated to a dosage 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 titrated to a dosage equivalent to about 72 mg of Compound 1.Formulations

[0123] In some embodiments, the Compound 1, or a pharmaceutically acceptable salt thereof, is an HC1 salt of Compound 1.51896-0040 WO1 1318-WO-PCT

[0124] In some embodiments, Compound 1, or a pharmaceutically acceptable salt thereof, is administered as a raw or pure chemical, for example as a powder in capsule formulation.

[0125] 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.

[0126] Pharmaceutical compositions may be prepared by any suitable method, typically by uniformly mixing the active compound(s) with liquids or finely divided solid carriers, or both, in the required proportions and then, if necessary, forming the resulting mixture into a desired shape.

[0127] Conventional excipients, such as binding agents, fillers, acceptable wetting agents, tableting lubricants and disintegrants may 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 in the art. Suitable pharmaceutically acceptable carriers, outside those mentioned herein, are known in the art; for example, see Remington, The Science and Practice of Pharmacy, 20thEdition, 2000, Lippincott Williams & Wilkins, (Editors: Gennaro et al.)

[0128] In some embodiments, the Compound 1, or a pharmaceutically acceptable salt thereof, is formulated in a manner suitable for oral administration.

[0129] For oral administration, the pharmaceutical composition may be in the form of, for example, a tablet or capsule. The pharmaceutical composition is preferably made in the form of a dosage unit containing a particular amount of the active ingredient. Examples of such dosage units are capsules, tablets, powders, granules or suspensions, with conventional additives such as lactose, mannitol, corn starch or potato starch; with binders such as crystalline cellulose, cellulose derivatives, acacia, com starch or gelatins; with disintegrators such as corn starch, potato starch or sodium carboxymethyl-cellulose; and with lubricants such as talc or magnesium stearate. Solid form preparations include powders, tablets, pills, capsules, cachets, suppositories, and dispersible granules. A solid carrier can be one or more substances which may also act as diluents, flavoring agents, solubilizers, lubricants, suspending agents, binders, preservatives, tablet disintegrating agents, or encapsulating materials.

[0130] In powders, the carrier is a finely divided solid which is in a mixture with the finely divided active component.51896-0040 WO1 1318-WO-PCT

[0131] In tablets, the active component is mixed with the carrier having the necessary binding capacity in suitable proportions and compacted to the desired shape and size.

[0132] The powders and tablets may contain varying percentage amounts of the active compound. A representative amount in a powder or tablet may be from 0.5 to about 90 percent of the active compound. However, an artisan would know when amounts outside of 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 carboxymethyl cellulose, a low melting wax, cocoa butter, and the like. The term “preparation” includes the formulation of the active compound with encapsulating material as carrier providing a capsule in which the active component, with or without carriers, is surrounded by a carrier, which is thus in association with it. Similarly, cachets and lozenges are included. Tablets, powders, capsules, pills, cachets, and lozenges can be used as solid forms suitable for oral administration.

[0133] For oral administration, the pharmaceutical composition may be in the form of suitable for administration via gastrostomy tube or percutaneous endoscopic gastrostomy tube.

[0134] The pharmaceutical preparations are preferably in unit dosage forms. In such form, the preparation is subdivided into unit doses containing appropriate quantities of the active component. The unit dosage form can be a packaged preparation, the package containing discrete quantities of preparation, such as packeted 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.

[0135] Further embodiments include the embodiments disclosed in the following Examples, which is not to be construed as limiting in any way.FURTHER EMBODIMENTS OF THE INVENTION:1. Provided is a method of reducing likelihood of seizure-induced sudden unexpected death in epilepsy (SUDEP) in a patient in need thereof, wherein the method comprises administering to the patient in need thereof a therapeutically effective amount of (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.51896-0040 WO1 1318-WO-PCT Also provided is a method of treating seizures in a patient suffering from a disease with which sudden unexpected death in epilepsy (SUDEP) can occur, wherein the method comprises administering to the patient in need thereof a therapeutically effective amount of (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. Also provided is a method of treating seizure-induced sudden unexpected death in epilepsy (SUDEP) in a patient suffering from a disease with which SUDEP can occur, wherein the method comprises administering to the patient in need thereof a therapeutically effective amount of (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. Also provided is a method of preventing or controlling seizure-induced sudden unexpected death in epilepsy (SUDEP) in a patient in need thereof, wherein the method comprises administering to the patient in need thereof a therapeutically effective amount of (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 the patient suffers from developmental and epileptic encephalopathy (DEE). In some embodiments, the DEE is selected from Lennox-Gastaut syndrome, Dravet syndrome, Prader-Willi, Doose syndrome (EM AS), West syndrome (infantile spasms), Landau-Kleffner syndrome, and genetic disorders such as CDKL5 encephalopathy (CDK5L deficiency disorder) or CHD3 encephalopathy. In some embodiments the patient suffers from a disease selected from Dravet syndrome, Ohtahara syndrome (EIDEE), tuberous sclerosis complex (TSC), Angelman syndrome, myoclonic astatic epilepsy, Lennox-Gastaut syndrome, Doose syndrome (EM AS), West51896-0040 WO 1 1318-WO-PCT syndrome (infantile spasms), Prader-Willi, Landau-Kleffner syndrome, CDKL5 encephalopathy (CDKL5 deficiency disorder), dupl5q syndrome, SCN2A related epilepsies, SCN8A related epilepsies, KCNQ2 related epilepsies, KCNQ3 related epilepsies, KCNT1 related epilepsies, SynGAPl related epilepsies, Rett syndrome, PCDH19 epilepsy, ring 14 syndrome, ring 20 syndrome, CHD2 encephalopathy, early myoclonic encephalopathy, epilepsy of infancy with migrating focal seizures, and epileptic encephalopathy with continuous spike-wave. In some embodiments, the patient has Dravet syndrome. In some embodiments, the patient has Lennox-Gastaut syndrome. In some embodiments, the patient suffers from a disease selected from epilepsy, epilepsy with generalized tonic-clonic seizures, epilepsy with myoclonic absences, frontal lobe epilepsy, temporal lobe epilepsy, Landau-Kleffner Syndrome, Rasmussen's syndrome, Dravet syndrome, Doose syndrome (epilepsy with myoclonic atonic seizures (EM AS)), CDKL5 deficiency disorder (CDKL5 encephalopathy, or CDD), infantile spasms (West syndrome), juvenile myoclonic epilepsy (JME), vaccine-related encephalopathy, intractable childhood epilepsy (ICE), Lennox-Gastaut syndrome (LGS), Rett syndrome, Ohtahara syndrome (early infantile DEE, EIDEE), childhood absence epilepsy, essential tremor, acute repetitive seizures, benign rolandic epilepsy, status epilepticus, refractory status epilepticus, super-refractory status epilepticus (SRSE), PCDH19 pediatric epilepsy, drug withdrawal induced seizures, alcohol withdrawal induced seizures, increased seizure activity and breakthrough seizures. In some embodiments, the patient has had more than three generalized tonic-clonic seizures per year prior to administration of Compound 1. In some embodiments, the patient has had more than 13-30 seizures in a year, such as 13- 20 or 13-25 seizures prior to administration of Compound 1.51896-0040 WO 1 1318-WO-PCT In some embodiments, the patient has had 1 1-20 generalized tonic-clonic seizures within the last three months prior to administration of Compound 1. In some embodiments, the patient has an IQ below 70, such as 50-70 or 60-70. In some embodiments, the patient has had 3-5 antiepileptic drug (AED) changes in the last year prior to administration of Compound 1. In some embodiments, the patient has been administered three or more AEDs, such as 3- 5, 3-6, or 3-7 AEDs, prior to administration of Compound 1. In some embodiments, the patient did not receive any AED treatment, prior to administration of Compound 1. In some embodiments, the patient has had an early age of epilepsy onset, such as an onset occurring at age 0-2, 3-5, or 6-11. In some embodiments, the patient has had uncontrolled or frequent seizures prior to administration of Compound 1. In some embodiments, Compound 1, or a pharmaceutically acceptable salt thereof, is administered twice daily. In some embodiments, the dose of Compound 1, or a pharmaceutically acceptable salt thereof, is equivalent to 5 mg / dose to 25 mg / dose, such as 12 mg / dose, 15 mg / dose, or 18 mg / dose, as a free base BID or TID. In some embodiments, Compound 1, or a pharmaceutically acceptable salt thereof, is administered three times daily.51896-0040 WO 1 1318-WO-PCT23. In some embodiments, the dose of Compound 1, or a pharmaceutically acceptable salt thereof, is equivalent to 3 mg-20 mg, such as 6 mg, 9 mg, or 12 mg, as a free base BID or TID.24. In some embodiments, Compound 1, or a pharmaceutically acceptable salt thereof, is administered via a titration scheme that comprises the up-titration of Compound 1, or a pharmaceutically acceptable salt thereof, until an optimized dosage is administered.25. In some embodiments, the dose of Compound 1, or a pharmaceutically acceptable salt thereof, is equivalent to 0.03 mg / kg-0.40 mg / kg, such as 0.11 mg / kg, 0.17 mg / kg, 0.24 mg / kg or 0.30 mg / kg, as a free base, for patients having a bodyweight <40 kg.26. In some embodiments, administration of Compound 1 via a titration scheme that comprises the up-titration of Compound 1, or a pharmaceutically acceptable salt thereof, until an optimized dosage is administered further comprises administering the optimized dosage of Compound 1, or a pharmaceutically acceptable salt thereof, to the patient.27. In some embodiments, Compound 1, or a pharmaceutically acceptable salt thereof, is an HC1 salt of Compound 1.FURTHER EMBODIMENTS OF THE INVENTION:The invention further relates to the following embodiments (E1-E27)El : (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 for use in reducing likelihood of seizure-induced sudden unexpected death in epilepsy (SUDEP) in a patient in need thereof, wherein the use comprises administering to the patient in need thereof a therapeutically effective amount of (R)-N-(2,2-difluoroethyl)-7-methyl-l,2,3,4,6,7-hexahydro-51896-0040 WO1 1318-WO-PCT[l,4]diazepino[6,7,l-hi]indole-8-carboxamide (Compound 1), or a pharmaceutically acceptable salt thereof.E2: (R)-N-(2,2-difhjoroethyl)-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 for use in treating seizures in a patient suffering from a disease with which sudden unexpected death in epilepsy (SUDEP) can occur, wherein the use comprises administering to the patient in need thereof a therapeutically effective amount of (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.E3: (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 for use in treating seizure-induced sudden unexpected death in epilepsy (SUDEP) in a patient suffering from a disease with which SUDEP can occur, wherein the use comprises administering to the patient in need thereof a therapeutically effective amount of (R)-N-(2,2-difhioroethyl)-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.E4: (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 for use in preventing or controlling seizure-induced sudden unexpected death in epilepsy (SUDEP) in a patient in need thereof, wherein the use comprises administering to the patient in need thereof a therapeutically effective amount of (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.51896-0040 WO1 1318-WO-PCTE5: Compound 1 for use according to any of the preceding embodiments, wherein said patient suffers from developmental and epileptic encephalopathy (DEE).E6: Compound 1 for use according to E5, wherein the DEE is selected from Lennox-Gastaut syndrome, Dravet syndrome, Prader-Willi, Doose syndrome (EM AS), West syndrome (infantile spasms), Landau-Kleffner syndrome, and genetic disorders such as CDKL5 encephalopathy (CDK5L deficiency disorder) or CHD3 encephalopathy.E7: Compound 1 for use according to any one of E1-E5, wherein said patient suffers from a disease selected from Dravet syndrome, Ohtahara syndrome (EIDEE), tuberous sclerosis complex (TSC), Angelman syndrome, myoclonic astatic epilepsy, Lennox-Gastaut syndrome, Doose syndrome (EM AS), West syndrome (infantile spasms), Prader-Willi, Landau-Kleffner syndrome, CDKL5 encephalopathy (CDKL5 deficiency disorder), dupl5q syndrome, SCN2A related epilepsies, SCN8A related epilepsies, KCNQ2 related epilepsies, KCNQ3 related epilepsies, KCNT1 related epilepsies, SynGAPl related epilepsies, Rett syndrome, PCDH19 epilepsy, ring 14 syndrome, ring 20 syndrome, CHD2 encephalopathy, early myoclonic encephalopathy, epilepsy of infancy with migrating focal seizures, and epileptic encephalopathy with continuous spike-wave.E8: Compound 1 for use according to any one of E1-E5, wherein said patient has Dravet syndrome.E9: Compound 1 for use according to any one of E1-E5, wherein said patient has Lennox- Gastaut syndrome.E10: Compound 1 for use according to any one of E1-E4, wherein said patient suffers from a disease selected from epilepsy, epilepsy with generalized tonic-clonic seizures, epilepsy with51896-0040 WO1 1318-WO-PCT myoclonic absences, frontal lobe epilepsy, temporal lobe epilepsy, Landau-Kleffner Syndrome, Rasmussen's syndrome, Dravet syndrome, Doose syndrome (epilepsy with myoclonic atonic seizures (EM AS)), CDKL5 deficiency disorder (CDKL5 encephalopathy, or CDD), infantile spasms (West syndrome), juvenile myoclonic epilepsy (JME), vaccine-related encephalopathy, intractable childhood epilepsy (ICE), Lennox-Gastaut syndrome (LGS), Rett syndrome, Ohtahara syndrome (early infantile DEE, EIDEE), childhood absence epilepsy, essential tremor, acute repetitive seizures, benign rolandic epilepsy, status epilepticus, refractory status epilepticus, super-refractory status epilepticus (SRSE), PCDH19 pediatric epilepsy, drug withdrawal induced seizures, alcohol withdrawal induced seizures, increased seizure activity and breakthrough seizures.El l : Compound 1 for use according to any of the preceding embodiments, wherein said patient has had more than three generalized tonic-clonic seizures per year prior to administration of Compound 1.E12: Compound 1 for use according to any one of the preceding embodiments, wherein said patient has had more than 13-30 seizures in a year, such as 13-20 or 13-25 seizures prior to administration of Compound 1.El 3: Compound 1 for use according to any one of the preceding embodiments, wherein said patient has had 11-20 generalized tonic-clonic seizures within the last three months prior to administration of Compound 1.E14: Compound 1 for use according to any one of the preceding embodiments, wherein said patient has an IQ below 70, such as 50-70 or 60-70.51896-0040 WO1 1318-WO-PCTEl 5: Compound 1 for use according to any one of the preceding embodiments, wherein said patient has had 3-5 antiepileptic drug (AED) changes in the last year prior to administration of Compound 1.E16: Compound 1 for use according to any one of the preceding embodiments, wherein said patient has been administered three or more AEDs, such as 3-5, 3-6, or 3-7 AEDs, prior to administration of Compound 1.E17: Compound 1 for use according to any one of E1-E14, wherein said patient did not receive any AED treatment, prior to administration of Compound 1.El 8: Compound 1 for use according to any one of the preceding embodiments, wherein said patient has had an early age of epilepsy onset, such as an onset occurring at age 0-2, 3-5, or 6-11.E19: Compound 1 for use according to any one of the preceding embodiments, wherein said patient has had uncontrolled or frequent seizures prior to administration of Compound 1.E20: Compound 1 for use according to any one of the preceding embodiments, wherein Compound 1, or a pharmaceutically acceptable salt thereof, is administered twice daily.E21: Compound 1 for use according to any one of the preceding embodiments, wherein the dose of Compound 1, or a pharmaceutically acceptable salt thereof, is equivalent to 5 mg / dose to 25 mg / dose, such as 12 mg / dose, 15 mg / dose, or 18 mg / dose, as a free base BID or TID.E22: Compound 1 for use according to any one of El -El 9 and E21, wherein Compound 1, or a pharmaceutically acceptable salt thereof, is administered three times daily.51896-0040 WO1 1318-WO-PCTE23: Compound 1 for use according to any one of E1-E20 and E22, wherein the dose of Compound 1, or a pharmaceutically acceptable salt thereof, is equivalent to 3 mg-20 mg, such as 6 mg, 9 mg, or 12 mg, as a free base BID or TID.E24: Compound 1 for use according to any one of the preceding embodiments, wherein Compound 1, or a pharmaceutically acceptable salt thereof, is administered via a titration scheme that comprises the up-titration of Compound 1, or a pharmaceutically acceptable salt thereof, until an optimized dosage is administered.E25: Compound 1 for use according to any one of E1-E20, E22 and E24, wherein the dose of Compound 1, or a pharmaceutically acceptable salt thereof, is equivalent to 0.03 mg / kg-0.40 mg / kg, such as 0.11 mg / kg, 0.17 mg / kg, 0.24 mg / kg or 0.30 mg / kg, as a free base, for patients having a bodyweight <40 kg.E26: Compound 1 for use according to E24, further comprising administering the optimized dosage of Compound 1, or a pharmaceutically acceptable salt thereof, to the patient.E27: Compound 1 for use according to any one of the preceding embodiments, wherein the Compound 1, or a pharmaceutically acceptable salt thereof, is an HC1 salt of Compound 1.FURTHER EMBODIMENTS OF THE INVENTION:The invention further relates to the following embodiments (EE1-EE27)EE1 : Use of (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 for the manufacture of a medicament for reducing likelihood of seizure-induced sudden unexpected51896-0040 WO1 1318-WO-PCT death in epilepsy (SUDEP) in a patient in need thereof, wherein the use comprises administering to the patient in need thereof a therapeutically effective amount of (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.EE2: Use of (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 for the manufacture of a medicament for treating seizures in a patient suffering from a disease with which sudden unexpected death in epilepsy (SUDEP) can occur, wherein the use comprises administering to the patient in need thereof a therapeutically effective amount of (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.EE3: Use of (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 for the manufacture of a medicament for treating seizure-induced sudden unexpected death in epilepsy (SUDEP) in a patient suffering from a disease with which SUDEP can occur, wherein the use comprises administering to the patient in need thereof a therapeutically effective amount of (R)- N-(2,2-difhioroethyl)-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.EE4: Use of (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 for the manufacture of a medicament for preventing or controlling seizure-induced sudden unexpected death in epilepsy (SUDEP) in a patient in need thereof, wherein the use comprises administering to the patient in need thereof a therapeutically effective amount of (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.51896-0040 WO1 1318-WO-PCTEE5: The use according to any one of the preceding embodiments, wherein said patient suffers from developmental and epileptic encephalopathy (DEE).EE6: The use according to EE5, wherein the DEE is selected from Lennox-Gastaut syndrome, Dravet syndrome, Prader-Willi, Doose syndrome (EM AS), West syndrome (infantile spasms), Landau-Kleffner syndrome, and genetic disorders such as CDKL5 encephalopathy (CDK5L deficiency disorder) or CHD3 encephalopathy.EE7: The use according to any one of EE1-EE5, wherein said patient suffers from a disease selected from Dravet syndrome, Ohtahara syndrome (EIDEE), tuberous sclerosis complex (TSC), Angelman syndrome, myoclonic astatic epilepsy, Lennox-Gastaut syndrome, Doose syndrome (EM AS), West syndrome (infantile spasms), Prader-Willi, Landau-Kleffner syndrome, CDKL5 encephalopathy (CDKL5 deficiency disorder), dupl5q syndrome, SCN2A related epilepsies, SCN8A related epilepsies, KCNQ2 related epilepsies, KCNQ3 related epilepsies, KCNT1 related epilepsies, SynGAPl related epilepsies, Rett syndrome, PCDH19 epilepsy, ring 14 syndrome, ring 20 syndrome, CHD2 encephalopathy, early myoclonic encephalopathy, epilepsy of infancy with migrating focal seizures, and epileptic encephalopathy with continuous spike-wave.EE8: The use according to any one of EE1-EE5, wherein said patient has Dravet syndrome.EE9: The use according to any one of EE1-EE5, wherein said patient has Lennox-Gastaut syndrome.EE10: The use according to any one of EE1-EE4, wherein said patient suffers from a disease selected from epilepsy, epilepsy with generalized tonic-clonic seizures, epilepsy with myoclonic51896-0040 WO1 1318-WO-PCT absences, frontal lobe epilepsy, temporal lobe epilepsy, Landau-Kleffner Syndrome, Rasmussen's syndrome, Dravet syndrome, Doose syndrome (epilepsy with myoclonic atonic seizures (EM AS)), CDKL5 deficiency disorder (CDKL5 encephalopathy, or CDD), infantile spasms (West syndrome), juvenile myoclonic epilepsy (JME), vaccine-related encephalopathy, intractable childhood epilepsy (ICE), Lennox-Gastaut syndrome (LGS), Rett syndrome, Ohtahara syndrome (early infantile DEE, EIDEE), childhood absence epilepsy, essential tremor, acute repetitive seizures, benign rolandic epilepsy, status epilepticus, refractory status epilepticus, super-refractory status epilepticus (SRSE), PCDH19 pediatric epilepsy, drug withdrawal induced seizures, alcohol withdrawal induced seizures, increased seizure activity and breakthrough seizures.EE11 : The use according to any one of the preceding embodiments, wherein said patient has had more than three generalized tonic-clonic seizures per year prior to administration of Compound 1.EE12: The use according to any one of the preceding embodiments, wherein said patient has had more than 13-30 seizures in a year, such as 13-20 or 13-25 seizures prior to administration of Compound 1.EE13: The use according to any one of the preceding embodiments, wherein said patient has had 11-20 generalized tonic-clonic seizures within the last three months prior to administration of Compound 1.EE14: The use according to any one of the preceding embodiments, wherein said patient has an IQ below 70, such as 50-70 or 60-70.51896-0040 WO 1 1318-WO-PCTEE15: The use according to any one of the preceding embodiments, wherein said patient has had 3-5 antiepileptic drug (AED) changes in the last year prior to administration of Compound 1.EE16: The use according to any one of the preceding embodiments, wherein said patient has been administered three or more AEDs, such as 3-5, 3-6, or 3-7 AEDs, prior to administration of Compound 1.EE17: The use according to any one of EE1-EE14, wherein said patient did not receive any AED treatment, prior to administration of Compound 1.EE18: The use according to any one of the preceding embodiments, wherein said patient has had an early age of epilepsy onset, such as an onset occurring at age 0-2, 3-5, or 6-11.EE19: The use according to any one of the preceding embodiments, wherein said patient has had uncontrolled or frequent seizures prior to administration of Compound 1.EE20: The use according to any one of the preceding embodiments, wherein Compound 1, or a pharmaceutically acceptable salt thereof, is administered twice daily.EE21 : The use according to any one of the preceding embodiments, wherein the dose of Compound 1, or a pharmaceutically acceptable salt thereof, is equivalent to 5 mg / dose to 25 mg / dose, such as 12 mg / dose, 15 mg / dose, or 18 mg / dose, as a free base BID or TID.EE22: The use according to any one of EE 1 -EE 19 and EE21, wherein Compound 1, or a pharmaceutically acceptable salt thereof, is administered three times daily.51896-0040 WO1 1318-WO-PCTEE23: The use according to any one of EE1-EE20 and EE22, wherein the dose of Compound 1, or a pharmaceutically acceptable salt thereof, is equivalent to 3 mg-20 mg, such as 6 mg, 9 mg, or 12 mg, as a free base BID or TID.EE24: The use according to any one of the preceding embodiments, wherein Compound 1, or a pharmaceutically acceptable salt thereof, is administered via a titration scheme that comprises the up-titration of Compound 1, or a pharmaceutically acceptable salt thereof, until an optimized dosage is administered.EE25: The use according to any one of EE1-EE20, EE22 and EE24, wherein the dose of Compound 1, or a pharmaceutically acceptable salt thereof, is equivalent to 0.03 mg / kg-0.40 mg / kg, such as 0.11 mg / kg, 0.17 mg / kg, 0.24 mg / kg or 0.30 mg / kg, as a free base, for patients having a bodyweight <40 kg.EE26: The use according to EE24, further comprising administering the optimized dosage of Compound 1, or a pharmaceutically acceptable salt thereof, to the patient.EE27: The use according to any one of the preceding embodiments, wherein the Compound 1, or a pharmaceutically acceptable salt thereof, is an HC1 salt of Compound 1.51896-0040 WO1 1318-WO-PCTEXAMPLESExample 1:

[0136] Poor seizure control and brainstem dysfunction are two main contributors of SUDEP. The brainstem is enriched with transcript levels of 5-HT2C receptors, and accordingly, Htr2c knockout mice are susceptible to both seizures and SUDEP (Massey 2021 Brain Commun. 3(3): fcab 149, Tecott et al., (1995) Nature. Apr 6;374(6522): 542-6)).

[0137] Since one of the major risk factors of SUDEP is frequent and uncontrolled GTCS (Harden et al. (2017). Neurology. 88(17): 1674-1680), Compound 1 (bexicaserin, LP352) was tested in the DBA / 1 mouse model of GTCS and SUDEP. DBA / 1 mice exhibit GTCS followed by respiratory arrest when presented with an audiogenic stimulus (Faingold et al. 2010 Epilepsy & Behavior). Respiratory arrest occurs as a consequence of respiratory dysfunction, one of the main contributors to SUDEP, which was demonstrated in the MORTEMUS study, wherein epilepsy patients died following seizure due to respiratory dysfunction. (Ryvlin et al., (2013) Lancet Neurol. 12(10):966-77.)

[0138] Male and female 23-24-day-old DBA / 1 mice were presented with a 110-120 dB tone (audiogenic stimulus) to induce GTCS, which progress from wild running to clonic and tonic seizures, and respiratory arrest, a measurable correlate of SUDEP. Prior to drug testing, mice underwent a priming phase that consisted of 3 consecutive days of a single tone presentation per day to induce seizures and respiratory arrest. Mice that exhibited respiratory arrest were resuscitated using a rodent respirator. Epileptic mice were defined as those showing respiratory arrest on at least 2 consecutive days of the 3-day priming period.

[0139] These highly susceptible epileptic mice were subsequently used for the testing phase on day 4, which involved oral administration of vehicle or Compound 1 (LP352), followed by a tone presentation at specified timepoints (0.5, 2, 4, 6 or 24 hours) post-treatment. The incidence of and latency to seizure types and respiratory arrest were recorded.Results:

[0140] As shown in Figure 1, vehicle-treated control mice exhibited a 100% incidence of all seizure types and respiratory arrest at almost all timepoints post-treatment (0.5, 2, 4, 6 or 24 hours). Compound 1 (LP352), or a pharmaceutically acceptable salt thereof, treatment dose- dependently decreased incidence of all seizure types and respiratory arrest compared to vehicle- treated mice. 1 mg / kg Compound 1 (LP352) decreased the symptoms of tonic extension and51896-0040 WO 1 1318-WO-PCT respiratory arrest, while 10 mg / kg Compound 1 (LP352) decreased incidences of all seizures and prevented respiratory arrest. At the highest dose of Compound 1 (LP352), respiratory arrest reduced by -40% after 0.5 hours and 100% after 2-, 4- and 6-hours post-dose. No effects of Compound 1 (LP352) at either dose remained at 24 hours post-dose.

[0141] Figure 2 shows testing data related to latency to seizure and respiratory arrest. 1 or 10 mg / kg Compound 1 (LP352) increased latency to seizures and respiratory arrest. Some effects of 10 mg / kg Compound 1 (LP352) on latency to tonic seizures and respiratory arrest remained at 24 hours post-dose.Conclusion:

[0142] Compound 1 (LP352) significantly reduced seizures and respiratory arrest in a mouse model of SUDEP. Given the risk of SUDEP in patients with epilepsy, including developmental and epileptic encephalopathies (DEEs), and the demonstrated efficacy of Compound 1 (LP352) in reducing seizures in participants with various DEEs in clinical trials (such as clinicaltrials.gov ID no. NCT05364021), these data support the potential of Compound 1 (LP352) to mitigate SUDEP risk in epilepsy patients, including those with DEEs.Example 2: Liquid Formulation

[0143] A liquid formulation for oral administration was prepared.51896-0040 WO1 1318-WO-PCTEP = European Pharmacopeia (Ph. Eur.); USP = United States Pharmacopeia; BP = BritishPharmacopeia; JP = Japanese Pharmacopoeia; CoA = Certificate of AnalysisaQuantity of Compound 1 HC1 salt required to provide 3 mg of Compound 1 free base

[0144] Although the 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 disclosure. The various embodiments described above can be combined to provide further embodiments. All of the U.S. patents, U.S. patent application publications, U.S. patent applications, foreign patents, foreign patent applications and non-patent publications referred to in this specification and / or listed in the Application Data Sheet are incorporated herein by reference, in their entirety. Aspects of the embodiments can be modified, if necessary to employ concepts of the various patents, applications and publications to provide yet further embodiments.

[0145] 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 scope of equivalents to which such claims are entitled. Accordingly, the claims are not limited by the disclosure.

Claims

51896-0040 WO1 1318-WO-PCTWHAT IS CLAIMED IS:

1. A method of reducing likelihood of seizure-induced sudden unexpected death in epilepsy (SUDEP) in a patient in need thereof, wherein the method comprises administering to the patient in need thereof a therapeutically effective amount of (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.

2. A method of treating seizures in a patient suffering from a disease with which sudden unexpected death in epilepsy (SUDEP) can occur, wherein the method comprises administering to the patient in need thereof a therapeutically effective amount of (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.

3. A method of treating seizure-induced sudden unexpected death in epilepsy (SUDEP) in a patient suffering from a disease with which SUDEP can occur, wherein the method comprises administering to the patient in need thereof a therapeutically effective amount of (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.

4. A method of preventing or controlling seizure-induced sudden unexpected death in epilepsy (SUDEP) in a patient in need thereof, wherein the method comprises administering to the patient in need thereof a therapeutically effective amount of (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.

5. The method of any one of the preceding claims, wherein the patient suffers from developmental and epileptic encephalopathy (DEE).

6. The method of claim 5, wherein the DEE is selected from Lennox-Gastaut syndrome, Dravet syndrome, Prader-Willi, Doose syndrome (EM AS), West syndrome (infantile spasms),51896-0040 WO1 1318-WO-PCTLandau-Kleffner syndrome, and genetic disorders such as CDKL5 encephalopathy (CDK5L deficiency disorder) or CHD3 encephalopathy.

7. The method of any one of claims 1-5, wherein the patient suffers from a disease selected from Dravet syndrome, Ohtahara syndrome (EIDEE), tuberous sclerosis complex (TSC), Angelman syndrome, myoclonic astatic epilepsy, Lennox-Gastaut syndrome, Doose syndrome (EM AS), West syndrome (infantile spasms), Prader-Willi, Landau-Kleffner syndrome, CDKL5 encephalopathy (CDKL5 deficiency disorder), dupl5q syndrome, SCN2A related epilepsies, SCN8A related epilepsies, KCNQ2 related epilepsies, KCNQ3 related epilepsies, KCNT1 related epilepsies, SynGAPl related epilepsies, Rett syndrome, PCDH19 epilepsy, ring 14 syndrome, ring 20 syndrome, CHD2 encephalopathy, early myoclonic encephalopathy, epilepsy of infancy with migrating focal seizures, and epileptic encephalopathy with continuous spikewave.

8. The method of any one of claims 1-5, wherein the patient has Dravet syndrome.

9. The method of any one of claims 1-5, wherein the patient has Lennox-Gastaut syndrome.

10. The method of any one of claims 1-4, wherein the patient suffers from a disease selected from epilepsy, epilepsy with generalized tonic-clonic seizures, epilepsy with myoclonic absences, frontal lobe epilepsy, temporal lobe epilepsy, Landau-Kleffner Syndrome, Rasmussen's syndrome, Dravet syndrome, Doose syndrome (epilepsy with myoclonic atonic seizures (EM AS)), CDKL5 deficiency disorder (CDKL5 encephalopathy, or CDD), infantile spasms (West syndrome), juvenile myoclonic epilepsy (JME), vaccine-related encephalopathy, intractable childhood epilepsy (ICE), Lennox-Gastaut syndrome (LGS), Rett syndrome, Ohtahara syndrome (early infantile DEE, EIDEE), childhood absence epilepsy, essential tremor, acute repetitive seizures, benign rolandic epilepsy, status epilepticus, refractory status epilepticus, super-refractory status epilepticus (SRSE), PCDH19 pediatric epilepsy, drug withdrawal induced seizures, alcohol withdrawal induced seizures, increased seizure activity and breakthrough seizures.51896-0040 WO 1 1318-WO-PCT11 . The method of any one of the preceding claims, wherein the patient has had more than three generalized tonic-clonic seizures per year prior to administration of Compound 1.

12. The method of any one of the preceding claims, wherein the patient has had more than 13-30 seizures in a year, such as 13-20 or 13-25 seizures prior to administration of Compound 1.

13. The method of any one of the preceding claims, wherein the patient has had 11-20 generalized tonic-clonic seizures within the last three months prior to administration of Compound 1.

14. The method of any one of the preceding claims, wherein the patient has an IQ below 70, such as 50-70 or 60-70.

15. The method of any one of the preceding claims, wherein the patient has had 3-5 antiepileptic drug (AED) changes in the last year prior to administration of Compound 1.

16. The method of any one of the preceding claims, wherein the patient has been administered three or more AEDs, such as 3-5, 3-6, or 3-7 AEDs, prior to administration of Compound 1.

17. The method of any one of claim 1-14, wherein the patient did not receive any AED treatment, prior to administration of Compound 1.

18. The method of any one of the preceding claims, wherein the patient has had an early age of epilepsy onset, such as an onset occurring at age 0-2, 3-5, or 6-11.

19. The method of any one of the preceding claims, wherein the patient has had uncontrolled or frequent seizures prior to administration of Compound 1.

20. The method of any one of the preceding claims, wherein Compound 1, or a pharmaceutically acceptable salt thereof, is administered twice daily.51896-0040 WO1 1318-WO-PCT21 . The method of any one of the preceding claims, wherein the dose of Compound 1 , or a pharmaceutically acceptable salt thereof, is equivalent to 5 mg / dose to 25 mg / dose, such as 12 mg / dose, 15 mg / dose, or 18 mg / dose, as a free base.

22. The method of any one of claims 1-19 and 21, wherein Compound 1, or a pharmaceutically acceptable salt thereof, is administered three times daily.

23. The method of any one of claims 1-20 and 22, wherein the dose of Compound 1, or a pharmaceutically acceptable salt thereof, is equivalent to 3 mg-20 mg, such as 6 mg, 9 mg, or 12 mg, as a free base.

24. The method of any one of the preceding claims, wherein Compound 1, or a pharmaceutically acceptable salt thereof, is administered via a titration scheme that comprises the up-titration of Compound 1, or a pharmaceutically acceptable salt thereof, until an optimized dosage is administered.

25. The method of any one of claims 1-20, 22 and 24, wherein the dose of Compound 1, or a pharmaceutically acceptable salt thereof, is equivalent to 0.03 mg / kg-0.40 mg / kg, such as 0.11 mg / kg, 0.17 mg / kg, 0.24 mg / kg or 0.30 mg / kg, as a free base, for patients having a bodyweight <40 kg.

26. The method of claim 24, further comprising administering the optimized dosage of Compound 1, or a pharmaceutically acceptable salt thereof, to the patient.

27. The method of any one of the preceding claims, wherein the Compound 1, or a pharmaceutically acceptable salt thereof, is an HC1 salt of Compound 1.

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