Methods of treatment of DRAVET syndrome

Abstract

Provided herein are methods of treating Dravot Syndrome in a subject by administering to the subject in need thereof a composition comprising an mGlu5 negative allosteric modulator (NAM).

Description

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS

[0002] This application claims the benefit of and priority to U.S. patent application No. 63 / 482,918, filed on February 2, 2023, the contents of which are incorporated herein by reference in their entirety. Technical Field

[0003] The present disclosure relates to the medical field and 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 treating or alleviating Dravet syndrome. Background Art

[0004] Dravet syndrome (DVS), also known as severe myoclonic epilepsy of infancy (SMEI), is a rare, catastrophic, lifelong form of epilepsy that begins in the first year of life with frequent or prolonged seizures. Children with DVS often experience delayed development of language and motor skills, hyperactivity and sleep difficulties, chronic infections, growth and balance problems, and difficulty interacting with others. In 70% to 90% of patients, DVS is caused by mutations in the SCN1A gene (voltage-gated sodium channel, type I, alpha subunit) that produce a premature stop codon and, therefore, a nonfunctional protein. See, e.g., Selmer et al., Clinical Genetics., 2009, 76(4): 398–403.

[0005] Current treatment options for DVS are limited. Seizures in DVS can be difficult to control but can be alleviated with anti-seizure medications such as clobazam, stiripentol, topiramate, valproate, fenfluramine, and cannabidiol. However, some drugs are known to exacerbate seizures in patients due to their effects on sodium ion channels. In addition, some drugs have significant side effects, limiting their medical use.

[0006] Therefore, there is an unmet medical need to develop new approaches for treating DVS without significant side effects. Summary of the Invention

[0007] The present disclosure provides, in part, 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:

[0008]

[0009] or a pharmaceutically acceptable salt thereof.

[0010] Also provided herein is, in part, a method for treating Dravet syndrome, 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:

[0011] BRIEF DESCRIPTION OF THE DRAWINGS

[0012] Figure 1 Depicted is an exemplary XRPD pattern of the crystalline anhydrate form of the monosulfate salt of the compound of Formula I (Form A).

[0013] Figure 2 Depicted is an exemplary XRPD pattern of the crystalline monohydrate form of the monosulfate salt of the compound of Formula I (Form B).

[0014] Figure 3 Depicted is an exemplary XRPD pattern of the crystalline hemihydrate form of the hemisulfate salt of the compound of Formula I (Form C).

[0015] Figure 4 Depicted are the frequency and percentage of animals exhibiting seizure freedom across the Compound 1 1 mg / kg group, Compound 1 0.3 mg / kg group, CTEP group, and untreated group.

[0016] Figure 5 Depicted are Kaplan-Meier plots showing how the percentage of seizure-free animals changed over time for the Compound 1 1 mg / kg group, the Compound 1 0.3 mg / kg group, the CTEP group, and the untreated group.

[0017] Figure 6 Depicted are graphs of individual total seizure burden data associated with the Compound 1 1 mg / kg group, the Compound 1 0.3 mg / kg group, the CTEP group, and the untreated group.

[0018] Figure 7 The y-axis is plotted using a logarithmic scale (log 10 )of Figure 6 A plot of the adjusted data.

[0019] Figure 8 Depicted are the total seizure burden (geometric means and 95% confidence intervals) for the Compound I 1 mg / kg group, the Compound I 0.3 mg / kg group, the CTEP group, and the untreated group.

[0020] Figure 9 Comparisons with the untreated group are depicted, expressed as ratios of geometric means and 95% confidence intervals.

[0021] Figure 10 Individual daily seizure count data across the Compound 1 1 mg / kg group, Compound 1 0.3 mg / kg group, CTEP group, and untreated group are depicted.

[0022] Figure 11 The logarithm (log 10 ) scale Figure 10 Adjusted data.

[0023] Figure 12 and Figure 13 Depicted are the results of ANOVA performed on log-transformed adjusted data for mean daily episodes. Figure 13 Comparisons with the untreated group are presented as ratios of geometric means and 95% confidence intervals. DETAILED DESCRIPTION

[0024] As generally described herein, the present disclosure provides methods of treating Dravet syndrome (DVS) in a subject in need thereof with a compound of Formula I, or a pharmaceutically acceptable salt thereof. Also provided herein are methods of treating a symptom (e.g., an attack) of Dravet syndrome in a subject in need thereof with a compound of Formula I, or a pharmaceutically acceptable salt thereof.

[0025] Compound

[0026] As depicted below, the compound of Formula I is a mGlu5 negative allosteric modulator (NAM), also known as 2-chloro-4-[1-(4-fluorophenyl)-2,5-dimethyl-1H-imidazol-4-ylethynyl]pyridine or Basimglurant:

[0027]

[0028] A method for chemically synthesizing compounds of Formula I is described in U.S. Patent No. 7,332,510 (including Example 1 provided herein), which is incorporated herein by reference in its entirety. As used herein, the compound of Formula I is referred to as "Compound I."

[0029] It is to be understood that the compounds of Formula I as described herein include crystalline solid forms of either the free base or pharmaceutically acceptable salts of the compounds of Formula I as described herein.

[0030] In certain embodiments, a pharmaceutically acceptable salt of a compound of Formula I can be a salt of a compound of Formula I with a physiologically compatible mineral acid such as hydrochloric acid, sulfuric acid, sulfurous acid, or 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, or salicylic acid. Exemplary pharmaceutically acceptable salts of a compound of Formula I are monosulfate or hemisulfate.

[0031] In certain embodiments, the pharmaceutically acceptable salt of the compound of Formula I is a monosulfate salt or a hemisulfate salt, each in the form of a hydrate or an anhydrate (eg, an anhydrate, hemihydrate, or monohydrate).

[0032] In certain embodiments, the pharmaceutically acceptable salt of the compound of Formula I is in crystalline or amorphous form.

[0033] In some embodiments, the compound is in the form of a crystalline anhydrate of the monosulfate salt of the compound of Formula I (Form A), wherein Form A has Figure 1 In some embodiments, Form A is characterized by at least three peaks selected from the group consisting of Cu Kα The following X-ray powder diffraction peaks obtained by irradiation at 2θ (2Theta) are: 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°). According to DSC analysis, the crystalline form A generally has a T of about 180°C to 190°C. m In some embodiments, Form A is characterized by an infrared spectrum with sharp bands at 3068, 2730, 2618, 2236, 2213, 1628, 1587, 1569, 1518, 1384, 1374, 1295, 1236, 1168, 1157, 1116, 1064, 1019, 902, 855, 786, and 674 cm -1 (±3cm -1 ).

[0034] In some embodiments, the compound is in the form of a crystalline monohydrate of the monosulfate salt of the compound of Formula I (Form B), wherein Form B has Figure 2 The XRPD pattern shown is substantially the same as that shown in FIG. 2 . By DSC analysis, the crystalline form B generally has a T of about 60°C to 70°C. m .

[0035] In some embodiments, the compound is in the form of a crystalline hemihydrate of the hemisulfate salt of the compound of Formula I (Form C), wherein Form C has Figure 3The XRPD pattern shown is substantially the same as that shown. By DSC analysis, the crystalline form C generally has a T of about 90°C to 100°C. m .

[0036] How to use and treatment methods

[0037] In one aspect, provided herein are methods for treating Dravet syndrome (DVS) in a subject in need thereof. Exemplary subjects include, but are not limited to, humans and patients, including infants, children, young adults, and adults. In one aspect, the present disclosure provides a method for treating a patient diagnosed with Dravet syndrome, the method comprising administering to the patient a therapeutically effective dose of a compound of Formula I.

[0038] On the other hand, provided herein are methods for treating symptoms associated with Dravet syndrome (DVS) in a subject in need thereof. Exemplary subjects include, but are not limited to, humans, participants, and patients, including infants, children, young adults, and adults. On the one hand, the present disclosure provides a method for treating a patient exhibiting symptoms associated with Dravet syndrome, the method comprising administering to the patient a therapeutically effective dose of a compound of Formula I. In an embodiment, the symptom is an attack. In an embodiment, Dravet syndrome is associated with various types of attacks, and the subject (e.g., a person, patient, or participant) experiences various types of attacks. Therefore, in various embodiments, provided herein are methods for treating attacks associated with Dravet syndrome (DVS) in a subject in need thereof.

[0039] Dravet syndrome (DVS) is a catastrophic form of epilepsy with prolonged seizures, often triggered by a high temperature or fever. DVS is characterized by prolonged febrile and non-febrile seizures that occur within a child's first year of life. Common problems associated with DVS include: prolonged seizures; frequent seizures; behavioral and developmental delays; movement and balance problems; orthopedic conditions; delayed speech and language problems; growth and nutrition problems; sleep difficulties; chronic infections; sensory integration disorders; and dysautonomia, or a disturbance of the autonomic nervous system, which can lead to difficulty regulating body temperature, heart rate, and blood pressure, among other problems.

[0040] In various embodiments, provided herein are methods for 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:

[0041] or a pharmaceutically acceptable salt thereof.

[0042] In various embodiments, provided herein are methods for treating symptoms (e.g., seizures) associated with 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:

[0043] or a pharmaceutically acceptable salt thereof.

[0044] 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 medical condition associated with Dravet syndrome (DVS) in a subject, wherein the compound is of Formula I:

[0045] or a pharmaceutically acceptable salt thereof.

[0046] 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 a 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, 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).

[0047] In certain embodiments, administering a therapeutically effective amount of a compound of Formula I, or a pharmaceutically acceptable salt thereof, comprises administering to a subject in need thereof from about 0.5 mg to about 3.5 mg of a compound of Formula I, or a pharmaceutically acceptable salt thereof. In certain embodiments, administering a therapeutically effective amount of a compound of Formula I, or a pharmaceutically acceptable salt thereof, comprises administering to a subject in need thereof 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.

[0048] In some embodiments, the compound of Formula I is administered at about 0.3 mg / kg. In some embodiments, the compound of Formula I is administered at about 1.0 mg / kg.

[0049] In some embodiments, the subject has a body weight of at least 40 kg. In some embodiments, the subject has a body weight of less than 40 kg. For example, the administration of Compound I can follow two body weight categories (<40 kg and ≥40 kg). The initial dose of Compound I can be 0.5 mg or 1.0 mg once a day for patients with a body weight of <40 kg, and can be 1.5 mg once a day for patients with a body weight of ≥40 kg. The maximum dose of Compound I is 3.0 mg once a day for patients with <40 kg, and 3.5 mg once a day for patients with ≥40 kg. Thereafter, the dose of Compound I can be increased in 0.5 mg increments at weekly intervals in a blinded manner according to individual tolerance.

[0050] In certain embodiments, provided herein is a method of administering a free base form of a compound of Formula I to treat DVS in a subject in need thereof.

[0051] In certain embodiments, provided herein is a method of administering a pharmaceutically acceptable salt of a compound of Formula I to treat DVS in a subject in need thereof. In certain embodiments, as described above, treatment 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., a monosulfate or hemisulfate salt). In some embodiments, the pharmaceutically acceptable salt of the compound of Formula I can be a salt of the compound of Formula I with a physiologically compatible mineral acid such as hydrochloric acid, sulfuric acid (sulfuric / sulphuric acid), sulfurous acid, or 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, or salicylic acid.

[0052] In certain embodiments, treatment comprises once daily administration of a compound of Formula I, or a pharmaceutically acceptable salt thereof.

[0053] In certain embodiments, treatment comprises administering a compound of Formula I, or a pharmaceutically acceptable salt thereof, by oral administration.

[0054] In certain embodiments, treatment comprises administering a compound of Formula I or a pharmaceutically acceptable salt thereof in a unit dose.

[0055] In some embodiments, provided herein are methods for treating DVS, comprising administering to a subject in need thereof a composition comprising a therapeutically effective amount of a mGlu5 negative allosteric modulator (NAM) or a pharmaceutically acceptable salt thereof, wherein the mGlu5 NAM is a compound of Formula I:

[0056]

[0057] In certain embodiments, the method comprises administering a compound of Formula I as monotherapy.

[0058] 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 a seizure. In some cases, the subject is currently receiving a second therapy for Dravet syndrome or a seizure.

[0059] In embodiments, the methods described herein can achieve, after treatment, for a subject: a reduction in the frequency of seizures; a reduction in the severity of seizures; a change in the type of seizure (e.g., from a more severe type to a less severe type) compared to no treatment (e.g., before treatment) or compared to treatment with an alternative conventional treatment. In one aspect, administration of a compound of Formula I as described herein, or a pharmaceutically acceptable salt thereof, or a crystalline form thereof, reduces the frequency of convulsive seizures in a 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, or completely eliminates seizures over a period of 10, 20, 30, 50, 84, 100, or more days. Administration of a compound of Formula I as described herein, or a pharmaceutically acceptable salt thereof, or a crystalline form thereof, reduces the frequency of non-convulsive seizures 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, or completely eliminates seizures over a period of 10 days, 20 days, 30 days, 50 days, 84 days, 100 days or more. In some embodiments, the method further comprises repeating the administration until the subject is permanently seizure-free.

[0060] Thus, the compound of Formula I described herein, or a pharmaceutically acceptable salt thereof, or a crystalline form thereof, can alleviate seizure types after administration to a subject in need thereof. One, two, three, or more specific seizure types can be alleviated. In some embodiments, one seizure type is alleviated. In some embodiments, two seizure types are alleviated. In some embodiments, three seizure types are alleviated. In some embodiments, multiple seizure types are alleviated. In some embodiments of the method, the seizure type alleviated 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, there are typically multiple seizure types, including: convulsive seizures, which consist of generalized clonic seizures (GCS), generalized tonic-clonic seizures (formerly known as grand mal seizures), or alternating unilateral clonic seizures; myoclonic seizures; atypical absence and confusional (obtuse or impaired consciousness) states; focal seizures, with or without secondary generalization; or rarer tonic seizures. In some embodiments, the type of seizure alleviated is selected from the group consisting of photosensitivity seizures and self-induced seizures. In some embodiments, the type of seizure alleviated is selected from atonic or focal seizures without obvious observable motor signs.

[0061] Examples of seizures also include, but are not limited to, seizures of focal origin, generalized origin, and seizures of unknown origin.

[0062] In one embodiment, the seizure of focal origin is selected from focal perceptual seizures and focal perceptual disorder seizures. In one embodiment, the seizure of focal origin is selected from focal motor seizures and focal non-motor seizures. In an embodiment, the seizure of focal motor origin can be selected from the group consisting of: focal motor automatism seizures, focal motor atonic seizures, focal motor clonic seizures, focal motor epileptic convulsive seizures, focal motor hypermotor seizures, focal motor myoclonic seizures and focal motor tonic seizures, or a combination thereof. In an embodiment, the seizure of focal non-motor origin can be selected from the group consisting of: focal non-motor autonomic seizures, focal non-motor behavioral termination seizures, focal non-motor cognitive seizures, focal non-motor affective seizures and focal non-motor sensory seizures, or a combination thereof. In some embodiments, the seizure is a tonic-clonic seizure that progresses focally to both sides.

[0063] In one embodiment, the generalized origin seizure is selected from a generalized motor seizure and a generalized non-motor (absence) seizure. In an embodiment, the generalized origin motor seizure is selected from the group consisting of a generalized origin motor tonic-clonic seizure, a generalized origin motor clonic seizure, a generalized origin motor tonic seizure, a generalized origin motor myoclonic seizure, a generalized origin motor myoclonic-tonic-clonic seizure, a generalized origin motor myoclonic-atonic seizure, a generalized origin motor atonic seizure, and a generalized origin motor epileptic seizure. In an embodiment, the generalized origin non-motor (absence) typical seizure, the generalized origin non-motor (absence) atypical seizure, the generalized origin non-motor (absence) myoclonic seizure, and the generalized origin non-motor (absence) eyelid myoclonic seizure.

[0064] In one embodiment, the seizure of unknown origin is selected from motor seizures of unknown origin and non-motor seizures of unknown origin. In one embodiment, the motor seizure of unknown origin is selected from motor tonic-clonic seizures of unknown origin and motor epileptic seizures of unknown origin. In one embodiment, the non-motor seizure of unknown origin is a non-motor behavior-terminating seizure of unknown origin.

[0065] In some embodiments, the seizure is an unclassified episode.

[0066] In embodiments, administration of a compound of Formula I as described herein, or a pharmaceutically acceptable salt thereof, or a crystalline form thereof, reduces the frequency of status epilepticus in a 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, or completely eliminates seizures over a period of 10 days, 20 days, 30 days, 50 days, 84 days, 100 days or more.

[0067] In another aspect of the present disclosure, administration of a compound of Formula I described herein, or a pharmaceutically acceptable salt or crystalline form thereof, reduces hospitalizations due to attacks in a subject by about 25% or more, about 50% or more, about 75% or more, or completely eliminates hospitalizations.

[0068] In another aspect of the present disclosure, administration of a compound of Formula I described herein, or a pharmaceutically acceptable salt thereof, or a crystalline form thereof, reduces the 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.

[0069] It is known that the attacks experienced in DVS are extremely resistant to treatment. Effective treatments can be developed to reduce the number of attacks, which can help make the condition more manageable. Further, children with DVS typically develop intellectual disabilities over time. They may have problems expressing and understanding language. They may also have an increased risk of developing autism, attention deficit hyperactivity disorder (ADHD) and other behavioral problems. Children with Dravet syndrome typically require speech, occupational, and social and play therapies to support cognitive development. In certain embodiments, the therapeutic effect of the treatment of the present invention is determined by:

[0070] a) a 50% or greater reduction in overall seizure rate;

[0071] b) decreased frequency of convulsive seizures;

[0072] c) increased likelihood of seizure-free status;

[0073] d) longest seizure-free interval;

[0074] e) seizure-free days;

[0075] f) improvement as assessed by Clinical Global Impression–Improvement;

[0076] g) improvement as assessed by the Patient's Global Impression of Change (PGI-C);

[0077] h) improvement as assessed by the Quality of Life in Children with Epilepsy (QOLCE);

[0078] i) By using the Pediatric Quality of Life Inventory TM Improvement in overall quality of life (PedsQL) scores;

[0079] j) improvement as assessed by the overall score from the PedsQL Family Impact Module score;

[0080] k) improvement in parent / caregiver quality of life (QoL) as assessed using the EQ-5D-5L scale;

[0081] l) improvement as assessed by the Hospital Anxiety and Depression Scale (HADS); or

[0082] m) Improvements related to behavioral or cognitive symptoms.

[0083] Without further elaboration, it is believed that one skilled in the art can, based on the above description, utilize the present invention to its fullest extent. Therefore, the following specific examples should be construed as merely illustrative and not limiting in any way the remainder of the present disclosure. All publications cited herein are incorporated by reference in their entirety.

[0084] Pharmaceutical composition

[0085] In one aspect, a pharmaceutical composition comprising a compound of Formula I or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable excipient can be administered to treat DVS in a subject in need thereof. In various embodiments, the composition is a solid pharmaceutical composition.

[0086] The pharmaceutical compositions provided herein can be administered to a subject by a variety of 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 implanted sustained-release devices (e.g., mini-osmotic pumps). In certain embodiments, the pharmaceutical compositions disclosed herein are administered orally.

[0087] definition

[0088] To facilitate understanding of the present invention, a number of terms and phrases are defined below.

[0089] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by those of ordinary skill in the art to which the present invention belongs. Unless otherwise defined, all abbreviations used herein have their conventional meanings in the fields of chemistry and biology. The chemical structures and formulas described herein are constructed according to standard rules of chemical valence known in the chemical art.

[0090] Throughout this specification, where compositions are described as having, including, or comprising specific components, or where processes and methods are described as having, including, or comprising specific steps, it is contemplated that, in addition, compositions of the present invention also consist essentially of, or consist of, the recited components, and that processes and methods according to the present invention also consist essentially of, or consist of, the recited process steps.

[0091] In this application, when an element or component is referred to as being included in and / or selected from a list of listed elements or components, it should be 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.

[0092] Further, it should be understood that, without departing from the spirit and scope of the present invention, the elements and / or features of the compositions or methods described herein can be combined in various ways, whether explicitly or implicitly herein. For example, when referring to a particular compound, unless otherwise understood from the context, the compound can be used in various embodiments of the compositions of the present invention and / or the methods of the present invention. In other words, within this application, embodiments have been described and depicted in a manner that allows for clear and concise writing and drawing of the application, but it is contemplated and should be understood that the embodiments can be combined or separated in various ways without departing from this teaching and the present invention. For example, it should be understood that all features described and depicted herein can be applied to all aspects of the invention described and depicted herein.

[0093] Unless the context does not apply, the articles "a" and "an" are used in this disclosure to refer to one or to more than one (ie, to at least one) of the grammatical object of the article. For example, "an element" means one element or more than one element.

[0094] Unless stated otherwise, the term "and / or" is used in this disclosure to mean "and" or "or."

[0095] It should be understood that the expression "at least one of" includes each of the items following the expression individually and in various combinations of two or more of the items, unless otherwise apparent from the context and usage. Unless otherwise apparent from the context, the expression "and / or" relating to three or more items should be understood to have the same meaning.

[0096] Use of the terms "comprise," "comprises," "comprising," "include," "includes," "including," "have," "has," "having," "contain," "contains," or "containing," including grammatical equivalents thereof, should be understood to be generally open-ended and non-limiting, e.g., does not exclude additional, unrecited elements or steps unless specifically stated otherwise or understood from the context.

[0097] Where the term "about" is used before a quantitative value, unless specifically stated otherwise, the invention also includes the specific quantitative value itself. As used herein, the term "about" refers to a ±10% deviation from the nominal value, unless otherwise indicated or inferred from the context.

[0098] In various places of this specification, variables or parameters are disclosed in groups or ranges. It is specifically intended that this specification includes each individual subcombination of members of such groups and ranges. For example, integers within the range of 0 to 40 are specifically intended to disclose individually 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 integers within the range of 1 to 20 are specifically intended to disclose individually 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, and 20.

[0099] The use of any and all examples or exemplary language, such as "such as" or "including," herein is intended merely to better illustrate the invention and does not limit the scope of the invention unless required to be included. No language in the specification should be construed as indicating any non-claimed element is essential to the practice of the invention.

[0100] Generally, compositions specified in percentage are by weight unless otherwise indicated. Additionally, if a variable is not accompanied by a definition, the preceding definition of the variable will prevail.

[0101] As used herein, "composition" or "pharmaceutical composition" or "pharmaceutical formulation" refers to the combination of an active agent with an inert or active excipient or carrier, making the composition particularly suitable for in vivo or ex vivo diagnostic or therapeutic use.

[0102] "Pharmaceutically acceptable" refers to compounds, molecular entities, compositions, materials, and / or dosage forms that do not produce an adverse, allergic, or other untoward reaction when administered to animals or humans, as appropriate, and / or which are or may be approved by federal or state regulatory agencies, or equivalent agencies in countries outside the United States, or which are listed in the U.S. Pharmacopoeia or other generally recognized pharmacopeia for use in animals, and more particularly in humans.

[0103] 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 invention (eg, a compound of Formula I) that is compatible with pharmaceutical administration.

[0104] 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, p-toluenesulfonic 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 pharmaceutically acceptable in themselves, may be used to prepare salts useful as intermediates in obtaining the compounds described herein and their pharmaceutically acceptable acid addition salts.

[0105] Examples of bases include, but are not limited to, alkali metal (eg, sodium and potassium) hydroxides, alkaline earth metal (eg, magnesium and calcium) hydroxides, ammonia, and compounds of the formula NW4 + (W is C 1-4 alkyl) compounds, etc.

[0106] Examples of salts include, but are not limited to, acetate, adipate, alginate, aspartate, benzoate, benzenesulfonate, bisulfate, butyrate, citrate, camphorate, camphorsulfonate, cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate, fumarate, flucoheptanoate, glycerophosphate, hemisulfate, heptanoate, hexanoate, hydrochloride, hydrobromide, hydroiodide, 2-hydroxyethanesulfonate, lactate, maleate, methanesulfonate, monosulfate, 2-naphthalenesulfonate, nicotinate, oxalate, palmitate, pectinate, persulfate, phenylpropionate, picrate, pivalate, propionate, succinate, tartrate, thiocyanate, toluenesulfonate, undecanoate, and the like. Other examples of salts include salts of compounds of the present invention with anions such as Na + , K + , Ca 2+ NH4 + and NW4 + (W can be C 1-4 Complex compounds of suitable cations such as alkyl) and the like.

[0107] For therapeutic use, salts of the compounds of the invention are considered pharmaceutically acceptable. However, salts of acids and bases that are not pharmaceutically acceptable may also be useful, for example, in the preparation or purification of pharmaceutically acceptable compounds.

[0108] As used herein, a "pharmaceutically acceptable excipient" refers to a substance that facilitates the administration of an active agent to a subject and absorption by a subject, and can be included in the compositions of the present invention without causing significant adverse toxicological effects on the patient. Non-limiting examples of pharmaceutically acceptable excipients include water, NaCl, physiological saline solutions (such as phosphate buffered saline solutions), emulsions (e.g., such as oil / water or water / oil emulsions), lactated Ringer's solution, ordinary sucrose, ordinary glucose, binders, fillers, disintegrants, lubricants, coatings, sweeteners, spices, salt solutions (such as Ringer's solution), alcohols, oils, gelatin, carbohydrates (such as lactose, amylose or starch), fatty acid esters, hydroxymethylcellulose, polyvinylpyrrolidine, and pigments. Such preparations can be sterilized and, if necessary, can be mixed with adjuvants that do not react harmfully with the compounds of the present invention, such as lubricants, preservatives, stabilizers, wetting agents, emulsifiers, salts for affecting osmotic pressure, buffers, coloring substances, and / or aromatic substances. For examples of excipients, see Martin, Remington's Pharmaceutical Sciences, 15th ed., Mack Publ. Co., Easton, PA (1975).

[0109] "Subjects" to which administration is contemplated include, but are not limited to, humans (i.e., males or females 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 participant. In some embodiments, the subject is a patient.

[0110] As used herein, "solid dosage form" means a pharmaceutical dosage form in solid form, for example, tablets, capsules, granules, powders, sachets, reconstitutable powders, dry powder inhalers, and chewable tablets.

[0111] As used herein, "administering" means oral administration to a subject, 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, sublingual, nasal or transdermal) or subcutaneous administration or implantation of a sustained-release device (e.g., a mini-osmotic pump). Parenteral administration includes, for example, intravenous, intramuscular, intraarterial, intradermal, subcutaneous, intraperitoneal, intraventricular and intracranial administration. Other modes of delivery include, but are not limited to, the use of liposome formulations, intravenous infusion, transdermal patches, etc.

[0112] "Co-administration" means that the compositions described herein are administered simultaneously with, before, or after administration of one or more additional therapies (e.g., anticancer agents, chemotherapeutic agents, or treatments for neurodegenerative diseases). The compound of Formula I or a pharmaceutically acceptable salt thereof can be administered to the patient alone or in combination. Co-administration means the simultaneous or sequential administration of individual or combined compounds (more than one compound or agent). Thus, when desired, the formulation can also be combined with other active substances (e.g., to reduce metabolic degradation).

[0113] As used herein, and unless otherwise indicated, the terms "treat," "treating," and "treatment" include actions performed when a subject is suffering from a particular disease, disorder, or condition that lessen the severity of the disease, disorder, or condition, or that delay or slow the progression of the disease, disorder, or condition (e.g., "therapeutic treatment"). As used herein, "treatment" can include any effect, such as reduction, alleviation, modulation, alleviation, or abrogation, that results in an improvement in a condition, disease, disorder, or the like, including one or more symptoms thereof. Treatment can be curing, ameliorating, or at least partially alleviating a condition.

[0114] As used herein, the phrase "therapeutically effective amount" refers to the 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 of a tissue, system, animal, or human being sought by a researcher, veterinarian, physician, or other clinician. The compounds described herein, or pharmaceutically acceptable salts thereof, can be administered in a therapeutically effective amount to treat a disease. The therapeutically effective amount of a compound or a pharmaceutically acceptable salt thereof can be the amount required to achieve the desired therapeutic and / or preventive effect, such as an amount that produces a reduction in the symptoms of a disease (such as DVS).

[0115] Examples

[0116] In order that the present disclosure described herein 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.

[0117] Example 1: 2-chloro-4-[1-(4-fluorophenyl)-2,5-dimethyl-1H-imidazol-4-ylethynyl]pyridine (Formula I things, See above ; see U.S. Patent No. 7,332,510) for its synthesis.

[0118] 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 mL, 0.91 mmol) was added and stirred at -75 ° C for 15 min. Iodomethane (0.05 mL, 0.85 mmol) was added and stirring was continued at -75 ° C for 2 hr. The reaction mixture was quenched with saturated NaHCO 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, 90: 10 to 20: 80) and by recrystallization from ethyl acetate. The title compound was obtained as a white solid. MS: m / z = 326.5 (M + H +).

[0119] Example 2: Preparation of polymorphs of salts of the compound of formula I (see US Pat. No. 8,063,076).

[0120] 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. A mixture of 30 mL of water and 18.91 g of sulfuric acid (97%) was added dropwise to the combined solution. The solution was cooled to 0° C. to 5° C. Inoculated at 58° C. as needed. The solid residue was filtered, washed with 2-propanol (0° C. to 5° C.) and dried at 50° C. and less than 1 mbar for 18 hr to provide a monosulfate of the compound of formula I in a yield of 69.1 g (87.1%). Form A seeding crystals can be prepared after cooling and crystallizing a hot solution of 250 mg of the monosulfate in 10 mL of 2-propanol. After cooling to 0°C, the solid residue was filtered and dried under vacuum at 50°C to give Form A monosulfate salt, which was prepared by Figure 1 The XRPD pattern shown is substantially confirmed.

[0121] 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 produce 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. Seeded 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 v / v) at room temperature. The slurry was stirred at room temperature for approximately 3 weeks. The solid was filtered through a glass 35 filter to obtain crystalline Form B monosulfate, which was prepared by Figure 2 The XRPD pattern shown is substantially confirmed.

[0122] 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 had been converted to the hemisulfate, the resulting crystals were collected by filtration and rinsed with water. The wet cake thus obtained was dried in a vacuum oven at 40° C. for 48 hours to obtain Form C hemisulfate in 93% yield. Form C hemisulfate was prepared by Figure 3 The XRPD spectrum shown is substantially confirmed.

[0123] Amorphous monosulfate: 0.53 g of the monosulfate salt of the compound of formula I was dissolved in 10 mL of methanol at approximately 65° C. After complete evaporation of the solvent under vacuum, the solid (foam) was further dried at approximately 50° C. under 5 to 20 mbar for 18 hours. Analysis (XRPD and DSC) showed that the amorphous form of the compound of formula I was obtained. The amorphous monosulfate salt is characterized by an infrared spectrum with bands at: 2730, 2592, 2219, 1633, 1586, 1570, 1513, 1375, 1343, 1293, 1226, 1157, 1130, 1084, 1040, 986, 903, 848, 788, 712 and 670 cm -1 (±3cm -1 The glass transition temperature (T) of the amorphous form was determined by DSC. g ) depends largely on the solvent content and was observed to be around 42°C for the wet sample (closed pan) and around 77°C for the field dried sample (pan with perforated lid).

[0124] Example 3: Study of Compounds of Formula I for the Treatment of Patients with Dravet Syndrome (DVS)

[0125] A 2-phase, multicenter, 12-week, prospective, parallel-group, double-blind, randomized, placebo-controlled 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") at a maintenance dose as adjunct to ongoing seizure therapy in patients with Dravet syndrome (DVS) who have an inadequate response to their current anti-seizure medications.

[0126] A. Main outcome goals

[0127] To evaluate:

[0128] 1. Change from baseline to the combined titration and maintenance period (T+M) in mean convulsive seizure frequency (MCSF) in participants receiving Compound I 0.5 to 3.5 mg compared to placebo [Time frame: approximately 18 weeks from baseline [titration period (6 weeks) plus maintenance period (12 weeks)]]

[0129] 2. Change in mean convulsive seizure frequency for the Compound I 0.5 to 3.5 mg groups compared to the placebo group, comparing baseline to the combined titration and maintenance periods.

[0130] B. Secondary outcome goals

[0131] To evaluate:

[0132] 1. Change from baseline to the combined titration and maintenance period (T+M) in the mean frequency of convulsive seizures in participants receiving 0.5 to 3.5 mg of Compound I compared to placebo [Time frame: approximately 18 weeks from baseline [titration period (6 weeks) plus maintenance period (12 weeks)]] Convulsive seizures included hemiclonic seizures, focal seizures (with obvious observable motor signs), generalized tonic-clonic seizures, secondarily generalized tonic-clonic seizures, tonic seizures, clonic seizures, and drop seizures (tonic / atonic).

[0133] 2. The percentage of participants in each Compound I treatment group who achieved a reduction in convulsive seizure frequency greater than or equal to 25% (≥25%) from baseline during the titration and maintenance periods compared to placebo [Time frame: approximately 18 weeks from baseline [titration period (6 weeks) plus maintenance period (12 weeks)]]. Convulsive seizures included hemiclonic seizures, focal seizures (with obvious observable motor signs), generalized tonic-clonic seizures, secondarily generalized tonic-clonic seizures, tonic seizures, clonic seizures, and drop seizures (tonic / atonic).

[0134] 3. The percentage of participants in each Compound I treatment group who achieved a ≥50% reduction from baseline in convulsive seizure frequency during the titration and maintenance periods compared to placebo [Time frame: approximately 18 weeks from baseline [titration period (6 weeks) plus maintenance period (12 weeks)]]. Convulsive seizures included hemiclonic seizures, focal seizures (with obvious observable motor signs), generalized tonic-clonic seizures, secondarily generalized tonic-clonic seizures, tonic seizures, clonic seizures, and drop seizures (tonic / atonic).

[0135] 4. The percentage of participants in each Compound I treatment group who achieved a ≥75% reduction from baseline in convulsive seizure frequency during the titration and maintenance periods compared to placebo [Time frame: approximately 18 weeks from baseline [titration period (6 weeks) plus maintenance period (12 weeks)]]. Convulsive seizures included hemiclonic seizures, focal seizures (with obvious observable motor signs), generalized tonic-clonic seizures, secondarily generalized tonic-clonic seizures, tonic seizures, clonic seizures, and drop seizures (tonic / atonic).

[0136] 5. The percentage of participants in each Compound I treatment group who achieved a 100% reduction from baseline in convulsive seizure frequency during the titration and maintenance periods compared to placebo [Time frame: approximately 18 weeks from baseline [titration period (6 weeks) plus maintenance period (12 weeks)]]. Convulsive seizures included hemiclonic seizures, focal seizures (with obvious observable motor signs), generalized tonic-clonic seizures, secondarily generalized tonic-clonic seizures, tonic seizures, clonic seizures, and drop seizures (tonic / atonic).

[0137] 6. Longest seizure-free interval during the titration and maintenance period for each Compound I treatment group compared to placebo [Time frame: approximately 18 weeks from baseline [titration period (6 weeks) plus maintenance period (12 weeks)]] The longest interval between convulsive seizures was calculated over the entire titration and maintenance period and derived as the maximum number of days between consecutive convulsive seizures.

[0138] 7. Number of seizure-free days during the titration and maintenance periods for each Compound I treatment group compared to placebo [Time frame: approximately 18 weeks from baseline [titration period (6 weeks) plus maintenance period (12 weeks)]]. A seizure-free day was defined as a day in which no seizure was reported.

[0139] 8. Change in the frequency of non-convulsive seizures from baseline to the combined titration and maintenance period for each Compound I treatment group compared to placebo [Time frame: approximately 18 weeks from baseline [titration period (6 weeks) plus maintenance period (12 weeks)]]. Non-convulsive seizures include focal seizures (without obvious observable motor signs), absence or atypical absence seizures, myoclonic seizures, and atonic seizures.

[0140] 9. Change in the frequency of convulsive + nonconvulsive seizures from baseline to the combined titration and maintenance period for each Compound I treatment group compared to placebo [Time frame: approximately 18 weeks from baseline [titration period (6 weeks) plus maintenance period (12 weeks)]] The total seizure frequency is defined as the combination of convulsive and nonconvulsive seizures. Convulsive seizures include hemiclonic seizures, focal seizures (with obvious observable motor signs), generalized tonic-clonic seizures, secondarily generalized tonic-clonic seizures, tonic seizures, clonic seizures, and drop seizures (tonic / atonic). Nonconvulsive seizures include focal seizures (without obvious observable motor signs), absence or atypical absence seizures, myoclonic seizures, and atonic seizures.

[0141] 10. Percentage of participants in each Compound I treatment group who used rescue medication during the titration and maintenance periods compared to placebo [Time frame: approximately 18 weeks from baseline [titration period (6 weeks) plus maintenance period (12 weeks)]]. Rescue medication was administered according to each participant's usual or prescribed regimen, which consisted of one or more medications.

[0142] 11. Percentage of participants in each Compound I treatment group who were hospitalized and utilized health care resources to treat an episode during the study period compared to placebo [Time Frame: Approximately 18 weeks from baseline [Titration Period (6 weeks) plus Maintenance Period (12 weeks)]] Exemplary participants utilized medical center care for treatment of an episode during the study period.

[0143] 12. Percentage of participants in each Compound I treatment group with status epilepticus (SE) during the titration and maintenance periods compared to placebo [Time frame: approximately 18 weeks from baseline [titration period (6 weeks) plus maintenance period (12 weeks)]] For each treatment group, exemplary participants experienced SE that occurred or lasted longer than 10 minutes and was recorded as an adverse event (AE) during the treatment period.

[0144] 13. Distribution of duration of convulsive seizures at baseline and during the titration and maintenance periods (in percentages) for each Compound I treatment group compared to placebo [Time frame: approximately 18 weeks from baseline [titration period (6 weeks) plus maintenance period (12 weeks)]]

[0145] 14. The percentage of participants in each Compound I treatment group who had a Clinical Global Impression-Improvement (CGI-I) evaluation score as assessed by the principal investigator compared to placebo. The CGI-I scale measures the improvement of the participant's clinical status from baseline. The severity of the participant's condition can be evaluated on a 7-point scale ranging from 1 (very improved) to 7 (very worsened), as follows: 1 - very improved, 2 - very much improved, 3 - slightly improved, 4 - no change, 5 - slightly worsened, 6 - very worsened, and 7 - very worsened. The principal investigator can evaluate the overall impression of the participant's condition during the study.

[0146] 15. The percentage of participants in each Compound I treatment group who had a Clinical Global Impression-Improvement Assessment score as assessed by parents / caregivers compared to placebo. The CGI-I scale measures the improvement of the participant's clinical status from baseline. The severity of the participant's condition can be assessed on a 7-point scale ranging from 1 (very improved) to 7 (very worsened), as follows: 1 - very improved, 2 - very much improved, 3 - slightly improved, 4 - no change, 5 - slightly worsened, 6 - very worsened, and 7 - very worsened. Parents / caregivers can assess the overall impression of the participant's condition during the study.

[0147] 16. Compared to placebo, the change from baseline in the Quality of Life in Children with Epilepsy (QOLCE) score for each Compound I treatment group to measure the quality of life. QOLCE is a low-burden assessment completed by parents / caregivers that assesses how epilepsy affects the participants' daily abilities in various areas of life (including physical activity, well-being, cognition, social activities, behavior, and overall health). QOLCE scores the items on 16 subscales, with a possible 5-point answer for each subscale, where a score of 5 is the best possible answer and a score of 1 is the worst possible answer. The item scores are then transformed into a 0 to 100 scale as follows: 1 to 0, 2 to 25, 3 to 50, 4 to 75, 5 to 100. The score for each participant for each subscale can be calculated by finding the average of the participant's answers to each item in the subscale. The subscale scores for each participant can be averaged to obtain an overall QoL score for each participant. The higher the subscale and overall QoL scores, the better the answer.

[0148] 17. Pediatric Quality of Life Inventory scores for each Compound I treatment group compared to placebo TMThe change from baseline in the overall quality of life score of the Pediatric Quality of Life Inventory (PedsQL) score. The Pediatric Quality of Life Inventory (PedsQL) is a modular measure of health-related quality of life (QoL) in children that is completed by parents / caregivers on behalf of the participant. It consists of 23 items across 4 core scales that measure: physical ability (8 items); emotional, social, and school abilities (5 items each). Each of the answers to the 23 items was initially scored on a 5-point Likert scale from 0 (never) to 4 (almost always). The score was linearly transformed into a scale of 0 to 100, where 0 = 100, 1 = 75, 2 = 50, 3 = 25, and 4 = 0, and a higher score corresponds to a better health-related QoL. The overall quality of life is the mean of all items on all scales divided by the number of items answered.

[0149] 18. Change from baseline in the total score of the PedsQL Family Impact module score for each Compound I treatment group compared to placebo. The PedsQL Family Impact measures the impact of pediatric chronic health conditions on parents and families by measuring parents' self-reported physical, emotional, social, and cognitive abilities, communication, worries, and daily activities and relationships at home. There are a total of 36 items in the PedsQL: 6 items for physical abilities, 5 items each for emotional abilities, cognitive abilities, and worries, 4 items for social abilities, 3 items for communication, 3 questions for daily activities, and 5 items for family relationships. Each of the answers was initially scored on a 5-point Likert scale from 0 (never) to 4 (almost always), and then linearly transformed into a scale of 0 to 100, where 0 = 100, 1 = 75, 2 = 50, 3 = 25, and 4 = 0, and higher scores mean better health-related QoL.

[0150] 19. Parent / caregiver quality of life (QoL) at baseline and during the day in each Compound I treatment group using the EQ-5D-5L scale compared to placebo. The EuroQOL-5 Dimensions-5 Levels scale, developed using the European QOL Group (EQ-5D-5L) health questionnaire, is a health-related QoL instrument with five dimensions: mobility, self-care, daily activities, pain / discomfort, and anxiety / depression. The five dimensions of the EQ-5D-5L health questionnaire are assessed using a Likert scale with five possible levels: no difficulty, some difficulty, moderate difficulty, severe difficulty, and extreme difficulty. The categories of "some difficulty," "moderate difficulty," "severe difficulty," and "extreme difficulty" were collapsed into a single response category, "difficulty." Parent / caregiver QoL was assessed, and the percentage of participants who responded correctly to each item was reported.

[0151] 20. Change from baseline in mood symptoms of parents / caregivers using the Hospital Anxiety and Depression Scale (HADS) in each Compound I treatment group compared to placebo. The HADS is a validated instrument for assessing the presence of anxiety or depression in an outpatient non-psychiatric population. The HADS is a 14-item scale that generates ordinal data for two dimensions: 1) anxiety (7 items) and 2) depression (7 items). Each item has 4 possible responses, with an evaluation score of 0 to 3, where 0 = no pain and 3 = the worst pain. All responses to the items for each dimension and their corresponding evaluations are summed to give a range of 0 to 21 for each dimension, where: 0 to 7 = normal; 8 to 10 = borderline abnormal; 11 to 21 = abnormal. Scores for the entire scale (emotional pain) range from 0 to 42, with higher scores indicating greater pain.

[0152] 21. The proportion of subjects in each Compound I treatment group who were considered treatment responders (defined as subjects with a ≥40% and ≥50% reduction in convulsive seizures from baseline) compared to placebo.

[0153] 22. Comparison of the longest seizure-free interval for subjects in each Compound I treatment group versus placebo. Comparisons of the longest seizure-free interval and the longest interval without any seizures for each subject during the 18-week titration + maintenance period were calculated independently for the Compound I 0.5 to 3.5 mg treatment groups versus placebo.

[0154] C. Additional secondary outcome measures [Time frame: comparison of baseline to titration + maintenance period or T + M (as appropriate)]

[0155] To evaluate:

[0156] i. Number of days without convulsive seizures.

[0157] ii. The proportion of subjects who achieved a ≥75% reduction in convulsive seizure frequency from baseline.

[0158] iii. Change from baseline in nonconvulsive seizure frequency and total seizure frequency.

[0159] iv. Prevalence of rescue medication use and medical utilization.

[0160] v. Incidence of status epilepticus.

[0161] vi. Clinical Global Impression-Improvement Assessment as rated by parents / caregivers.

[0162] vii. Change from baseline in quality of life.

[0163] viii. Change from baseline in parents' / caregivers' emotional symptoms D. Safety and tolerability

[0164] The safety and tolerability of Compound I 0.5 to 3.5 mg / day were compared with placebo. The safety and tolerability of Compound I 0.5 to 3.5 mg / day were compared with placebo in terms of adverse events (AEs), laboratory parameters, physical examination, neurological examination, vital signs (blood pressure, heart rate, temperature and respiratory rate), electrocardiogram (ECG), echocardiogram (ECHO), body weight and cognitive function.

[0165] E. Research Design

[0166] This was a multicenter, randomized, double-blind, parallel, placebo-controlled study of patients who presented with at least one type of generalized (convulsive) seizure, including drop seizures (atonic, tonic, tonic-clonic, or myoclonic), lasting for at least six months despite optimal antiseizure medication.

[0167] Patients who have been treated with therapeutic doses of anti-seizure medication for at least 6 months, have signed informed consent or have their legally authorized representative sign informed consent, meet the study eligibility criteria, and agree to participate in the study or have their legally authorized representative agree to the patient's participation in the study will enter a screening and stabilization period of up to 8 weeks.

[0168] Eligible patients will be maintained on their anti-seizure medication (same dose) and will be randomized via an interactive voice / web response system to receive one of two treatments in addition to the patient's previous anti-seizure medication.

[0169] Treatment A: Compound I 0.5 to 3.5 mg, orally every 24 hours (QD refers to once daily)

[0170] Treatment B: Placebo, taken orally every 24 hours

[0171] At the end of the stabilization period, patients who continue to meet all entry criteria will be randomized to receive double-blind treatment.

[0172] F. Research Phase

[0173] The total double-blind study duration was approximately 18 weeks

[0174] Screening and stabilization phase: up to 8 weeks

[0175] Treatment phase: includes a titration phase of up to 6 weeks, followed by a 12-week maintenance phase. G. Target group

[0176] Patients must meet the following study entry criteria:

[0177] 1. Able and willing to provide written informed consent and comply with study procedures, or have a legally authorized representative who is able and willing to provide written informed consent and comply with study procedures for patients (ranging from infants to adults). Documented history of DVS. This includes DNA-confirmed evidence of at least one type of generalized seizure, including convulsive seizures (atonic, tonic, tonic-clonic, or myoclonic) lasting at least six months.

[0178] 2. The subject should be refractory; that is, have documented failure with more than one anti-seizure medication (ASM).

[0179] 3. Subjects must be taking one or more ASMs at a dose that has been stable for at least four weeks prior to screening.

[0180] 4. All medications or interventions for seizures (including ketogenic diet and neurostimulator devices) must be stable for four weeks prior to screening, and the patient must be willing to maintain the stable regimen throughout the study. Ketogenic diet and neurostimulator devices are not counted as ASM.

[0181] Patients meeting any of the following criteria will be excluded from study participation:

[0182] 1. The subject's seizure was caused by a progressive neurological disease.

[0183] 2. The subject has experienced hypoxia requiring resuscitation within six months prior to screening.

[0184] 3. The subject suffers from a clinically significant unstable medical condition other than epilepsy.

[0185] 4. The subject has suffered from clinically relevant symptoms or clinically significant diseases other than epilepsy within four weeks before screening or random assignment.

[0186] 5. The subject has participated in a clinical trial involving another IMP within the past six months.

[0187] 6. Active suicidal behavior or any of the four or five types of suicidal ideation on the Columbia Suicide Severity Rating Scale in the past month or at screening.

[0188] 7. Subjects are currently taking long-term systemic steroids (excluding inhaled medications for asthma treatment) or any other daily medication known to exacerbate epilepsy. Preventive medications, such as those for idiopathic nephrotic syndrome or asthma, will be excluded.

[0189] 8. Subjects are currently taking felbamate, and they have been taking felbamate for less than one year prior to screening.

[0190] 9. Concomitant use of fenfluramine. Participants who have previously used fenfluramine within the past 3 months or do not have appropriate documentation of an echocardiogram within at least 3 months after the last dose of fenfluramine to ensure that the participant does not meet any criteria for drug-related (fenfluramine) valvular heart disease and / or drug-related pulmonary arterial hypertension (PAH)

[0191] 10. Pregnancy or lactation

[0192] H. Primary outcome measure (efficacy)

[0193] The main outcome measures were:

[0194] 1. Change from baseline to the combined titration and maintenance period (T+M) in mean convulsive seizure frequency (MCSF) in participants receiving Compound I 0.5 to 3.5 mg compared to placebo [Time frame: approximately 18 weeks from baseline [titration period (6 weeks) plus maintenance period (12 weeks)]]

[0195] 2. Change in mean convulsive seizure frequency for the Compound I 0.5 to 3.5 mg groups compared to the placebo group, comparing baseline to the combined titration and maintenance periods.

[0196] I. Secondary Outcome Measures (Efficacy)

[0197] Secondary outcome measures were:

[0198] 1. Change from baseline to the combined titration and maintenance period (T+M) in mean convulsive seizure frequency in participants receiving Compound I 0.5 to 3.5 mg compared to placebo.

[0199] 2. The percentage of participants in each Compound I treatment group who achieved a reduction in convulsive seizure frequency greater than or equal to 25% (≧25%) from baseline during the titration and maintenance periods compared to placebo.

[0200] 3. The percentage of participants in each Compound I treatment group who achieved a ≥50% reduction from baseline in convulsive seizure frequency during the titration and maintenance periods compared to placebo.

[0201] 4. The percentage of participants in each Compound I treatment group who achieved a ≥75% reduction from baseline in convulsive seizure frequency during the titration and maintenance periods compared to placebo.

[0202] 5. The percentage of participants in each Compound I treatment group who achieved a 100% reduction from baseline in convulsive seizure frequency during the titration and maintenance periods compared to placebo.

[0203] 6. The longest seizure-free interval during the titration and maintenance periods for each Compound I treatment group compared to placebo.

[0204] 7. Number of seizure-free days during the titration and maintenance periods for each Compound I treatment group compared to placebo.

[0205] 8. Change from baseline in non-convulsive seizure frequency during the combined titration and maintenance periods for each Compound I treatment group compared to placebo.

[0206] 9. Change from baseline to the combined titration and maintenance period in convulsive + nonconvulsive seizure frequency for each Compound I treatment group compared to placebo.

[0207] 10. Percentage of participants in each Compound I treatment group using rescue medication during the titration and maintenance periods compared to placebo.

[0208] 11. The percentage of participants in each Compound I treatment group who were hospitalized and utilized health care resources to treat an episode during the period compared to placebo.

[0209] 12. The percentage of participants in each Compound I treatment group with status epilepticus (SE) during the titration and maintenance periods compared to placebo.

[0210] 13. Distribution of duration of convulsive seizures at baseline and during the titration and maintenance periods for each Compound I treatment group compared to placebo (in percentage units).

[0211] 14. Percentage of participants in each Compound I treatment group with a Clinical Global Impression - Improved (CGI-I) assessment score as rated by the principal investigator compared to placebo.

[0212] 15. Percentage of participants in each Compound I treatment group with a Clinical Global Impression - Improvement score as rated by parents / caregivers compared to placebo. The CGI-I scale measures improvement from baseline in a participant's clinical status.

[0213] 16. Change from baseline to Day 99 in the Quality of Life in Children with Epilepsy (QOLCE) score, a measure of quality of life, for each Compound I treatment group compared to placebo.

[0214] 17. Pediatric Quality of Life Inventory scores for each Compound I treatment group compared to placebo TMChange from baseline to day 99 in the overall quality of life score (PedsQL) score.

[0215] 18. Change from baseline to Day 99 in the total score from the PedsQL Family Impact Module score for each Compound I treatment group compared to placebo.

[0216] 19. Parent / caregiver quality of life (QoL) using the EQ-5D-5L scale at baseline and during the day in each Compound I treatment group compared to placebo.

[0217] 20. Change from baseline to Day 99 in parent / caregiver mood symptoms using the Hospital Anxiety and Depression Scale (HADS) in each Compound I treatment group compared to placebo.

[0218] 21. The proportion of subjects in each Compound I treatment group who were considered treatment responders (defined as subjects with a ≥40% and ≥50% reduction in convulsive seizures from baseline) compared to placebo.

[0219] 22. Comparison of the longest seizure-free interval for subjects in each Compound I treatment group versus placebo.

[0220] J. Additional secondary outcome measures [Time frame: comparison of baseline to titration + maintenance period or T + M (as appropriate)]

[0221] Additional secondary outcome measures were:

[0222] ix. Number of days without convulsive seizures.

[0223] x. Proportion of subjects achieving a ≥75% reduction in convulsive seizure frequency from baseline.

[0224] xi. Change from baseline in nonconvulsive seizure frequency and total seizure frequency.

[0225] xii. Prevalence of rescue medication use and medical utilization.

[0226] xiii. Incidence of status epilepticus.

[0227] xiv. Clinical Global Impression - Improvement Assessment as rated by parents / caregivers.

[0228] xv. Change from baseline in quality of life.

[0229] xvi. Change from baseline in parents' / caregivers' emotional symptoms

[0230] Example 4: Seizure-free study of Compound I

[0231] Dravet syndrome is a severe developmental and epileptic encephalopathy (DEE) that is most commonly caused by de novo pathogenic variants in SCN1A (voltage-gated sodium channel alpha subunit 1). In most Dravet cases, there is a loss of SCN1A function (particularly in interneurons), resulting in a reduced ability to modify electrical activity and, therefore, electrical hyperexcitability and seizure propensity. 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. In addition, Scn1a+ / - mice exhibit similar clinical responses to standard anti-seizure drugs, including seizure exacerbation associated with lamotrigine and seizure suppression associated with drugs such as clobazam and fenfluramine. Therefore, Scn1a+ / - mice are a promising model for translating novel ASMs with different mechanisms of action into the clinic.

[0232] As used herein, "Compound I" refers to a compound of Formula I.

[0233] As used herein, "CTEP" refers to a compound having the formula C 19 H 13 ClF3N3O and structure The compound is referred to as a selective mGluR5 allosteric antagonist or negative allosteric modulator.

[0234] As used herein, "RO6807794" refers to a compound having the formula C 18 H 18 FN3O and structure This compound is called a positive allosteric modulator.

[0235] As used herein, "NAM" refers to a negative allosteric modulator, and "PAM" refers to a positive allosteric modulator.

[0236] A. Purpose

[0237] This experiment was performed to evaluate the effects of Compound I, CTEP, and RO6807794 on seizure frequency, seizure freedom, and survival in Scn1a+ / - mice.

[0238] B. Methods

[0239] Five treatment groups were studied to evaluate the effects of both positive and negative allosteric modulators of mGluR5 on seizure frequency, seizure freedom, and survival in Scn1a+ / - mice:

[0240] (1) Compound I 0.3 mg / kg PO, administered once daily for 28 days, starting from postnatal day 10 (P10).

[0241] (2) 1 mg / kg PO of Compound I, administered once daily for 28 days, starting from P10.

[0242] (3) CTEP 0.3 mg / kg PO, administered every other day for 28 days, starting from P01.

[0243] (4) RO6807794 0.3 mg / kg IP, once daily for 5 days, starting from P21.

[0244] (5) Untreated group, which did not receive dose administration.

[0245] Frontal cortex recordings were selected as representative of seizure phenomena in mice experiencing generalized seizures. An EEG headset was implanted between P20 and P22, and continuous monitoring recordings were initiated for both the NAM and PAM groups over a period of approximately 14 days. Individual frontal cortical seizure measurements over time were visually explored, and summaries across time courses were calculated.

[0246] 1. Frequency of attacks

[0247] Seizure frequency was measured by counting the number of seizures observed daily. This frequency was analyzed using the chi-square test (all treatments) and Fisher's exact test (pairwise treatment comparisons).

[0248] 2. No seizures

[0249] Seizure freedom was measured using a binary (0 or 1) endpoint, where seizure freedom was recorded as 0 if no seizures were observed on all study days, or as 1 if at least 1 seizure was recorded across the entire study. Seizure freedom was summarized in a contingency table across all animals and analyzed using a generalized linear model (GLM) with a binomial distribution for error and a logit link function. Results are presented as probabilities and odds ratios between groups with 95% confidence intervals. The odds ratio describes how likely it is that an animal in the treated group will be seizure-free (seizure freedom = 1) compared to the untreated group. Analyses were performed using GraphPad Prism 9 (contingency table) and SAS 9.4 (binomial model).

[0250] 3. Time to first attack:

[0251] The time to first seizure is the time recorded as follows: the day on which the first seizure occurred (observed, uncensored observation); or the last day on which the animal was recorded if no seizure was observed (censored observation). The time to first seizure was visualized using a Kaplan-Meier plot and analyzed using the log-rank (Mantel-Cox) test. GraphPad Prism 9 was used for analysis.

[0252] 4. Total seizure burden

[0253] The total seizure burden was the sum of seizure frequencies across all study days.

[0254] 5. Daily attacks

[0255] Daily seizures were measured by dividing the total seizure count by the number of study days, where the seizure count measurement was adjusted for the number of days the animal was on study.

[0256] The time to first onset and daily onset were visually explored and analyzed using analysis of variance (ANOVA). The results are presented as geometric means, ratios of geometric means, confidence intervals, and p-values. Additional nonparametric analyses Kruskal-Wallis and Wilcoxon paired comparisons with untreated groups were explored. Generalized linear models (GLMs) with Poisson distribution for error and logarithmic link function were also used to analyze the data. A linear predictor describes a model suitable for exploring the fixed effects of the treatment group.

[0257] C. Results

[0258] 1. No seizures

[0259] Seizure freedom was measured and analyzed for the Compound I 1 mg / kg group, the Compound I 0.3 mg / kg group, the CTEP group, and the untreated group. Figure 4 The frequency and percentage of animals exhibiting seizure freedom across the four treatment groups are provided in Tables 4 and 5. The RO6807794 group was not included in the seizure freedom analysis because this group was dosed for only 5 days. Figure 4 As shown in Table 4, the percentage of animals exhibiting seizure freedom was greater in the Compound 1 mg / kg group compared to the untreated group. Compound I administration was associated with an increased probability of seizure freedom, with Compound I 1 mg / kg demonstrating a 77% seizure-free rate compared to 25% in the untreated group ( Figure 4 ).

[0260] Table 1. Frequency and percentage of animals exhibiting seizure freedom

[0261] Treatment group At least 1 episode No seizures Untreated 12(75％) 4(25％) Compound I 0.3 mg / kg 10(90.9％) 1(9.1％) Compound I 1 mg / kg 3(23.1％) 10(76.9％) CTEP 4(26.7％) 11(73.3％) total 29(52.7％) 26(47.3％)

[0262] As part of the contingency table analysis, a chi-square test was performed on Table 4. The test returned a statistically significant p-value (p = 0.0004), indicating that the proportion of animals that were seizure-free depended on the treatment group. The dependence on treatment group was further demonstrated in the GLM analysis, where the results were quantified in Table 5 by the probability of seizure-free, odds ratio (relative to untreated), and 95% confidence interval. As shown in Table 5, the Compound I 1 mg / kg group was associated with an increased probability of seizure-free, and animals in the Compound I 1 mg / kg group were more likely to be seizure-free (seizure-free = 1) than in the untreated group.

[0263] Table 2. Dependence of seizure freedom on treatment group

[0264]

[0265] 2. Time to first attack

[0266] For the Compound I 1 mg / kg group, the Compound I 0.3 mg / kg group, the CTEP group, the RO6807794 group, and the untreated group, a time-to-event type analysis (commonly referred to as a survival analysis) was performed using the date on which each animal exhibited its first seizure. Each animal was defined as seizure-free prior to the date on which it exhibited its first seizure. If an animal was removed from the study early, or maintained seizure-free until Day 15, the animal was classified as a censored observation, where the time to first seizure was not observed during the study period. It was understood that this time was greater than the last study day.

[0267] Figure 5 Kaplan-Meier plots are presented showing how the percentage of animals free of seizures changed over time for all treatment groups. Figure 5 In the graph, all groups begin with 100% of animals exhibiting no seizures, and the line is stepped down (decreasing percentage) each time an animal in that group exhibits at least 1 seizure that day. Figure 5 The Compound I 1 mg / kg group and the CTEP group showed more animals that were seizure-free for a longer duration, as quantified by the median time to first seizure. The median time to first seizure (or the time it took for 50% of the animals to experience at least one seizure) was 2 days for the Compound I 0.3 mg / kg group, 3 days for the RO6807794 group, and 7 days for the untreated group. By the end of 15 days, Compound I 1 mg / kg maintained seizure freedom in more than 50% of the animals.

[0268] Compound 1 1 mg / kg demonstrated an increase in the time spent before at least one observed seizure, with 50% of the untreated group experiencing at least one seizure by day 7 and 77% of the Compound 1 1 mg / kg group remaining seizure-free by day 15.

[0269] 3. Total seizure burden

[0270] The sum of seizure frequencies across all study days was measured and analyzed for the Compound 1 1 mg / kg group, the Compound 1 0.3 mg / kg group, the CTEP group, and the untreated group. Figure 6 Graphs showing individual total seizure burden data in relation to the main treatment group. Figure 7 shows the use of a logarithmic scale on the y-axis Figure 6 To generate the adjusted data Figure 7 In the graph, a small constant (10% of the smallest non-zero value, i.e. 0.1) is added to each reaction to Figure 6 Data visualization in the log 10 The RO6807794 group was not included in the total seizure burden analysis because this group was dosed for only 5 days.

[0271] In the log 10 Exploratory ANOVA on transformed scale: Exploratory ANOVA was performed on the log-transformed data. The results are presented in Figure 8 and Figure 9 middle. Figure 8 Contains geometric means and 95% confidence intervals for the four treatment groups. Figure 9 Comparisons with the untreated group are presented as ratios of geometric means and 95% confidence intervals. Comparisons where the confidence intervals do not cross the reference line (Y=1) are considered statistically significant at the 5% significance level (p<0.05). The ratios in Table 6 are presented as percentage change. Both the CTEP-treated group and the Compound I 1 mg / kg-treated group exhibited a statistically significantly lower total seizure burden compared to the untreated group (reduced by 82% and 84%, respectively, and p<0.05 for both). The Compound I 1 mg / kg-treated group exhibited a statistically lower total seizure burden compared to both the CTEP group and the untreated group.

[0272] Table 3. Geometric Means and 95% Confidence Intervals for Total Seizure Burden and Ratios of Means and 95% Confidence Intervals for Total Seizure Burden Compared to the Untreated Group

[0273]

[0274] Nonparametric analysis Kruskal-Wallis analysis and Wilcoxon paired tests were performed to explore the total seizure burden without assuming a specific underlying distribution. As with the exploratory ANOVA, these methods also indicated that the Compound 1 1 mg / kg group and the CTEP group exhibited a lower total seizure burden compared to the untreated group (p < 0.05 for both).

[0275] GLM suitable for discrete data: The GLM analysis performed was appropriate for discrete (count) data and is presented in Table 7 using geometric means and 95% confidence intervals for the four treatment groups and comparisons with the untreated group, expressed as ratios of geometric means and 95% confidence intervals. Both the CTEP-treated group and the Compound I 1 mg / kg-treated group exhibited statistically significantly lower total seizure burden compared to the untreated group (reductions of 62% and 44%, respectively, and p < 0.01 for both).

[0276] Table 4. Generalized Linear Model Analysis of Discrete (Count) Data for Total Seizure Burden

[0277]

[0278] 4. Daily attacks

[0279] Total seizure burden measures were adjusted for the number of days each animal was present on the study by simple division. Figure 10 Individual daily seizure data are presented for all treatment groups in To enable visualization of the data on a log10 transformed scale, a small constant (10% of the smallest non-zero value, ie 0.0067) was added to each response. Figure 11 Adjusted data using a logarithmic scale on the y-axis are shown.

[0280] In the log 10 Exploratory ANOVA on transformed scale: ANOVA was performed on the log-transformed adjusted data. The results are shown in Figure 12 、 Figure 13 and Table 8. Figure 12 The graph contains the geometric means and 95% confidence intervals for the four treatment groups, and Figure 13 Comparisons with the untreated group are presented as ratios of geometric means and 95% confidence intervals. Comparisons for which the confidence intervals do not cross the reference line (Y=1) are considered statistically significant at the 5% significance level (p<0.05). Ratios in Table 8 are presented as percentage change. Both the CTEP-treated group and the Compound I 1 mg / kg-treated group exhibited statistically significantly lower mean daily seizures (85% and 79% reduction, respectively, and for log-negative seizures) compared to the untreated group. 10 Two-way ANOVA on adjusted scale, p<0.05). The Compound 1 1 mg / kg treated group exhibited statistically lower mean daily seizures compared to the untreated group.

[0281] Table 5. Ratios of geometric means and 95% confidence intervals for daily attacks and ratios of means and 95% confidence intervals for daily attacks compared to the untreated group

[0282]

[0283] Nonparametric analysis Kruskal-Wallis analysis and Wilcoxon paired tests were performed to explore the daily seizure data without assuming a specific underlying distribution. Like ANOVA, these methods also indicated that the Compound 1 1 mg / kg group and the CTEP group exhibited reduced daily seizure rates compared to the untreated group (p < 0.05 for both), while the RO6807794 (PAM) group exhibited increased daily seizure rates compared to the untreated group (p < 0.05).

[0284] GLM suitable for discrete data: The GLM analysis performed was appropriate for discrete (count) data and is presented in Table 9 using the geometric means and 95% confidence intervals for the five treatment groups and comparisons with the untreated group, expressed as the ratio of the geometric means and 95% confidence intervals. No group exhibited a statistically significantly lower daily seizure rate compared to the untreated group, but the RO6807794 treatment group exhibited a statistically significantly increased daily seizure rate compared to the untreated group (p < 0.001).

[0285] Table 6. Generalized Linear Model Analysis for Discrete (Count) Data on Daily Seizures

[0286]

[0287] Other embodiments

[0288] All of the features disclosed in this specification may be combined in any combination. Each feature disclosed in this specification may be replaced by an alternative feature serving the same, equivalent, or similar purpose. Therefore, unless expressly stated otherwise, each feature disclosed is merely an example of a general series of equivalent or similar features.

[0289] Further, from the above description, those skilled in the art can easily ascertain the essential characteristics of the present invention, and without departing from the spirit and scope of the present invention, various changes and modifications can be made to the present invention to adapt it to various uses and conditions. Therefore, other embodiments are also within the scope of the claims.

Claims

1. A method for 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: or a pharmaceutically acceptable salt thereof.

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

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

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

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

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

7. The method of any one of claims 1 to 6, wherein administering the therapeutic agent comprises administering the 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. The method of any one of claims 1 to 7, wherein administering the therapeutic agent comprises administering the therapeutic agent once daily.

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

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

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

13. The method of claim 12, wherein the subject's 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 are completely eliminated over a period of 10, 20, 30, 50, 84 or more days.

14. The method of claim 12, wherein the subject's 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 are completely eliminated over a period of 10, 20, 30, 50, 84 or more days.

15. The method of claim 11, wherein the seizure type is a seizure of focal origin, a seizure of generalized origin, or a seizure of unknown origin.

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

17. The method of claim 16, wherein the subject has a decrease in 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 complete elimination of seizures over a period of 10 days, 20 days, 30 days, 50 days, 84 days or more.

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

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

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

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

22. The method according to any one of claims 1 to 10, wherein the therapeutic efficacy of the treatment is determined by: TM Improvement was assessed by the overall quality of life score (PedsQL) score.

23. 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 PedsQL Family Impact Module score.

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

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

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

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

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

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

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

32. The method of any one of claims 1 to 31, wherein the therapeutic effect of the treatment is determined by: a. A 50% or greater reduction in overall seizure rate; b. The frequency of convulsive seizures decreases; c. The likelihood of no seizures increases; d. Improvements related to behavioral or cognitive symptoms; or e. The longest seizure-free period.

33. A method for treating Dravet syndrome, 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:

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