Treatment for Dravet syndrome

Abstract

Provided herein is a method of treating Dravet syndrome in a subject in need thereof by administering to the subject a composition comprising an mGlu5 negative allosteric modulator (NAM).

Description

[Technical Field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS This application claims the benefit of and priority to U.S. Patent Application No. 63 / 482,918, filed February 2, 2023, the entire contents of which are incorporated herein by reference.

[0002] Field The present disclosure relates to the field of medicine and to the treatment of Dravet syndrome. More specifically, the present disclosure relates to the use of a composition comprising 2-chloro-4-[1-(4-fluorophenyl)-2,5-dimethyl-1H-imidazol-4-ylethynyl]pyridine or a pharmaceutically acceptable salt thereof in the treatment or amelioration of Dravet syndrome. [Background technology]

[0003] background Dravet syndrome (DVS), also known as severe myoclonic epilepsy of infancy (SMEI), is a rare, fatal, lifelong form of epilepsy that begins in the first year of life with frequent or prolonged seizures. Children with DVS typically experience delays in language and motor development, hyperactivity and sleep disorders, chronic infections, growth and balance problems, and difficulty relating to others. In 70–90% of patients, DVS is caused by mutations in the SCN1A gene (voltage-gated sodium channel, type I, alpha subunit), which result in a premature stop codon and render the protein nonfunctional. See, e.g., Selmer et al., Clinical Genetics., 2009, 76(4):398–403 (Non-Patent Document 1).

[0004] Current treatments for DVS are limited. DVS seizures can be difficult to manage but may be alleviated by antiepileptic drugs such as clobazam, stiripentol, topiramate, valproate, fenfluramine, and cannabidiol. However, certain drugs are known to worsen patients' seizures due to their effects on sodium ion channels. Additionally, some drugs have significant side effects that limit their medical use.

[0005] Therefore, there is an unmet medical need to develop new methods to treat DVS without significant side effects. [Prior art documents] [Non-patent literature]

[0006] [Non-Patent Document 1] Selmer et al.,Clinical Genetics.,2009,76(4):398-403 Summary of the Invention

[0007] overview The disclosure is directed, in part, to a method of treating Dravet Syndrome (DVS), comprising administering to a subject in need thereof a composition comprising a therapeutically effective amount of a therapeutic agent, wherein the therapeutic agent is a compound of Formula I: TIFF2026503754000002.tif31128 or a pharmaceutically acceptable salt thereof.

[0008] Also provided herein, in part, is a method of treating Dravet syndrome, the method comprising administering to a subject in need thereof a composition comprising a therapeutically effective amount of an mGlu5 negative allosteric modulator (NAM) or a pharmaceutically acceptable salt thereof, wherein the mGlu5 NAM is a compound of Formula I. TIFF2026503754000003.tif31128 [Brief explanation of the drawings]

[0009] [Figure 1] 1 shows an example of an XRPD pattern of the crystalline anhydrous form of the monosulfate salt of the compound of Formula I (Form A). [Figure 2] 1 shows an example of an XRPD pattern of the crystalline monohydrate form of the monosulfate salt of the compound of Formula I (Form B). [Figure 3] 1 shows an example of an XRPD pattern of the crystalline hemihydrate form of the hemisulfate salt of the compound of Formula I (Form C). [Figure 4] The frequency and percentage of seizure-free animals across the 1 mg / kg Compound I, 0.3 mg / kg Compound I, CTEP, and untreated groups are shown. [Figure 5] 1 shows a Kaplan-Meier plot of the percentage of seizure-free animals over time for the 1 mg / kg Compound I group, the 0.3 mg / kg Compound I group, the CTEP group, and the untreated group. [Figure 6] Plots of individual total seizure burden data are shown for the 1 mg / kg Compound I group, the 0.3 mg / kg Compound I group, the CTEP group, and the untreated group. [Figure 7] The adjusted data from Figure 6 is plotted using a logarithmic scale (log10) on the Y axis. [Figure 8] Total seizure burden (geometric means and 95% confidence intervals) is shown for the 1 mg / kg Compound I group, the 0.3 mg / kg Compound I group, the CTEP group, and the untreated group. [Figure 9] Comparisons to the untreated group are presented as ratios of geometric means and 95% confidence intervals. [Figure 10] Data for the number of individual seizures per day across the 1 mg / kg Compound I group, the 0.3 mg / kg Compound I group, the CTEP group, and the untreated group are shown. [Figure 11] The data in Figure 10 are adjusted and shown using a logarithmic (log10) scale on the Y axis. [Figure 12]Shown are the results of an ANOVA performed on log-transformed adjusted data for the mean number of seizures per day. [Figure 13] Comparisons with the untreated group are included, expressed as ratios of geometric means and 95% confidence intervals. DETAILED DESCRIPTION OF THE INVENTION

[0010] Detailed Description As generally described herein, the disclosure provides methods of treating Dravet Syndrome (DVS) in a subject in need thereof using a compound of Formula I, or a pharmaceutically acceptable salt thereof. Also provided herein are methods of treating a symptom of Dravet Syndrome, e.g., seizures, in a subject in need thereof using a compound of Formula I, or a pharmaceutically acceptable salt thereof.

[0011] compound The compound of Formula I, shown below, is an mGlu5 negative allosteric modulator (NAM), also known as 2-chloro-4-[1-(4-fluorophenyl)-2,5-dimethyl-1H-imidazol-4-ylethynyl]pyridine, or Basimglurant. TIFF2026503754000004.tif25128

[0012] Methods for chemically synthesizing compounds of Formula I (including Example 1 provided herein) are described in U.S. Patent No. 7,332,510, which is incorporated by reference in its entirety. As used herein, compounds of Formula I are referred to as "Compound I."

[0013] It should be understood that the compounds of Formula I described herein include crystalline solid forms of either the free base or pharmaceutically acceptable salts of the compounds of Formula I described herein.

[0014] In certain embodiments, a pharmaceutically acceptable salt of a compound of Formula I may be a salt of a compound of Formula I with a physiologically compatible inorganic acid such as hydrochloric acid, sulfuric acid (sulfuric or sulfuric), sulfurous acid, phosphoric acid, or an organic acid such as methanesulfonic acid, p-toluenesulfonic acid, acetic acid, lactic acid, trifluoroacetic acid, citric acid, fumaric acid, maleic acid, tartaric acid, succinic acid, salicylic acid, etc. An example of a pharmaceutically acceptable salt of a compound of Formula I is a monosulfate or hemisulfate.

[0015] In certain embodiments, a pharmaceutically acceptable salt of a compound of Formula I is a monosulfate or hemisulfate salt, each in hydrate or anhydrous form (e.g., anhydrous, hemihydrate, or monohydrate).

[0016] In certain embodiments, the pharmaceutically acceptable salt of the compound of Formula I is in a crystalline or amorphous form.

[0017] In some embodiments, the compound is a crystalline anhydrous form of the monosulfate salt of the compound of Formula I (Form A), and Form A has an X-ray powder diffraction (XRPD) pattern substantially as shown in Figure 1. In some embodiments, Form A has an X-ray powder diffraction (XRPD) pattern substantially as shown in Figure 1. Kα Form A is characterized by at least three peaks selected from the following X-ray powder diffraction peaks obtained by radiation: 9.8, 13.4, 14.2, 18.1, 18.9, 19.6, 22.6, 22.9, 25.7, 27.1, and 29.9 (±0.2°C). Form A typically exhibits a T of about 180-190°C by DSC analysis. m In some embodiments, Form A has a molecular weight of 3068 cm -1 , 2730cm -1 , 2618cm -1 , 2236cm -1 , 2213cm -1 , 1628cm -1 , 1587cm -1 , 1569cm -1 , 1518cm -1 , 1384cm -1 , 1374cm-1 , 1295cm -1 , 1236cm -1 , 1168cm -1 , 1157cm -1 , 1116cm -1 , 1064cm -1 , 1019cm -1 , 902cm -1 , 855cm -1 , 786cm -1 , and 674 cm -1 (±3cm -1 ) is characterized by an infrared spectrum with a sharp band in the

[0018] In some embodiments, the compound is a crystalline monohydrate form of the monosulfate salt of the compound of Formula I (Form B), which has an XRPD pattern substantially as shown in Figure 2. Crystalline Form B typically has a T of about 60-70°C by DSC analysis. m It has.

[0019] In some embodiments, the compound is a crystalline hemihydrate form of the hemisulfate salt of the compound of Formula I (Form C), which has an XRPD pattern substantially as shown in Figure 3. Crystalline Form C typically has a T of about 90-100°C by DSC analysis. m It has.

[0020] Uses and Treatment In one aspect, provided herein is a method of treating Dravet syndrome (DVS) in a subject in need thereof. Examples of subjects include humans and patients, including, but not limited to, infants, children, young adults, and adults. In one aspect, the present disclosure provides a method of treating a patient diagnosed with Dravet syndrome, the method comprising administering to the patient a therapeutically effective dose of a compound of Formula I.

[0021] In another aspect, provided herein is a method of treating a symptom associated with Dravet syndrome (DVS) in a subject in need thereof. Examples of subjects include humans, test subjects, and patients, including infants, children, young adults, and adults. In one aspect, the present disclosure provides a method of treating a patient exhibiting a symptom associated with Dravet syndrome, the method comprising administering a therapeutically effective dose of a compound of Formula I to the patient. In embodiments, the symptom is seizures. In embodiments, Dravet syndrome is associated with multiple types of seizures, and the subject (e.g., a human, patient, or test subject) experiences multiple types of seizures. Thus, in various embodiments, provided herein is a method of treating a seizure associated with Dravet syndrome (DVS) in a subject in need thereof.

[0022] Dravet syndrome (DVS) is a devastating form of epilepsy characterized by prolonged seizures often precipitated by high temperatures or fever. DVS is characterized by a prolonged series of febrile and non-febrile seizures during the first year of life. Common problems associated with DVS include prolonged seizures, frequent seizures, behavioral and developmental delays, movement and balance problems, orthopedic disorders, speech and language delays, growth and nutritional problems, sleep disorders, chronic infections, sensory integration disorders, and autonomic dysreflexia, or disorders of the autonomic nervous system that result in difficulty regulating body temperature, heart rate, and blood pressure.

[0023] In various embodiments, provided herein are methods for treating Dravet Syndrome (DVS), the methods comprising administering to a subject in need thereof a composition comprising a therapeutically effective amount of a therapeutic agent, wherein the therapeutic agent is a compound of Formula I: TIFF2026503754000005.tif25128 or a pharmaceutically acceptable salt thereof.

[0024] In various embodiments, provided herein are methods for treating symptoms (e.g., seizures) associated with Dravet Syndrome (DVS), the methods comprising administering to a subject in need thereof a composition comprising a therapeutically effective amount of a therapeutic agent, wherein the therapeutic agent is a compound of Formula I: TIFF2026503754000006.tif25128, or a pharmaceutically acceptable salt thereof.

[0025] In various embodiments, provided herein is the use of a compound, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for treating a condition associated with Dravet Syndrome (DVS) in a subject, wherein the compound is a compound of Formula I: TIFF2026503754000007.tif25128 or a pharmaceutically acceptable salt thereof.

[0026] In various embodiments, administering a therapeutically effective amount of a compound of Formula I or a pharmaceutically acceptable salt thereof comprises administering to the subject about 0.1 mg to about 5 mg (e.g., about 0.1 mg, about 0.3 mg, about 0.5 mg, about 1 mg, about 1.5 mg, about 2 mg, about 2.5 mg, about 3 mg, about 3.5 mg, about 4 mg, about 4.5 mg, about 5 mg) of a compound of Formula I or a pharmaceutically acceptable salt thereof. In various embodiments, administering a therapeutically effective amount of a compound of Formula I or a pharmaceutically acceptable salt thereof comprises administering to the subject about 0.5 mg to about 4 mg (e.g., about 0.5 mg, about 0.7 mg, about 1 mg, about 1.2 mg, about 1.3 mg, about 1.4 mg, about 1.5 mg, about 1.6 mg, about 1.7 mg, about 1.8 mg, about 1.9 mg, about 2.0 mg, about 2.1 mg, about 2.2 mg, about 2.3 mg, about 2.4 mg, about 2.5 mg, about 2.6 mg, about 2.7 mg, about 2.8 mg, about 2.9 mg, about 3.0 mg, about 3.1 mg, about 3.2 mg, about 3.3 mg, about 3.4 mg, about 3.5 mg, about 3.6 mg, about 3.7 mg, about 3.8 mg, about 3.9 mg, about 4.0 mg).

[0027] In certain embodiments, administering a therapeutically effective amount of a compound of Formula I or a pharmaceutically acceptable salt thereof comprises administering about 0.5 mg to about 3.5 mg of a compound of Formula I or a pharmaceutically acceptable salt thereof to a subject in need thereof. In certain embodiments, administering a therapeutically effective amount of a compound of Formula I or a pharmaceutically acceptable salt thereof comprises administering about 0.5 mg, about 0.8 mg, about 1.0 mg, about 1.3 mg, about 1.5 mg, about 1.8 mg, about 2 mg, about 2.3 mg, about 2.5 mg, about 2.8 mg, about 3 mg, about 3.3 mg, about 3.5 mg, about 3.8 mg, or about 4.0 mg of a compound of Formula I or a pharmaceutically acceptable salt thereof to a subject in need thereof.

[0028] In some embodiments, the dose of the compound of formula I is about 0.3 mg / kg. In some embodiments, the dose of the compound of formula I is about 1.0 mg / kg.

[0029] In some embodiments, the subject weighs at least 40 kg. In some embodiments, the subject weighs less than 40 kg. For example, Compound I may be administered according to two weight categories (less than 40 kg and 40 kg or more). The initial dose of Compound I may be 0.5 mg or 1.0 mg once daily for patients weighing less than 40 kg, and 1.5 mg once daily for patients weighing 40 kg or more. The maximum dose of Compound I is 3.0 mg once daily for patients weighing less than 40 kg, and 3.5 mg once daily for patients weighing 40 kg or more. Thereafter, the dose of Compound I may be increased by 0.5 mg every week in a blinded manner, depending on individual tolerability.

[0030] In certain embodiments, provided herein are methods of administering the free base form of the compound of Formula I to treat DVS in a subject in need thereof.

[0031] In certain embodiments, provided herein are methods for administering a pharmaceutically acceptable salt of a compound of Formula I to treat DVS in a subject in need thereof. In certain embodiments, treating, as described above, comprises administering a compound of Formula I in a crystalline form (e.g., Form A, Form B, or Form C) in the form of a sulfate salt (e.g., monosulfate or hemisulfate). In some embodiments, the pharmaceutically acceptable salt of a compound of Formula I may be a salt of a compound of Formula I with a physiologically compatible inorganic acid such as hydrochloric acid, sulfuric acid (sulfuric or sulfuric), sulfurous acid, phosphoric acid, or an organic acid such as methanesulfonic acid, p-toluenesulfonic acid, acetic acid, lactic acid, trifluoroacetic acid, citric acid, fumaric acid, maleic acid, tartaric acid, succinic acid, salicylic acid, or the like.

[0032] In certain embodiments, treatment comprises administering a compound of formula I or a pharmaceutically acceptable salt thereof once daily.

[0033] In certain embodiments, treatment comprises administering a compound of formula I or a pharmaceutically acceptable salt thereof by oral administration.

[0034] In certain embodiments, treatment comprises administering a compound of formula I or a pharmaceutically acceptable salt thereof as a unit dose.

[0035] In some embodiments, provided herein is a method of treating DVS, the method comprising administering to a subject in need thereof a composition comprising a therapeutically effective amount of an mGlu5 negative allosteric modulator (NAM) or a pharmaceutically acceptable salt thereof, wherein the mGlu5 NAM is a compound of Formula I. TIFF2026503754000008.tif25128

[0036] In certain embodiments, the methods include administering a compound of formula I as monotherapy.

[0037] In some embodiments, the method further comprises administering a second therapy for Dravet syndrome. In some embodiments, the method further comprises administering a second therapy for seizures. In some cases, the subject may be receiving a second therapy for Dravet syndrome or seizures.

[0038] In embodiments, the methods described herein may reduce the frequency of seizures, reduce the severity of seizures, or change the type of seizures (e.g., from a more severe type to a less severe type), or a combination thereof, in a subject after treatment compared to no treatment (e.g., before treatment) or compared to treatment with an alternative conventional therapy. In one aspect, administration of a compound of Formula I, or a pharmaceutically acceptable salt thereof, or a crystalline form thereof, as described herein, reduces convulsive seizure frequency by about 50% or more, about 55% or more, about 60% or more, about 65% or more, about 70% or more, about 75% or more, about 80% or more, about 85% or more, about 90% or more, about 95% or more, or completely eliminates seizures in a subject over a period of 10 days, 20 days, 30 days, 50 days, 84 days, 100 days, or more. Administration of a compound of Formula I, or a pharmaceutically acceptable salt thereof, or a crystalline form thereof, as described herein, reduces non-convulsive seizure frequency by about 50% or more, about 55% or more, about 60% or more, about 65% or more, about 70% or more, about 75% or more, about 80% or more, about 85% or more, about 90% or more, about 95% or more for a period of 10 days, 20 days, 30 days, 50 days, 84 days, 100 days or more, or completely eliminates seizures in a subject. In some embodiments, the method further comprises repeating the administration until the subject is permanently seizure-free.

[0039] Thus, the compounds of Formula I, their pharmaceutically acceptable salts, or crystalline forms thereof described herein can reduce seizure types after administration to a subject in need thereof. The reduction can be one, two, three, or more specific types of seizures. In some embodiments, one seizure type is reduced. In some embodiments, two or more seizure types are reduced. In some embodiments, three or more seizure types are reduced. In some embodiments, multiple seizure types are reduced. In some embodiments of the method, the reduced seizure type is selected from the group consisting of non-convulsive seizures, generalized seizures, myoclonic seizures, absence / atypical absence seizures, and febrile seizures, or any combination thereof. In some embodiments, particularly in Dravet syndrome, multiple seizure types are typically present, including convulsive seizures consisting of generalized clonic seizures (GCS), generalized tonic-clonic seizures (previously known as grand mal seizures), or alternating hemiclonic seizures, myoclonic seizures, atypical absence and syncope (blunted or impaired consciousness), partial seizures with or without secondary generalization, or more rarely tonic seizures. In some embodiments, the reduced seizure type is selected from the group consisting of photosensitive seizures and self-induced seizures. In some embodiments, the reduced seizure type is selected from atonic seizures or focal seizures without clear observable motor signs.

[0040] Examples of seizures include, but are not limited to, focal onset seizures, generalized onset seizures, and seizures of unknown onset.

[0041] In one embodiment, the focal-onset seizures are selected from partial seizures with preserved consciousness and partial seizures with impaired consciousness. In one embodiment, the focal-onset seizures are selected from partial seizures with motor symptoms and partial seizures with non-motor symptoms. In one embodiment, the partial seizures with motor symptoms may be selected from the group consisting of motor partial seizures with automatisms, atonic motor partial seizures, clonic motor partial seizures, motor partial seizures with epileptic spasms, hyperkinetic motor partial seizures, motor partial myoclonic seizures, tonic motor partial seizures, or a combination thereof. In one embodiment, the partial seizures with non-motor symptoms may be selected from the group consisting of non-motor partial seizures with autonomic symptoms, non-motor partial seizures with behavioral arrest, non-motor partial seizures with cognitive symptoms, non-motor partial seizures with affective symptoms, non-motor partial seizures with sensory symptoms, or a combination thereof. In some embodiments, the seizures are focal to bilateral tonic-clonic seizures followed by partial seizures.

[0042] In embodiments, the generalized-onset seizures are selected from generalized motor seizures or generalized non-motor (absence) seizures. In embodiments, the generalized motor seizures are selected from the group consisting of generalized motor tonic-clonic seizures, generalized motor clonic seizures, generalized motor tonic seizures, generalized motor myoclonic seizures, generalized motor myoclonic-tonic-clonic seizures, generalized motor myoclonic-atonic seizures, generalized motor atonic seizures, and generalized motor seizures with epileptic spasms. In embodiments, the generalized non-motor (absence) typical seizures, generalized non-motor (absence) atypical seizures, generalized non-motor (absence) myoclonic seizures, and generalized non-motor (absence) eyelid myoclonic seizures.

[0043] In embodiments, the unknown onset seizures are selected from unknown motor seizures and unknown non-motor seizures. In embodiments, the unknown motor seizures are selected from unknown motor tonic-clonic seizures and unknown motor seizures with epileptic spasms. In embodiments, the unknown non-motor seizures are unknown non-motor seizures with behavioral arrest.

[0044] In some embodiments, the seizure is an unclassified seizure.

[0045] In embodiments, administration of a compound of Formula I, or a pharmaceutically acceptable salt thereof, or a crystalline form thereof, as described herein, reduces the frequency of status epilepticus by about 50% or more, about 55% or more, about 60% or more, about 65% or more, about 70% or more, about 75% or more, about 80% or more, about 85% or more, about 90% or more, about 95% or more, or completely eliminates seizures in a subject over a period of 10 days, 20 days, 30 days, 50 days, 84 days, 100 days or more.

[0046] In another aspect of the disclosure, administration of a compound of Formula I, or a pharmaceutically acceptable salt thereof, or a crystalline form thereof, as described herein, reduces a subject's hospital visits by about 25% or more, about 50% or more, about 75% or more, or completely eliminates hospital visits due to stroke.

[0047] In another aspect of the disclosure, administration of a compound of Formula I, or a pharmaceutically acceptable salt thereof, or a crystalline form thereof, as described herein, reduces a subject's need for rescue medication by about 25% or more, about 50% or more, about 75% or more, or completely eliminates the need for rescue medication.

[0048] Seizures experienced in DVS are known to be highly resistant to treatment. The development of effective treatments that reduce the number of seizures could make the condition more manageable. Furthermore, children with DVS typically develop intellectual disability over time. They may have problems expressing and understanding language. They may also be at increased risk of developing autism, attention deficit hyperactivity disorder (ADHD), and other behavioral disorders. Children with Dravet syndrome often require speech therapy, occupational therapy, social therapy, and play therapy to support cognitive development. In certain embodiments, the effectiveness of the treatment of the present invention is determined by: a) A reduction of 50% or more in overall seizure rate b) A reduction in seizure frequency c) Increased chances of not having a seizure d) Longest seizure-free interval e) Number of seizure-free days f) Improvement assessed by Clinical Global Impression-Improvement g) Improvement assessed by Patient Global Impression of Change (PGI-C) h) Improvement as assessed by Quality of Life in Pediatric Epilepsy (QOLCE) i) Improvement as assessed by the overall quality of life score from the Pediatric Quality of Life Inventory™ (PedsQL) j) Improvement assessed by the total score of the PedsQL Family Impact Module Score k) Improvement in parent / caregiver quality of life (QoL) as assessed by the EQ-5D-5L scale l) Improvement as assessed by the Hospital Anxiety and Depression Scale (HADS), or m) Improvement in behavioral or cognitive symptoms

[0049] Without further elaboration, it is believed that one skilled in the art can, based on the preceding description, utilize the present invention to its fullest extent. The following specific examples, therefore, are to be construed as merely illustrative, and not limitative of the remainder of the disclosure in any way whatsoever. All publications cited herein are incorporated by reference in their entirety.

[0050] Pharmaceutical Composition In one aspect, a pharmaceutical composition comprising a compound of Formula I or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable excipient may be administered to a subject in need thereof for the treatment of DVS. In various embodiments, the composition is a solid pharmaceutical composition.

[0051] The pharmaceutical compositions provided herein can be administered to a subject by various routes, including, but not limited to, oral administration, administration as a suppository, topical contact, parenteral administration (e.g., intravenous, intramuscular, intraarterial, intradermal, subcutaneous, intraperitoneal, intraventricular, and intracranial), intralesional administration, intrathecal administration, intranasal administration, transmucosal administration (e.g., buccal, sublingual, nasal, or transdermal), or implantation of a sustained-release device (e.g., a mini-osmotic pump). In certain embodiments, the pharmaceutical compositions disclosed herein are administered orally.

[0052] definition To facilitate the understanding of the present invention, several terms and phrases are defined below.

[0053] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by those skilled in the art to which this invention belongs.Unless otherwise defined, the abbreviations used herein have their conventional meaning in the fields of chemistry and biology.The chemical structures and formulas described herein are constructed according to the standard rules of chemical valence known in the field of chemistry.

[0054] Throughout this specification, when compositions are described as having, including, or comprising certain components, or when processes and methods are described as having, including, or comprising certain steps, it is contemplated that there are additional compositions of the invention that consist essentially of, or consist of, the recited components, and processes and methods of the invention that consist essentially of, or consist of, the recited processing steps.

[0055] In this application, when an element or component is said to be included in and / or selected from a list of enumerated elements or components, it is understood that the element or component can be any one of the listed elements or components, or the element or component can be selected from a group consisting of two or more of the listed elements or components.

[0056] Furthermore, it should be understood that the elements and / or features of the compositions or methods described herein, whether expressly or implicitly stated herein, can be combined in various ways without departing from the spirit and scope of the invention. For example, when a particular compound is referenced, that compound can be used in various embodiments of the compositions of the invention and / or methods of the invention, unless otherwise understood from the context. In other words, although embodiments have been described and depicted in this application in a manner that permits clear and concise writing and drawing of the application, it is intended and understood that the embodiments can be combined or separated in various ways without departing from the present teachings and invention(s). For example, it should be understood that all features described and depicted herein are applicable to all aspects of the invention described and depicted herein.

[0057] In this disclosure, the articles "a" and "an" are used, unless the context indicates otherwise, to refer to one or to more than one (i.e., to at least one) of the grammatical object of their association. By way of example, "an element" means one element or more than one element.

[0058] The term "and / or" is used in this disclosure to mean either "and" or "or," unless otherwise specified.

[0059] The phrase "at least one" should be understood to include each of the listed objects separately and various combinations of two or more of the listed objects, unless otherwise understood from context or usage. The phrase "and / or" in connection with more than two listed objects should be understood to have the same meaning, unless otherwise understood from context.

[0060] Use of the terms "comprise," "comprises," "comprising," "include," "includes," "including," "have," "has," "having," "contain," "contains," or "containing" (including their grammatical equivalents) should generally be understood as open-ended and open-ended, e.g., as not excluding additional, unrecited elements or steps, unless otherwise specified or understood from context.

[0061] When the term "about" is used before a quantitative value, the present invention also includes the specific quantitative value itself, unless otherwise specified. As used herein, the term "about" refers to a ±10% variation from the nominal value, unless otherwise indicated or inferred from the context.

[0062] At various points in this specification, variables or parameters are disclosed in groups or ranges. The description is specifically intended to include each and every individual subcombination of the members of such groups and ranges. For example, an integer in the range of 0 to 40 is specifically intended to individually disclose 0, 1, 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, and 40, and an integer in the range of 1 to 20 is specifically intended to individually disclose 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, and 20.

[0063] The use of any and all examples or exemplary language (e.g., "such as," or "including") herein is intended merely to better define the invention and does not limit the scope of the claims unless otherwise stated. No language in the specification should be construed as indicating any non-claimed element as essential to the practice of the invention.

[0064] As a general matter, compositions specifying percentages are by weight unless otherwise specified. Furthermore, if a variable is not accompanied by a definition, the previous definition of the variable applies.

[0065] As used herein, a "composition" or "pharmaceutical composition" or "pharmaceutical formulation" refers to a combination of an active agent with an inert or active excipient or carrier that makes the composition particularly suitable for diagnostic or therapeutic use in vivo or ex vivo.

[0066] "Pharmaceutically acceptable" refers to compounds, molecular entities, compositions, materials, and / or dosage forms that do not produce adverse, allergic, or other untoward reactions when administered to animals or humans, as appropriate, and / or that are approved or approvable by a federal or state government regulatory agency or a corresponding agency in a country other than the United States, or are listed in the United States Pharmacopeia or other generally recognized pharmacopoeias for use in animals, and more particularly in humans.

[0067] As used herein, "pharmaceutically acceptable salt" refers to any salt of an acidic or basic group that may be present in a compound of the present invention (e.g., a compound of Formula I), which salt is compatible with pharmaceutical administration.

[0068] Examples of acids include, but are not limited to, hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, perchloric acid, fumaric acid, maleic acid, phosphoric acid, glycolic acid, lactic acid, salicylic acid, succinic acid, toluene-p-sulfonic acid, tartaric acid, acetic acid, citric acid, methanesulfonic acid, ethanesulfonic acid, formic acid, benzoic acid, malonic acid, naphthalene-2-sulfonic acid, and benzenesulfonic acid. Other acids, such as oxalic acid, while not themselves pharmaceutically acceptable, may be used in the preparation of salts useful as intermediates to obtain the compounds described herein and their pharmaceutically acceptable acid addition salts.

[0069] Examples of bases include alkali metal (e.g., sodium and potassium) hydroxides, alkaline earth metal (e.g., magnesium and calcium) hydroxides, ammonia, and bases of the formula NW4 + (Wherein W is C 1-4 Examples of suitable compounds include, but are not limited to, compounds in which the aryl group is alkyl.

[0070] Examples of salts include, but are not limited to, acetate, adipate, alginate, aspartate, benzoate, benzenesulfonate, bisulfate, butyrate, citrate, camphorate, camphorsulfonate, cyclopentanepropionate, digluconate, dodecyl sulfate, ethanesulfonate, fumarate, flucoheptanoate, glycerophosphate, hemisulfate, heptanoate, hexanoate, hydrochloride, hydrobromide, hydroiodide, 2-hydroxyethanesulfonate, lactate, maleate, methanesulfonate, monosulfate, 2-naphthalenesulfonate, nicotinate, oxalate, palmoate, pectinate, persulfate, phenylpropionate, picrate, pivalate, propionate, succinate, tartrate, thiocyanate, tosylate, and undecanoate. + , K. + , Ca 2+ , NH4 + , and NW4 + (Where, W is C 1-4 Examples of suitable cations include the anions of the compounds of the present invention combined with suitable cations such as aryl, aryl, aryl ...

[0071] For therapeutic use, salts of compounds of the invention are contemplated to be pharmaceutically acceptable. However, salts of acids and bases that are non-pharmaceutically acceptable may also find use, for example, in the preparation or purification of a pharmaceutically acceptable compound.

[0072] As used herein, a "pharmaceutically acceptable excipient" refers to a substance that aids in the administration and / or absorption of an active agent by a subject and can be included in the compositions of the invention without causing significant adverse toxicological effects to the patient. Non-limiting examples of pharmaceutically acceptable excipients include water, NaCl, normal saline (such as phosphate-buffered saline, emulsions (e.g., oil / water emulsions or water / oil emulsions)), lactated Ringer's solution, normal sucrose, normal glucose, binders, fillers, disintegrants, lubricants, coatings, sweeteners, flavoring agents, salt solutions (such as Ringer's solution), alcohol, oils, gelatin, carbohydrates such as lactose, amylose, or starch, fatty acid esters, hydroxymethylcellulose, polyvinylpyrrolidine, and coloring agents. Such preparations may be sterilized and, if necessary, mixed with auxiliary agents such as lubricants, preservatives, stabilizers, wetting agents, emulsifiers, salts for influencing osmotic pressure, buffers, coloring agents, and / or aromatic substances that do not deleteriously react with the compounds of the invention. For examples of excipients, see, e.g., Martin, Remington's Pharmaceutical Sciences, 15th Ed., Mack Publ. Co., Easton, PA (1975).

[0073] "Subjects" to which administration is contemplated include, but are not limited to, humans (i.e., male or female of any age group, e.g., pediatric subjects (e.g., infants, children, adolescents) or adult subjects (e.g., young adults, middle-aged adults, or elderly adults)), and / or non-human animals, e.g., mammals such as primates (e.g., cynomolgus monkeys, rhesus monkeys), cows, pigs, horses, sheep, goats, rodents, cats, and / or dogs. In certain embodiments, the subject is a human. In certain embodiments, the subject is a non-human animal. In some embodiments, the subject is a test subject. In some embodiments, the subject is a patient.

[0074] As used herein, "solid dosage form" means a pharmaceutical dose or doses in solid form, such as tablets, capsules, granules, powders, sachets, reconstitutable powders, dry powder inhalants, chewables, and the like.

[0075] As used herein, "administering" means oral administration, administration as a suppository, topical contact, intravenous administration, parenteral administration, intraperitoneal administration, intramuscular administration, intralesional administration, intrathecal administration, intracranial administration, intranasal administration, transmucosal administration (e.g., buccal administration, sublingual administration, intranasal administration, transdermal administration), or subcutaneous administration, or by implantation of a sustained-release device (e.g., a mini-osmotic pump) into a subject. Parenteral administration includes, for example, intravenous, intramuscular, intraarteriolar, intradermal, subcutaneous, intraperitoneal, intraventricular, and intracranial. Other modes of delivery include, but are not limited to, the use of liposomal formulations, intravenous infusion, transdermal patches, and the like.

[0076] "Co-administration" means that the compositions described herein are administered simultaneously with, immediately before, or immediately after the administration of one or more additional treatments (e.g., anti-cancer agents, chemotherapeutic agents, agents for treating neurodegenerative diseases). The compound of Formula I or a pharmaceutically acceptable salt thereof can be administered alone or co-administered to a patient. Co-administration includes administering the compounds individually or in combination (more than one compound or agent), simultaneously or sequentially. Thus, the preparation can also be combined with other active substances (e.g., to reduce metabolic degradation) if necessary.

[0077] As used herein, unless otherwise specified, the terms "treat," "treating," and "treatment" include actions that occur while a subject is afflicted with a particular disease, disorder, or condition, and that reduce the severity of the disease, disorder, or condition or delay or slow the progression of the disease, disorder, or condition (e.g., "therapeutic treatment"). "Treat," "treating," and "treatment," as used herein, can include any effect that results in the improvement of a condition, disease, disorder, etc., including one or more symptoms thereof, e.g., alleviation, reduction, modulation, amelioration, or elimination. Treating refers to curing, improving, or at least partially ameliorating a disorder.

[0078] As used herein, "therapeutically effective amount" refers to an amount of a compound (e.g., a compound of Formula I) or a pharmaceutically acceptable salt thereof that will elicit the biological or medical response in a tissue, system, animal, or human that is desired by a researcher, veterinarian, physician, or other clinician. The compounds described in the present disclosure, or a pharmaceutically acceptable salt thereof, can be administered in a therapeutically effective amount to treat a disease. A therapeutically effective amount of a compound or a pharmaceutically acceptable salt thereof can be the amount necessary to achieve the desired therapeutic and / or prophylactic effect, such as an amount that results in the alleviation of symptoms of a disease, such as DVS. [Example]

[0079] In order that the disclosure set forth in this disclosure may be more fully understood, the following examples are set forth. The examples described in this application are provided to illustrate the compounds, pharmaceutical compositions, and methods described herein, and should not be construed in any way as limiting the scope thereof.

[0080] Example 1: Synthesis of 2-chloro-4-[1-(4-fluorophenyl)-2,5-dimethyl-1H-imidazol-4-ylethynyl]pyridine (compound of Formula I above; see U.S. Pat. No. 7,332,510) 2-Chloro-4-[1-(4-fluorophenyl)-2-methyl-1H-imidazol-4-ylethynyl]-pyridine (200 mg, 0.6 mmol) was dissolved in 10 mL of tetrahydrofuran (THF) and cooled to −75°C. Lithium diisopropylamide (0.45 L, 0.91 mmol) was added, and the mixture was stirred at −75°C for 15 minutes. Iodomethane (0.05 mL, 0.85 mmol) was added, and stirring was continued at −75°C for 2 hours. The reaction mixture was quenched with saturated NaHCO3 solution and extracted with water and ethyl acetate. The combined organic extracts were dried over sodium sulfate, filtered, and evaporated. The crude product was purified by flash chromatography on silica gel (heptane / ethyl acetate gradient from 90:10 to 20:80) and recrystallization from ethyl acetate. The title compound was obtained as a white solid. MS: m / z = 326.5 (M+H+).

[0081] Example 2: Preparation of Polymorphs of Salts of the Compound of Formula I (See U.S. Patent No. 8,063,076) Form A Monosulfate: 61.0 g of 2-chloro-4-[1-(4-fluoro-phenyl)-2,5-dimethyl-1H-imidazol-4-ylethynyl]-pyridine was dissolved in 610 mL of 2-propanol. The solution was filtered, and the filter was rinsed with 31 mL of 2-propanol. To this mixture, a mixture of 30 mL of water and 18.91 g of sulfuric acid (97%) was added dropwise. The solution was cooled to 0-5 °C. Seeding was performed at 58 °C, if necessary. The solid residue was filtered, washed with 2-propanol (0-5 °C), and dried at 50 °C and <1 mbar for 18 hours to give 69.1 g (87.1%) of the monosulfate salt of the compound of Formula I. Seed crystals of Form A can be prepared by cooling and crystallizing a hot solution of 250 mg of the monosulfate salt in 10 mL of 2-propanol. After cooling to 0° C., the solid residue could be filtered and dried under vacuum at 50° C. to obtain Form A monosulfate, which was confirmed by an XRPD pattern substantially as shown in FIG. 1.

[0082] Form B Monosulfate: 300 mg of Form A monosulfate of the compound of Formula I was dissolved in 3 mL of 2-propanol and 1 mL of water at 60° C. to obtain a clear solution. The clear solution was seeded with Form B monosulfate and sealed at room temperature (e.g., about 25° C.). Single crystals formed after 3 days. Seed crystals can be prepared by forming a saturated slurry of Form A monosulfate of the compound of Formula I in 2-propanol and water (3:1 volume ratio) at room temperature. The slurry was stirred at room temperature for approximately 3 weeks. The solids were filtered through a glass 35 filter to obtain crystalline Form B monosulfate, which was confirmed by the XRPD pattern substantially as shown in FIG. 2.

[0083] Form C Hemisulfate: 41 g of Form A monosulfate of the compound of Formula I was mixed with 128 g of water. The slurry was stirred at room temperature for 2 to 16 hours. After all of the Form A monosulfate was converted to the hemisulfate, the resulting crystals were collected by filtration and washed with water. The resulting wet cake was dried in a vacuum oven at 40°C for 48 hours to obtain Form C hemisulfate in 93% yield. Form C hemisulfate was confirmed by an XRPD pattern substantially as shown in Figure 3.

[0084] Amorphous monosulfate: 0.53 g of the monosulfate salt of the compound of formula I was dissolved in 10 mL of methanol at about 65°C. After complete evaporation of the solvent under vacuum, the solid (foam) was further dried at about 50°C under 5-20 mbar for 18 hours. Analysis (XRPD and DSC) showed that an amorphous form of the compound of formula I was obtained. The amorphous monosulfate salt exhibited a peak at 2730 cm -1 , 2592cm -1 , 2219cm -1 , 1633cm -1 , 1586cm -1 , 1570cm -1 , 1513cm -1 , 1375cm -1 , 1343cm -1 , 1293cm -1 , 1226cm -1 , 1157cm -1 , 1130cm -1 , 1084cm -1 , 1040cm -1 , 986cm -1 , 903cm -1 , 848cm -1 , 788cm -1 , 712cm -1 , 670cm -1 (±3cm -1 The amorphous form was characterized by its infrared spectrum with a band at 1000 MHz. The glass transition temperature (T g ) was highly dependent on the solvent content and was approximately 42°C for wet samples (sealed pans) and approximately 77°C for in-situ dried samples (pans with perforated lids).

[0085] Example 3: Study of the Compound of Formula I in the Treatment of Subjects with Dravet Syndrome (DVS) A multicenter, maintenance-dose, 12-week, prospective, parallel-group, double-blind, randomized, placebo-controlled Phase 2 study will be conducted to evaluate the efficacy and safety of 0.5 to 3.5 mg daily of the compound of formula I (referred to herein as "CF-I" or "Compound I") administered adjunctively to ongoing seizure treatment in patients with Dravet syndrome (DVS) who have an inadequate response to current antiseizure medications.

[0086] A. Objective of the Primary Endpoint Evaluate the following:

[0087] 1. Change from baseline (compared to placebo) in mean convulsive seizure frequency (MCSF) during the combined titration and maintenance periods (T+M) in subjects receiving 0.5 to 3.5 mg of Compound I [Time frame: approximately 18 weeks from baseline (6-week titration period and 12-week maintenance period)]

[0088] 2. Change in mean frequency of seizures (compared to placebo) between baseline and the combined dose adjustment and maintenance periods for the 0.5-3.5 mg Compound I groups.

[0089] B. Secondary endpoint objectives Evaluate the following:

[0090] 1. Change from baseline (compared to placebo) in mean frequency of convulsive seizures during the combined dose adjustment and maintenance periods (T+M) in subjects receiving 0.5 to 3.5 mg of Compound I [Time frame: approximately 18 weeks from baseline (dose adjustment period (6 weeks) and maintenance period (12 weeks))]. Convulsive seizures include hemiclonic seizures, partial seizures with clear observable motor signs, generalized tonic-clonic seizures, secondary generalized tonic-clonic seizures, tonic seizures, clonic seizures, and atonic / atonic seizures.

[0091] 2. Percentage of subjects in each Compound I treatment group who achieved a 25% or greater (≥25%) reduction in seizure frequency compared to baseline during the dose adjustment and maintenance period (compared to the placebo group) [Time Frame: Approximately 18 weeks from baseline (6-week dose adjustment period and 12-week maintenance period)]. Seizures include hemiclonic, partial-onset seizures with clear observable motor signs, generalized tonic-clonic, secondary generalized tonic-clonic, tonic, clonic, and atonic / atonic.

[0092] 3. Percentage of subjects in each Compound I treatment group who achieved a 50% or greater reduction in seizure frequency compared to baseline during the dose adjustment and maintenance period (compared to the placebo group) [Time Frame: Approximately 18 weeks from baseline (6-week dose adjustment period and 12-week maintenance period)]. Seizures include hemiclonic, partial seizures with clear observable motor signs, generalized tonic-clonic, secondary generalized tonic-clonic, tonic, clonic, and atonic / atonic.

[0093] 4. Percentage of subjects in each Compound I treatment group who achieved a 75% or greater reduction in seizure frequency compared to baseline during the dose adjustment and maintenance period (compared to the placebo group) [Time Frame: Approximately 18 weeks from baseline (6-week dose adjustment period and 12-week maintenance period))] Seizures include hemiclonic, partial seizures with clear observable motor signs, generalized tonic-clonic, secondary generalized tonic-clonic, tonic, clonic, and atonic / atonic seizures.

[0094] 5. Percentage of subjects in each Compound I treatment group who achieved a 100% reduction in seizure frequency compared to baseline during the dose adjustment and maintenance period (compared to the placebo group) [Time Frame: Approximately 18 weeks from baseline (6-week dose adjustment period and 12-week maintenance period))] Seizures include hemiclonic, partial seizures with clear observable motor signs, generalized tonic-clonic, secondary generalized tonic-clonic, tonic, clonic, and atonic / atonic seizures.

[0095] 6. Longest seizure-free interval during the dose adjustment and maintenance periods in each Compound I treatment group (compared to the placebo group) [Time frame: approximately 18 weeks from baseline (6-week dose adjustment period and 12-week maintenance period)]. The longest interval between seizures is calculated across the entire dose adjustment and maintenance period and is derived as the maximum number of days between consecutive seizures.

[0096] 7. Number of seizure-free days during the dose titration and maintenance periods in each Compound I treatment group (compared to the placebo group) [Time Frame: Approximately 18 weeks from baseline (6-week dose titration period and 12-week maintenance period)]. A seizure-free day is defined as a day on which no seizures were reported.

[0097] 8. Change from baseline (compared to placebo) in frequency of non-convulsive seizures for each Compound I treatment group over the combined dose adjustment and maintenance periods [Time frame: approximately 18 weeks from baseline (6-week dose adjustment period and 12-week maintenance period)]. Non-convulsive seizures include partial-onset seizures without clear observable motor signs, absence or atypical absence seizures, myoclonic seizures, and atonic seizures.

[0098] 9. Change from baseline (compared to placebo) in seizure and non-convulsive seizure frequency for each Compound I treatment group over the combined dose-adjustment and maintenance periods [Time frame: approximately 18 weeks from baseline (6-week dose-adjustment period and 12-week maintenance period)]. Total seizure frequency is defined as the sum of convulsive and non-convulsive seizures. Convulsive seizures include hemiclonic, partial-onset seizures with clearly observable motor signs, generalized tonic-clonic, secondary generalized tonic-clonic, tonic, clonic, and atonic / atonic seizures. Non-convulsive seizures include partial-onset seizures without clearly observable motor signs, absence or atypical absence seizures, myoclonic, and atonic seizures.

[0099] 10. Percentage of subjects in each Compound I treatment group who used rescue medication during the dose titration and maintenance periods (compared to the placebo group) [Time Frame: Approximately 18 weeks from baseline (6-week titration period and 12-week maintenance period)]. Rescue medications will be administered according to each subject's usual or prescribed regimen of one or more medications.

[0100] 11. Percentage of subjects in each Compound I treatment group who were hospitalized and utilized medical resources for seizure treatment (compared to the placebo group) [Time Frame: Approximately 18 weeks from baseline (6-week dose adjustment period and 12-week maintenance period)]. An example would be subject utilization of a medical center for seizure treatment during the study period.

[0101] 12. Percentage of subjects with status epilepticus (SE) during the dose titration and maintenance periods in each Compound I treatment group (compared to the placebo group) [Time Frame: Approximately 18 weeks from baseline (6-week dose titration period and 12-week maintenance period)]. Examples include, for each treatment group, if a subject had an SE seizure recorded as an adverse event (AE) during treatment, if they had a seizure lasting 10 minutes or longer, etc.

[0102] 13. Distribution of seizure duration in each Compound I treatment group (compared to the placebo group) at baseline and during the dose adjustment and maintenance periods [Time frame: from baseline to approximately 18 weeks (6-week dose adjustment period and 12-week maintenance period)]

[0103] 14. The proportion (percentage) of subjects in each Compound I treatment group with an investigator-assessed Clinical Global Impression-Improvement (CGI-I) rating score (compared to the placebo group). The CGI-I scale measures improvement in a subject's clinical condition from baseline. The severity of a subject's condition can be rated on a 7-point scale ranging from 1 (much improved) to 7 (much worse): 1-much improved, 2-much improved, 3-slightly improved, 4-no change, 5-slightly worse, 6-much worse, 7-much worse. The investigator may also assess the subject's global impression of their condition during the study.

[0104] 15. Percentage of subjects in each Compound I treatment group with a parent / caregiver-rated Clinical Global Impression-Improvement (CGI-I) rating score (compared to the placebo group). The CGI-I scale measures improvement in a subject's clinical condition from baseline. The severity of a subject's condition can be rated on a 7-point scale ranging from 1 (much improved) to 7 (much worse): 1-much improved, 2-much improved, 3-slightly improved, 4-no change, 5-slightly worse, 6-much worse, 7-much worse. Parents / caregivers can rate the subject's global impression of their condition throughout the study.

[0105] 16. Change from baseline in the "Quality of Life in Pediatric Epilepsy (QOLCE)" score, a measure of quality of life, for each Compound I treatment group compared with the placebo group. The QOLCE assesses how epilepsy affects a subject's daily life in various life domains, including physical activity, well-being, cognition, social activities, behavior, and general health. It is a low-burden, easy-to-complete assessment for parents / caregivers. The QOLCE scores each item across 16 subscales using a 5-point scale. Item scores for each item are calculated using the following 5-point scales: 1-0, 2-25, 3-50, 4-75, and 5-100. Each subject's score for each subscale can be calculated by averaging the subject's responses to each item on that subscale. The subscale scores for each subject are then averaged to obtain each subject's overall QoL score. Higher QoL subscale and overall scores indicate better response.

[0106] 17. Change from baseline (compared to placebo) in overall quality of life scores on the Pediatric Quality of Life Inventory™ (PedsQL) for each Compound I treatment group. The Pediatric Quality of Life Inventory (PedsQL) is a modular measure of children's health-related quality of life (QoL) completed by a parent / caregiver on behalf of the subject. It consists of 23 items across four main scales measuring physical functioning (8 items), emotional, social, and school functioning (5 items each). Responses to each of the 23 items are scored on a 5-point Likert scale ranging from 0 (never) to 4 (almost always). Scores are linearly transformed to a 0-100 scale, with 0=100, 1=75, 2=50, 3=25, and 4=0, with higher scores corresponding to better health-related QoL. Overall quality of life is the average of all items over the number of items answered across all scales.

[0107] 18. Change from baseline in the "PedsQL Family Impact Module Total Score" for each Compound I treatment group (compared to placebo). The "PedsQL Family Impact" measures the impact of a child's chronic health condition on parents and families by measuring parental self-reported physical, emotional, social, and cognitive functioning, communication, worries, and family daily activities and relationships. The PedsQL has a total of 36 items: 6 for "Physical Functioning," 5 for "Emotional Functioning," 5 for "Cognitive Functioning," and 5 for "Worries," 4 for "Social Functioning," 3 for "Communication," 3 for "Daily Activities," and 5 for "Family Relationships." Each response was first scored on a 5-point Likert scale ranging from 0 (never) to 4 (almost always) and then linearly transformed to a 0-100 scale, where 0 = 100, 1 = 75, 2 = 50, 3 = 25, and 4 = 0, with higher scores indicating better health-related QoL.

[0108] 19. Parent / caregiver quality of life (QoL) using the EQ-5D-5L scale at baseline and on the same day in each Compound I treatment group (compared to placebo). The EuroQOL-5 Dimensions-5 Levels scale (EQ-5D-5L) health questionnaire, developed by the Euro-QOL Group, is a health-related QoL scale consisting of five dimensions: mobility, personal care, usual activities, pain / discomfort, and anxiety / depression. The five dimensions of the EQ-5D-5L health questionnaire are rated on a 5-point Likert scale: no problems, mild problems, moderate problems, severe problems, and extreme problems. The categories of mild problems, moderate problems, severe problems, and extreme problems are combined into a single response category called "problems." Parent / caregiver QoL will be assessed and the percentage of subjects for each item will be reported.

[0109] 20. Change from baseline in parent / caregiver emotional symptoms using the Hospital Anxiety and Depression Scale (HADS) for each Compound I treatment group compared with placebo. The HADS is a validated tool for assessing the presence or absence of anxiety or depression in non-psychiatric outpatient populations. The HADS generates original data on a 14-item scale across two dimensions: 1. Anxiety (7 items) and 2. Depression (7 items). Each item has a 4-point response range from 0 to 3, with 0 = no distress and 3 = worst distress. All responses to items within each dimension and their respective ratings are summed, resulting in a range of 0 to 21 for each dimension, with 0 to 7 = normal, 8 to 10 = borderline abnormal, and 11 to 21 = abnormal. The overall scale score (emotional distress) ranges from 0 to 42, with higher scores indicating greater distress.

[0110] 21. The proportion of subjects in each Compound I treatment group who were considered responders, defined as subjects who experienced a 40% or greater and a 50% or greater reduction in seizures from baseline (compared to the placebo group).

[0111] 22. Comparison of subjects' longest seizure-free intervals in each Compound I treatment group (compared to the placebo group). The longest seizure-free interval and the longest interval free of any seizures for each subject during the 18-week dose adjustment and maintenance period were calculated and compared independently for the Compound I 0.5-3.5 mg treatment group and the placebo group.

[0112] C. Measurement of additional secondary endpoints [Timeframe: baseline vs. dose adjustment + maintenance period or T+M as appropriate]. Evaluate the following: i. Number of seizure-free days. ii. Proportion of subjects with a 75% or greater reduction in seizure frequency from baseline. iii. Change from baseline in non-convulsive seizure frequency and total seizure frequency. iv. Incidence of emergency medication use and healthcare utilization during an attack. v. Incidence of status epilepticus. vi. Clinical Global Impression - Improvement rating - Parent / Caregiver rating. vii. Change from baseline in "Quality of Life." viii. Change from baseline in parent / caregiver emotional symptoms

[0113] D. Safety and Tolerability This study compares the safety and tolerability of 0.5-3.5mg of Compound I administered daily with placebo. The safety and tolerability of 0.5-3.5mg of Compound I administered daily with placebo will be compared in terms of adverse events (AEs), clinical test parameters, physical examination, neurological examination, vital signs (blood pressure, heart rate, body temperature, respiratory rate), electrocardiogram (ECG), echocardiogram (ECHO), body weight, and cognitive function.

[0114] E. Study Design This study was a multicenter, randomized, double-blind, parallel, placebo-controlled trial in patients with at least one type of generalized seizure (convulsive seizure) including atonic seizures (atonic, tonic, tonic-clonic, or myoclonic) for at least 6 months despite optimal antiepileptic drug treatment.

[0115] Patients who have been receiving treatment with therapeutic doses of antiepileptic medication for at least 6 months, who have signed an informed consent form or have their legally authorized representative sign an informed consent form, who meet the eligibility criteria for the study, and who agree to participate in the study or have their legally authorized representative agree to participate in the study will enter a screening and stabilization period of up to 8 weeks.

[0116] Eligible patients will continue to take their anticonvulsant medication (at the same dose) and will be randomly assigned via an interactive voice / web response system to receive one of two treatments in addition to their conventional anticonvulsant medication. Treatment A: Oral administration of 0.5 to 3.5 mg QD of Compound I (Note: QD refers to once daily) Treatment B: Placebo QD orally At the end of the stabilization period, patients who continue to meet all enrollment criteria will be randomly assigned to receive double-blind treatment.

[0117] F. Testing Phases The total duration of the double-blind study is approximately 18 weeks. Screening and stabilization phase: up to 8 weeks The treatment phase includes a dose adjustment phase of up to 6 weeks followed by a 12-week maintenance phase.

[0118] G. Target Population Patients must meet the following criteria for study participation: 1. Ability and willingness to provide written informed consent and comply with study procedures, or, for patients ranging from infants to adults, a legally authorized representative who is able and willing to provide written informed consent and comply with study procedures. Have a documented history of DVS, including DNA-confirmed evidence of at least one type of generalized seizure, including convulsive seizures (atonic, tonic, tonic-clonic, or myoclonic), lasting for at least 6 months. 2. Subjects must be refractory, i.e., have documented failure to respond to two or more antiepileptic medications (ASMs). 3. Subjects must be taking one or more ASMs on a stable dose for at least 4 weeks prior to screening. 4. All medications or interventions for seizures (including ketogenic diet and neurostimulators) must be stable for 4 weeks prior to screening, and patients must be willing to maintain a stable medication regimen for the duration of the study. Ketogenic diet and neurostimulators are not included in the ASM.

[0119] Patients who meet any of the following criteria will be excluded from participating in the study. 1. The etiology of the subject's seizures is a progressive neurological disease. 2. Subject has experienced an anoxic episode requiring resuscitation within 6 months of screening. 3. Subject has a clinically significant unstable medical condition other than epilepsy. 4. Subject had a clinically relevant condition or clinically significant illness other than epilepsy in the 4 weeks prior to screening or randomization. 5. Subject has participated in a clinical trial involving another IMP within the past 6 months. 6. Active suicidal behavior or suicidal ideation rated as type 4 or 5 on the Columbia-Suicide Severity Scale within the past month or at screening. 7. Subject is currently taking chronic systemic steroids (excluding inhaled medications for the treatment of asthma) or other routine medications known to exacerbate epilepsy, with the exception of preventative medications for idiopathic nephrotic syndrome, asthma, etc. 8.Subject is taking felbamate for less than one year prior to screening. 9. Concomitant use of fenfluramine. Subjects who have used fenfluramine within the past 3 months or who do not have adequate documentation of an echocardiogram at least 3 months after their last dose of fenfluramine to confirm the absence of criteria for drug-related (fenfluramine) valvular heart disease and / or drug-related pulmonary arterial hypertension (PAH). 10. Pregnant or breastfeeding.

[0120] H. Primary endpoint (efficacy) The primary endpoints are as follows:

[0121] 1. Change from baseline (compared to placebo) in mean seizure frequency (MCSF) during the combined dose titration and maintenance periods (T+M) in subjects receiving 0.5 to 3.5 mg of Compound I [Time frame: approximately 18 weeks from baseline (6-week dose titration period and 12-week maintenance period)].

[0122] 2. Change in mean frequency of seizures (compared to placebo) between baseline and the combined dose adjustment and maintenance periods for the 0.5-3.5 mg Compound I groups.

[0123] I. Secondary endpoints (efficacy) Secondary endpoints are as follows:

[0124] 1. Change from baseline (compared to placebo) in mean seizure frequency during the combined dose adjustment and maintenance periods (T+M) in subjects receiving 0.5 to 3.5 mg of Compound I.

[0125] 2. The proportion (percentage) of subjects in each Compound I treatment group who achieved a 25% or greater (≥ 25%) reduction in seizure frequency compared to baseline during the dose adjustment and maintenance period (compared to the placebo group).

[0126] 3. The percentage of subjects in each Compound I treatment group who achieved a 50% or greater reduction in seizure frequency compared to baseline during the dose adjustment and maintenance periods (compared to the placebo group).

[0127] 4. The percentage of subjects in each Compound I treatment group who achieved a 75% or greater reduction in seizure frequency compared to baseline during the dose adjustment and maintenance periods (compared to the placebo group).

[0128] 5. The percentage of subjects in each Compound I treatment group who achieved a 100% or greater reduction in seizure frequency compared to baseline during the dose adjustment and maintenance periods (compared to the placebo group).

[0129] 6. Longest seizure-free interval during dose adjustment and maintenance periods in each Compound I treatment group (compared to the placebo group).

[0130] 7. Number of seizure-free days during the dose adjustment and maintenance periods in each Compound I treatment group (compared to the placebo group).

[0131] 8. Change from baseline (compared to placebo) in non-convulsive seizure frequency for each Compound I treatment group over the combined dose adjustment and maintenance periods.

[0132] 9. Change from baseline (compared to placebo) in frequency of convulsive + non-convulsive seizures for the combined dose adjustment and maintenance periods in each Compound I treatment group.

[0133] 10. Percentage of subjects in each Compound I treatment group who used rescue medication during the dose adjustment and maintenance periods (compared to the placebo group).

[0134] 11. Percentage of subjects in each Compound I treatment group who were hospitalized and utilized medical resources for seizure treatment (compared to the placebo group).

[0135] 12. Percentage of subjects with status epilepticus (SE) during the dose adjustment and maintenance periods in each Compound I treatment group (compared to the placebo group).

[0136] 13. Distribution (percent) of seizure duration in each Compound I treatment group (compared to the placebo group) at baseline and during the dose adjustment and maintenance periods.

[0137] 14. The proportion (percentage) of subjects in each Compound I treatment group with an investigator-assessed Clinical Global Impression-Improvement (CGI-I) rating score (compared to the placebo group).

[0138] 15. Percentage of subjects in each Compound I treatment group with a parent / caregiver-rated Clinical Global Impression-Improvement (CGI-I) rating score (compared to the placebo group). The CGI-I scale measures improvement in a subject's clinical status from baseline.

[0139] 16. Change from baseline to Day 99 in the Quality of Life in Pediatric Epilepsy (QOLCE) score, a measure of quality of life, in each Compound I treatment group (compared to the placebo group).

[0140] 17. Change from baseline to Day 99 in overall quality of life score on the Pediatric Quality of Life Inventory™ (PedsQL) in the Compound I treatment group compared to the placebo group.

[0141] 18. Change from baseline to day 99 in the "PedsQL Family Impact Module Score Total Score" in each Compound I treatment group (compared to the placebo group).

[0142] 19. Parent / Caregiver Quality of Life (QoL) using the EQ-5D-5L scale in each Compound I treatment group (compared to placebo) at baseline and on the same day.

[0143] 20. Change from baseline to Day 99 in parent / caregiver emotional symptoms using the Hospital Anxiety and Depression Scale (HADS) in each Compound I treatment group compared to the placebo group.

[0144] 21. The proportion of subjects in each Compound I treatment group who were considered responders, defined as subjects who experienced a 40% or greater and a 50% or greater reduction in seizures from baseline (compared to the placebo group).

[0145] 22. Comparison of subjects' longest seizure-free interval in each Compound I treatment group (compared to the placebo group).

[0146] J. Measurement of additional secondary endpoints [Timeframe: baseline vs. dose adjustment + maintenance period or T+M as appropriate]. Additional secondary endpoints include: ix. Number of seizure-free days. x. Percentage of subjects achieving a 75% or greater reduction in seizure frequency from baseline. xi. Change from baseline in non-convulsive seizure frequency and total seizure frequency. xii. Incidence of emergency medication use and healthcare utilization. xiii. Incidence of status epilepticus. xiv. Clinical Global Impression - Improvement Rating - Parent / Caregiver Rating. xv. Change from baseline in "Quality of Life." xvi. Change from baseline in parent / caregiver emotional symptoms.

[0147] Example 4: Study of seizure freedom with Compound I Dravet syndrome is a severe developmental epileptic encephalopathy (DEE) most frequently caused by de novo pathogenic mutations in SCN1A (sodium voltage-gated channel α subunit 1). Most Dravet syndrome cases show loss of function of SCN1A, particularly in interneurons, resulting in a reduced ability to modify electrical activity, resulting in electrical hyperexcitability and a predisposition to seizures. Heterozygous deletion of Scn1a in mice (Scn1a+ / -) recapitulates several core phenotypes of clinical Dravet syndrome, including temperature-dependent and spontaneous seizures, SUDEP, and behavioral abnormalities. Furthermore, Scn1a+ / - mice exhibit similar clinical responses to standard anticonvulsants, including lamotrigine-induced seizure exacerbation and seizure suppression by clobazam and fenfluramine. Thus, Scn1a+ / - mice are a suitable model for clinical application of novel ASMs with various mechanisms of action.

[0148] As used herein, "Compound I" refers to the compound of formula I.

[0149] As used herein, "CTEP" refers to a compound of formula C 19 H 13 ClF3N3O and structure Refers to compounds with TIFF2026503754000009.tif23128. This compound is known as a selective mGluR5 allosteric antagonist or negative allosteric modulator.

[0150] As used herein, "RO6807794" refers to a compound of formula C 18 H 18 FN3O and structure Refers to the compound with TIFF2026503754000010.tif21128. This compound is known as a positive allosteric modulator.

[0151] As used herein, "NAM" refers to a negative allosteric modulator and "PAM" refers to a positive allosteric modulator.

[0152] A.Purpose Experiments were conducted to evaluate the effects of Compound I, CTEP, and RO6807794 on seizure frequency, seizure freedom, and survival in Scn1a+ / − mice.

[0153] B. Method Five treatment groups were studied to evaluate the effects of negative and positive allosteric modulators of mGluR5 on seizure frequency, seizure freedom, and survival in Scn1a+ / − mice. (1) Compound I is orally administered at 0.3 mg / kg once a day for 28 days starting from postnatal day 10 (P10). (2) Compound I is orally administered at 1 mg / kg once a day for 28 days from P10. (3) CTEP will be orally administered at a dose of 0.3 mg / kg every other day for 28 days from P01. (4) RO6807794 will be administered intraperitoneally at 0.3 mg / kg once daily for 5 days starting from P21. (5) Untreated group.

[0154] Frontal cortex recordings were chosen as representative of seizure phenomena in mice experiencing generalized seizures. EEG headmounts were implanted between P20 and P22, and recordings were initiated for approximately 14 days of continuous monitoring in the NAM and PAM groups. Individual frontal cortex seizure measures over time were visually explored, and summaries over time were calculated.

[0155] 1. Seizure frequency Seizure frequency was measured by counting the number of seizures observed each day, and frequencies were analyzed using the chi-squared test (across all treatment groups) and Fisher's exact test (pairwise comparisons between treatment groups).

[0156] 2. Seizure-free Seizure-free status was measured as a binary value (0 or 1), with 0 indicating no seizures were observed on all test days and 1 indicating at least one seizure was recorded on all test days. Seizure-free status was summarized in contingency tables for all animals and analyzed using a generalized linear model (GLM) with a binomial distribution of errors and a logit link function. Results were presented as probability and odds ratios with 95% confidence intervals between groups. The odds ratio represented the increased likelihood that animals in the treated group were seizure-free (seizure-free = 1) compared with the untreated group. Analyses were performed using GraphPad Prism 9 (contingency tables) and SAS 9.4 (binomial model).

[0157] 3. Time to first seizure: Time to first seizure refers to the time recorded as the day the first seizure occurred (observed, uncensored observation) or the last day of recording for that animal if a seizure was observed (censored observation). Time to first seizure was visualized using Kaplan-Meier curves and analyzed by the log-rank (Mantel-Cox) test. Analysis was performed using GraphPad Prism 9.

[0158] 4. Total seizure burden Total seizure burden is the sum of seizure frequencies across all test days.

[0159] 5. Number of seizures per day Seizures per day were measured as the total number of seizures divided by the number of study days, and the seizure count was adjusted for the number of days the animal was on study.

[0160] Time to first seizure and number of seizures per day were visually examined and analyzed using analysis of variance (ANOVA). Results were presented as geometric means, ratios of geometric means, confidence intervals, and p-values. Additional nonparametric analyses included the Kruskal-Wallis test, along with pairwise comparisons with the untreated group using the Wilcoxon test. Data were analyzed using a generalized linear model (GLM) with a Poisson error distribution and a logarithmic link function. Linear predictors described a suitable model to explore fixed effects for treatment group.

[0161] C. Results 1. Seizure-free Seizure-free status was measured and analyzed for the 1 mg / kg Compound I group, the 0.3 mg / kg Compound I group, the CTEP group, and the untreated group. Figure 4 and Table 4 show the frequency and percentage of seizure-free animals across the four treatment groups. The RO6807794 group was only treated for 5 days and was therefore not included in the seizure-free analysis. Figure 4 and Table 4 reveal that the percentage of seizure-free animals in the 1 mg / kg Compound I group was greater than in the untreated group. Compound I administration was associated with an increased probability of seizure-free status, with the 1 mg / kg Compound I group having a 77% seizure-free probability compared to 25% in the untreated group (Figure 4).

[0162] Table 1. Frequency and percentage of seizure-free animals TIFF2026503754000011.tif36164

[0163] As part of the contingency table analysis, a chi-squared test was performed on Table 4. This test showed a statistically significant p-value (p=0.0004), indicating that the proportion of seizure-free animals differed by treatment group. This difference in treatment group was further demonstrated by GLM analysis, the results of which are quantified in Table 5 by the probability of seizure-freeness, odds ratio (compared to the untreated group), and 95% confidence interval. As shown in Table 5, the 1 mg / kg dose of Compound I group had an increased probability of being seizure-free, and animals in the 1 mg / kg dose of Compound I group were much more likely to be seizure-free (seizure-free=1) compared to the untreated group.

[0164] Table 2. Seizure-free treatment group dependency TIFF2026503754000012.tif36168

[0165] 2. Time to first seizure A time-to-event analysis (often called survival analysis) was performed for the 1 mg / kg Compound I group, the 0.3 mg / kg Compound I group, the CTEP group, the RO6807794 group, and the untreated group, using the date on which each animal experienced its first seizure. Each animal was defined as seizure-free until the day on which it experienced its first seizure. If an animal was removed from the study early or remained seizure-free until day 15, it was classified as a censored observation, meaning that the time to first seizure was not observed during the study period. In this case, the time to first seizure was considered to exceed the last day of the study.

[0166] Figure 5 shows a Kaplan-Meier plot of the percentage of seizure-free animals over time for all treatment groups. In Figure 5, all groups start with 100% of animals being seizure-free, and the line steps down (the percentage decreases) each time an animal in that group experiences at least one seizure on that day. Figure 5 shows that the 1 mg / kg Compound I and CTEP groups had more animals that were seizure-free for a longer period, as quantified through the median time to first seizure. The median time to first seizure (or time until 50% of animals had at least one seizure) was 2 days for the 0.3 mg / kg Compound I group, 3 days for the RO6807794 group, and 7 days for the untreated group. By the end of the 15-day period, more than 50% of animals in the 1 mg / kg Compound I group remained seizure-free.

[0167] The 1 mg / kg Compound I group increased the time to observe at least one seizure, with 50% of the untreated group experiencing at least one seizure by day 7 and 77% of the 1 mg / kg Compound I group being seizure-free by day 15.

[0168] 3. Total seizure burden Total seizure frequency across all study days was measured and analyzed for the 1 mg / kg Compound I group, the 0.3 mg / kg Compound 1 group, the CTEP group, and the untreated group. Figure 6 shows plots of the individual total seizure burden data for the main treatment groups. Figure 7 shows the adjusted data from Figure 6 plotted using a logarithmic scale on the Y-axis. To generate the plot in Figure 7, a small constant (10% of the smallest non-zero value, i.e., 0.1) was added to all responses, and the data from Figure 6 were scaled logarithmically. 10 The RO6807794 group was not included in the analysis of total seizure burden because it was only administered for 5 days.

[0169] log 10Exploratory ANOVA on a transformed scale: Exploratory ANOVA was performed on the log-transformed log data. The results are shown in Figures 8 and 9. Figure 8 contains the geometric means and 95% confidence intervals for the four treatment groups. Figure 9 contains the comparison with the untreated group, expressed as a ratio of geometric means and 95% confidence intervals. Comparisons whose confidence intervals do not cross the baseline (Y=1) are considered statistically significant at a significance level of 5% (p<0.05). In Table 6, ratios are expressed as percentage change. Both the CTEP-treated group and the 1 mg / kg Compound I group showed statistically significantly lower total seizure burden compared to the untreated group (82% and 84% reductions, respectively, both p<0.05). The 1 mg / kg Compound I group showed statistically lower total seizure burden compared to the CTEP-treated group and the untreated group.

[0170] Table 3. Geometric means and 95% confidence intervals for total seizure burden, and mean ratios and 95% confidence intervals for total seizure burden compared to the untreated group. TIFF2026503754000013.tif61168

[0171] Nonparametric analysis: To examine total seizure burden without assuming a specific underlying distribution, Kruskal-Wallis analysis with Wilcoxon pairwise tests was performed. Similar to exploratory ANOVA, these methods also demonstrated that the 1 mg / kg Compound I and CTEP treatment groups had lower total seizure burden compared to the untreated group (both p<0.05).

[0172] GLM analysis suitable for discrete data was performed using the geometric means and 95% confidence intervals of the four treatment groups, with comparisons to the untreated group expressed as ratios of geometric means and 95% confidence intervals, as shown in Table 7. Both the CTEP and 1 mg / kg Compound I groups had statistically significantly lower total seizure burden compared to the untreated group (62% and 44% reductions, respectively, both p<0.01).

[0173] Table 4. Generalized linear model analysis of discrete data (count data) for total seizure burden. TIFF2026503754000014.tif61168

[0174] 4. Number of seizures per day Total seizure burden measurements were adjusted by simple division for the number of days each animal participated in the study. Figure 10 shows the seizure data per day for all treatment groups. To allow the data to be visualized on a log10 transformed scale, a small constant (10% of the smallest non-zero value, i.e., 0.0067) was added to all responses. Figure 11 shows the adjusted data using a logarithmic scale on the y-axis.

[0175] log 10 Exploratory ANOVA on a transformed scale: ANOVA was performed on the log-transformed adjusted data. The results are shown in Figure 12, Figure 13, and Table 8. The plot in Figure 12 contains the geometric means and 95% confidence intervals for the four treatment groups, while Figure 13 contains the comparison with the untreated group, expressed as a ratio of geometric means and 95% confidence intervals. Comparisons where the confidence interval does not cross the baseline (Y=1) are considered statistically significant at a significance level of 5% (p<0.05). In Table 8, this ratio is expressed as a percentage change. Both the CTEP-treated group and the 1 mg / kg Compound I-treated group showed statistically significantly lower mean daily seizure counts compared to the untreated group (85% and 79% reductions, respectively, both p<0.05, log 10 (ANOVA on adjusted scale) The 1 mg / kg Compound I group showed a statistically lower mean number of seizures per day compared to the untreated group.

[0176] Table 5. Geometric mean ratios and 95% confidence intervals for the number of seizures per day, and the mean ratios and 95% confidence intervals for the number of seizures per day compared with the untreated group. TIFF2026503754000015.tif67168

[0177] Nonparametric analysis: To examine the daily seizure data without assuming a specific underlying distribution, Kruskal-Wallis analysis with Wilcoxon pairwise tests was performed. Similar to ANOVA, these methods demonstrated that the 1 mg / kg Compound I and CTEP treatment groups had reduced daily seizure rates compared to the untreated group (both p<0.05), whereas the RO6807794 (PAM) treatment group had increased daily seizure rates compared to the untreated group (p<0.05).

[0178] GLM Suitable for Discrete Data: The GLM analysis performed was suitable for discrete (count) data and used the geometric means and 95% confidence intervals for the five treatment groups, with comparisons to the untreated group expressed as ratios of geometric means and 95% confidence intervals, as shown in Table 9. None of the groups demonstrated a statistically significant lower daily seizure rate compared to the untreated group, however, the RO6807794-treated group had a statistically significant increase in daily seizure rate compared to the untreated group (p<0.001).

[0179] Table 6. Generalized linear model analysis of discrete data (count data) on seizures per day TIFF2026503754000016.tif72168

[0180] Other embodiments All features disclosed herein may be combined in any combination. Each feature disclosed herein may be replaced by an alternative feature serving the same, equivalent, or similar purpose. Thus, unless expressly stated otherwise, each disclosed feature is only an example of a generic series of equivalent or similar features.

[0181] Furthermore, from the above description, those skilled in the art can ascertain the essential features of the present invention, and can make various changes and modifications to the present invention to adapt it to various uses and conditions without departing from the spirit and scope thereof. Accordingly, other embodiments are within the scope of the appended claims.

Claims

1. It includes administering to a subject in need thereof a composition comprising a therapeutically effective amount of a therapeutic agent, said therapeutic agent being a compound of formula I: or a pharmaceutically acceptable salt thereof.

2. 10. The method of claim 1, wherein administering comprises administering the therapeutic agent in its free base form.

3. 10. The method of claim 1, wherein administering comprises administering the therapeutic agent in the form of a pharmaceutically acceptable salt thereof.

4. 4. The method of any one of claims 1 to 3, wherein said administering said therapeutic agent comprises administering said therapeutic agent in an amount of about 0.05 mg to about 5 mg.

5. 5. The method of any one of claims 1 to 4, wherein said administering said therapeutic agent comprises administering said therapeutic agent in an amount of about 0.1 mg to about 4 mg.

6. 6. The method of any one of claims 1 to 5, wherein said administering said therapeutic agent comprises administering said therapeutic agent in an amount of about 0.5 mg to about 3.5 mg.

7. 7. The method of any one of claims 1 to 6, wherein said administering said therapeutic agent comprises administering said therapeutic agent in an amount of about 0.1 mg, about 0.5 mg, about 0.8 mg, about 1.0 mg, about 1.3 mg, about 1.5 mg, about 1.8 mg, about 2 mg, about 2.3 mg, about 2.5 mg, about 2.8 mg, about 3 mg, about 3.3 mg, about 3.5 mg, about 3.8 mg, or about 4.0 mg.

8. 8. The method of any one of claims 1 to 7, wherein said administering said therapeutic agent comprises administering said therapeutic agent once daily.

9. The method of any one of claims 1 to 8, wherein the subject is a human.

10. The method of any one of claims 1 to 9, wherein the subject is a patient.

11. 11. The method of any one of claims 1 to 10, wherein after administration of the compound, the subject has one or more reduced seizure types.

12. 12. The method of claim 11, wherein the seizure type is a convulsive seizure or a non-convulsive seizure.

13. 13. The method of claim 12, wherein the seizures are reduced by about 50% or more, about 55% or more, about 60% or more, about 65% or more, about 70% or more, about 75% or more, about 80% or more, about 85% or more, about 90% or more, about 95% or more, or completely eliminate seizures in the subject over a period of 10 days, 20 days, 30 days, 50 days, 84 days, or more.

14. 13. The method of claim 12, wherein the non-convulsive seizures are reduced by about 50% or more, about 55% or more, about 60% or more, about 65% or more, about 70% or more, about 75% or more, about 80% or more, about 85% or more, about 90% or more, about 95% or more, or seizures are completely eliminated in the subject over a period of 10 days, 20 days, 30 days, 50 days, 84 days, or more.

15. 12. The method of claim 11, wherein the seizure type is focal onset seizures, generalized onset seizures, or seizures of unknown onset.

16. 11. The method of any one of claims 1 to 10, wherein after administration of the compound, the subject has alleviated status epilepticus.

17. 17. The method of claim 16, wherein the method reduces status epilepticus frequency in the subject by about 50% or more, about 55% or more, about 60% or more, about 65% or more, about 70% or more, about 75% or more, about 80% or more, about 85% or more, about 90% or more, about 95% or more over a period of 10 days, 20 days, 30 days, 50 days, 84 days, or more, or completely eliminates seizures in the subject.

18. 11. The method of any one of claims 1 to 10, wherein after administration of the compound, the subject's hospital visits due to stroke are eliminated by about 25% or more, about 50% or more, about 75% or more, or completely eliminated.

19. 11. The method of any one of claims 1 to 10, wherein after administration of the compound, the subject's need for emergency medication is reduced by about 25% or more, about 50% or more, about 75% or more, or the need for emergency medication is completely eliminated.

20. 11. The method of any one of claims 1 to 10, wherein the therapeutic efficacy of the treatment is determined by assessing improvement based on the Clinical Global Impression-Improvement (CGI-I) rating score.

21. 11. The method of any one of claims 1 to 10, wherein the therapeutic efficacy of the treatment is determined by assessing improvement based on Quality of Life in Pediatric Epilepsy (QOLCE) score.

22. 11. The method of any one of claims 1 to 10, wherein the therapeutic effectiveness of the treatment is determined by assessing improvement based on the overall quality of life score from the Pediatric Quality of Life Inventory™ (PedsQL).

23. 11. The method of any one of claims 1 to 10, wherein the therapeutic efficacy of the treatment is determined by assessing improvement based on PedsQL Family Impact Module score.

24. 11. The method of any one of claims 1 to 10, wherein the therapeutic efficacy of said treatment is determined by assessing improvement based on the EuroQOL-5 dimensions-5 level scale.

25. 11. The method of any one of claims 1 to 10, wherein the therapeutic efficacy of the treatment is determined by assessing improvement based on the Hospital Anxiety and Depression Scale (HADS).

26. 11. The method of any one of claims 1 to 10, wherein the therapeutic effectiveness of the treatment is determined by assessing improvement in seizure-free interval.

27. 10. The method of claim 1, wherein the therapeutic efficacy of the treatment is determined by assessing a reduction in seizure frequency.

28. 10. The method of claim 1, wherein the therapeutic efficacy of the treatment is determined by assessing an increase in seizure freedom.

29. 10. The method of claim 1, wherein the therapeutic efficacy of the treatment is determined by assessing the increase in time to first seizure.

30. 10. The method of claim 1, wherein the therapeutic efficacy of the treatment is determined by assessing a reduction in total seizure burden.

31. 10. The method of claim 1, wherein the therapeutic efficacy of the treatment is determined by assessing a reduction in total seizures per day.

32. the therapeutic effect of the treatment: a. A reduction in overall seizure rate of 50% or more; b. A decrease in the frequency of seizures; c. Increased likelihood of seizure freedom; d. Improvement in behavioral or cognitive symptoms, or e. Longest seizure-free interval 32. The method of any one of claims 1 to 31, wherein the value is determined by:

33. The method comprises administering to a subject in need thereof a composition comprising a therapeutically effective amount of an mGlu5 negative allosteric modulator (NAM) or a pharmaceutically acceptable salt thereof, wherein said mGlu5 NAM is a compound of Formula I: A method for treating Dravet syndrome.

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