Methods of treatment of neurological disorders

Abstract

The present disclosure is generally directed to methods of treating a disease, disorder, or condition, e.g., a neurological disorder, a disorder associated with excessive neuronal excitability, or a disorder associated with de novo gain-of-function or loss-of-function mutations in major central nervous system sodium channel genes, using Compound 1 of the following formula: or a pharmaceutically acceptable salt thereof.

Description

[0001] METHODS OF TREATMENT OF NEUROLOGICAL DISORDERS

[0002] RELATED APPLICATIONS

[0003] This application claims priority to U.S. Provisional Patent Application No. 63 / 708,100, filed on October 16, 2024; U.S. Provisional Patent Application No. 63 / 689,392, filed on August 30, 2024; U.S. Provisional Patent Application No. 63 / 682,558, filed on August 13, 2024; U.S. Provisional Patent Application No. 63 / 657,910, filed on June 9, 2024; U.S. Provisional Patent Application No. 63 / 651,743, filed on May 24, 2024; U.S. Provisional Patent Application No. 63 / 572,886, filed on April 1, 2024; and U.S. Provisional Patent Application No. 63 / 570,200, filed on March 26, 2024. The entire contents of each of the foregoing applications are hereby incorporated herein by reference.

[0004] BACKGROUND OF THE DISCLOSURE

[0005] Sodium ion (Na+) channels primarily open in a transient manner and are quickly inactivated, thereby generating a fast Na+current to initiate the action potential. The late or persistent sodium current (NaL) is a sustained component of the fast Na current of cardiac myocytes and neurons. Many common neurological and cardiac conditions are associated with abnormal NaL enhancement, which contributes to the pathogenesis of both electrical and contractile dysfunction in mammals (see e.g., Pharmacol. Ther., 2008, 119:326-339).

[0006] Epilepsy is the fourth most common neurological disorder, affecting 3.4 million people in the United States, including 470,000 children. Epilepsy is a group of heterogeneous disorders classified into distinct syndromes by etiology, seizure type(s), and comorbidities. The most common cause of genetic epilepsy is mutations within voltagegated sodium channel (Nav) genes leading to gain-of-function and / or loss-of-function changes in channel activity. Affected patients typically present as children or neonates and have prognoses ranging from benign seizures that spontaneously remit to devastating developmental and epileptic encephalopathies (DEEs).

[0007] Nav channels are an important therapeutic target for antiepileptic drugs (AEDs). Their blockade, and consequent inhibition of neuronal sodium current (Na), is ideally positioned to reduce excitability, as peak Na in the axonal initial segment and node of Ranvier is responsible for the initiation and propagation of action potentials (APs), respectively. However, the clinical utility of standard Nav-targeting AEDs is limited because current agents, including cenobamate, oxcarbazepine, and phenytoin, can show severe toxicity at therapeutic doses. This toxicity includes ataxia, lethargy, vomiting, and seizures and reflects compromised physiologic neuronal function resulting from excessive peak Na inhibition or off-target (non-Nav-mediated) activities. Identification of novel Na inhibitors with improved tolerability would thus represent a clinically meaningful alternative treatment option.

[0008] Physiological persistent Na is a small, subthreshold current that contributes to the amplification of synaptic responses and the enhancement of repetitive firing. Functional studies of SCN2A (encoding Navi .2) and SCN8A (encoding Navi .6) DEE variants have demonstrated small increases in persistent Na that can cause hyperexcitability, seizures, and developmental comorbidities. Current Nav-targeting AEDs are predicted to inhibit both peak Na and persistent Na at or near therapeutic concentrations (high pmol / L range), with excessive peak Na inhibition compromising physiological neuronal activity. Therefore, improved selectivity for Nav activity and preference in the targeting of persistent Na could meaningfully improve tolerability.

[0009] Accordingly, additional therapeutic options with improved efficacy and tolerability to treat epilepsy, to achieve seizure freedom, or both are needed.

[0010] SUMMARY OF THE DISCLOSURE

[0011] In some aspects, the present disclosure provides a method of treating a condition relating to aberrant function of a sodium ion channel in a subject in need thereof, the method comprising administering to the subject Compound 1, or a pharmaceutically acceptable salt thereof, once daily at a dose of about 10 mg to about 45 mg, wherein Compound 1 is represented by the following structural formula:

[0012] In some embodiments, the subject experiences at least a partial suppression of PPR response. In some aspects, the present disclosure provides a method of treating a condition relating to aberrant function of a sodium ion channel in a subject in need thereof, the method comprising administering to the subject Compound 1, or a pharmaceutically acceptable salt thereof, at a dose of about 10 mg to about 45 mg; wherein Compound 1 is represented by the following structural formula: such that the subject experiences at least a partial suppression of PPR response.

[0013] In some embodiments, Compound 1 is administered once daily.

[0014] In some embodiments, the subject experiences a partial suppression of PPR response. In some embodiments, the subject experiences a complete suppression of PPR response. In some embodiments, the subject experiences suppression of PPR response about 1 or more hours following administration of the Compound 1, or a pharmaceutically acceptable salt thereof. In some embodiments, the subject experiences suppression of PPR response about 1 hour following, about 2 hours following, about 3 hours following, about 4 hours following, about 5 hours following, about 6 hours following, about 7 hours following or about 8 hours following administration of Compound 1, or a pharmaceutically acceptable salt thereof.

[0015] In some embodiments, the suppression of PPR response lasts for at least about 1 hour, at least about 2 hours, at least about 3 hours, at least about 4 hours, at least about 5 hours, at least about 6 hours, at least about 7 hours at least about 8 hours, at least about 9 hours, at least about 10 hours, at least about 11 hours, at least about 12 hours, at least about 13 hours, at least about 14 hours, at least about 15 hours, at least about 16 hours, at least about 17 hours, at least about 18 hours, at least about 19 hours, at least about 20 hours, at least about 21 hours, at least about 22 hours, at least about 23 hours or at least about 24 hours following administration of Compound 1, or a pharmaceutically acceptable salt thereof.

[0016] In some embodiments, the dose is about 10 mg to about 40 mg, about 15 mg to about

[0017] 35 mg, about 10 mg to about 30 mg, about 15 mg to about 25 mg, about 20 mg to about 45 mg, about 20 mg to about 40 mg, about 25 mg to about 35 mg, about 25 mg to about 30 mg, about 20 mg to about 35 mg, about 25 mg to about 40 mg, about 30 mg to about 45 mg, or about 30 mg to about 40 mg. In some embodiments, the dose is about 10 mg, about 15 mg, about 20 mg, about 25 mg, about 30 mg, about 35 mg, about 40 mg or about 45 mg.

[0018] In some embodiments, the dose is administered for at least 1 day, at least 2 days, at least 3 days, at least 4 days, at least 5 days, at least 6 days, at least 7 days, at least 14 days, at least 21 days, at least 28 days, at least 35 days or at least 42 days.

[0019] In some embodiments, the subject does not experience adverse events. In some embodiments, the subject experiences mild adverse events.

[0020] In some embodiments, the subject does not experience a clinically meaningful change in at least one ECG parameter. In some embodiments, the at least one ECG parameter is selected from the group consisting of heart rate (HR), PR interval, QRS, QT interval and any combination thereof.

[0021] In some embodiments, a therapeutic concentration of Compound 1 is achieved in a subject and maintained for at least 1 hour following administration of a dose of Compound 1, or a pharmaceutically acceptable salt thereof. In other embodiments, a therapeutic concentration is achieved in a subject and maintained for at least about 2 hours, at least about 3 hours, at least about 4 hours, at least about 5 hours, at least about 6 hours, at least about 7 hours at least about 8 hours, at least about 9 hours, at least about 10 hours, at least about 11 hours, at least about 12 hours, at least about 13 hours, at least about 14 hours, at least about 15 hours, at least about 16 hours, at least about 17 hours, at least about 18 hours, at least about 19 hours, at least about 20 hours, at least about 21 hours, at least about 22 hours, at least about 23 hours or at least about 24 hours following administration of a dose of Compound 1, or a pharmaceutically acceptable salt thereof. In some embodiments, the dose is about 10 mg to about 40 mg, about 10 mg to about 35 mg, about 10 mg to about 30 mg, about 15 mg to about 25 mg, about 20 mg to about 45 mg, about 20 mg to about 40 mg, about 25 mg to about 35 mg, about 25 mg to about 30 mg, about 20 mg to about 35 mg, about 25 mg to about 40 mg, about 30 mg to about 45 mg, or about 30 mg to about 40 mg. In some embodiments, the dose is about 10 mg, about 15 mg, about 20 mg, about 25 mg, about 30 mg, about 35 mg, about 40 mg or about 45 mg. In one embodiment, the dose is about 10 mg. In another embodiment, the dose is about 20 mg. In a further embodiment, the dose is about 30 mg. In various embodiments, the dose is about 10, 20, or 30 mg and a therapeutic concentration is achieved in a subject and maintained for at least 23 hours or at least about a day.

[0022] In some embodiments, a therapeutic concentration of Compound 1, or a pharmaceutically acceptable salt thereof, is achieved in a subject 1 or more hours following administration of Compound 1, or a pharmaceutically acceptable salt thereof. In some embodiments, a therapeutic concentration of Compound 1, or a pharmaceutically acceptable salt thereof, is achieved in a subject about 1 hour following, about 2 hours following, about 3 hours following, about 4 hours following, about 5 hours following, about 6 hours following, about 7 hours following or about 8 hours following administration of Compound 1, or a pharmaceutically acceptable salt thereof. In some embodiments, the dose is about 10 mg to about 40 mg, about 15 mg to about 35 mg, about 10 mg to about 30 mg, about 15 mg to about 25 mg, about 20 mg to about 45 mg, about 20 mg to about 40 mg, about 25 mg to about 35 mg, about 25 mg to about 30 mg, about 20 mg to about 35 mg, about 25 mg to about 40 mg, about 30 mg to about 45 mg, or about 30 mg to about 40 mg. In some embodiments, the dose is about 10 mg, about 15 mg, about 20 mg, about 25 mg, about 30 mg, about 35 mg, about 40 mg or about 45 mg. In one embodiment, the dose is about 10 mg. In another embodiment, the dose is about 20 mg. In a further embodiment, the dose is about 30 mg.

[0023] In some embodiments, the condition relating to aberrant function of a sodium ion channel is a neurological disorder. In some embodiments, the neurological disorder is a disorder associated with excessive neuronal excitability. In some embodiments, the neurological disorder is associated with one or more de novo gain-of-function or loss-of- function mutations in central nervous system sodium ion channel genes.

[0024] In some embodiments, the condition is epilepsy or an epilepsy syndrome. In some embodiments, the condition is a genetic epilepsy or a genetic epilepsy syndrome. In some embodiments, the condition is a pediatric epilepsy or a pediatric epilepsy syndrome. In some embodiments, the condition is selected from the group consisting of malignant migrating focal seizures of infancy (MMFSI), epilepsy of infancy with migrating focal seizures (EIMFS), autosomal dominant nocturnal frontal lobe epilepsy (ADNFLE), West syndrome, infantile spasms, epileptic encephalopathy, focal epilepsy, Ohtahara syndrome, developmental and epileptic encephalopathy, Lennox-Gastaut syndrome, seizures, leukodystrophy, leukoencephalopathy, intellectual disability, multifocal epilepsy, drug- resistant epilepsy, temporal lobe epilepsy and cerebellar ataxia. In some embodiments, the condition is epileptic encephalopathy. In some embodiments, the condition is focal epilepsy. In some embodiments, the focal epilepsy is adult focal epilepsy. In some embodiments, the seizures are generalized tonic clonic seizures or asymmetric tonic seizures.

[0025] In some embodiments, the subject is a human.

[0026] In some aspects, the present disclosure provides a method of achieving at least a partial suppression of PPR response in a subject with an epilepsy or an epilepsy syndrome, the method comprising administering to said subject Compound 1, or a pharmaceutically acceptable salt thereof, once daily at a dose of about 10 mg to about 45 mg, wherein Compound 1 is represented by the following structural formula:

[0027] In some embodiments, the method achieves a complete suppression of PPR response in said subject.

[0028] In some embodiments, the dose is about 10 mg to about 40 mg, about 10 mg to about 35 mg, about 15 mg to about 30 mg, about 15 mg to about 25 mg, about 20 mg to about 45 mg, about 20 mg to about 40 mg, about 25 mg to about 35 mg, about 25 mg to about 30 mg, about 20 mg to about 35 mg, about 25 mg to about 40 mg, about 30 mg to about 45 mg, or about 30 mg to about 40 mg. In some embodiments, the dose is about 10 mg, about 15 mg, about 20 mg, about 25 mg, about 30 mg, about 35 mg, about 40 mg or about 45 mg. In one embodiment, the dose is about 10 mg. In another embodiment, the dose is about 20 mg. In a further embodiment, the dose is about 30 mg.

[0029] In some embodiments, the dose is administered for at least 1 day, at least 2 days, at least 3 days, at least 4 days, at least 5 days, at least 6 days, at least 7 days, at least 14 days, at least 21 days, at least 28 days, at least 35 days or at least 42 days. In some embodiments, the subject experiences suppression of PPR response 1 or more hours following administration of the Compound 1, or a pharmaceutically acceptable salt thereof.

[0030] In some embodiments, the subject experiences suppression PPR response about 1 hour following, about 2 hours following, about 3 hours following, about 4 hours following, about 5 hours following, about 6 hours following, about 7 hours following or about 8 hours following administration of Compound 1, or a pharmaceutically acceptable salt thereof. In some embodiments, the suppression of PPR response lasts for at least about 1 hour, at least about 2 hours, at least about 3 hours, at least about 4 hours, at least about 5 hours, at least about 6 hours, at least about 7 hours at least about 8 hours, at least about 9 hours, at least about 10 hours, at least about 11 hours, at least about 12 hours, at least about 13 hours, at least about 14 hours, at least about 15 hours, at least about 16 hours, at least about 17 hours, at least about 18 hours, at least about 19 hours, at least about 20 hours, at least about 21 hours, at least about 22 hours, at least about 23 hours or at least about 24 hours following administration of Compound 1, or a pharmaceutically acceptable salt thereof.

[0031] In some embodiments, the subject does not experience adverse events. In some embodiments, the subject experiences mild adverse events.

[0032] In some embodiments, the subject does not experience a clinically meaningful change in at least one ECG parameter. In some embodiments, the at least one ECG parameter is selected from the group consisting of heart rate (HR), PR interval, QRS, QT interval and any combination thereof.

[0033] In some embodiments, the epilepsy or epilepsy syndrome is a genetic epilepsy or a genetic epilepsy syndrome. In some embodiments, the epilepsy or epilepsy syndrome is a pediatric epilepsy or a pediatric epilepsy syndrome. In some embodiments, the epilepsy or epilepsy syndrome is selected from the group consisting of malignant migrating focal seizures of infancy (MMFSI), epilepsy of infancy with migrating focal seizures (EIMFS), autosomal dominant nocturnal frontal lobe epilepsy (ADNFLE), West syndrome, infantile spasms, epileptic encephalopathy, focal epilepsy, Ohtahara syndrome, developmental and epileptic encephalopathy, Lennox-Gastaut syndrome, seizures, leukodystrophy, leukoencephalopathy, intellectual disability, multifocal epilepsy, drug -resistant epilepsy, temporal lobe epilepsy and cerebellar ataxia. In some embodiments, the epilepsy or epilepsy syndrome is epileptic encephalopathy. In some embodiments, the epilepsy or epilepsy syndrome is focal epilepsy. In some embodiments, the focal epilepsy is adult focal epilepsy. In some embodiments, the seizures are generalized tonic clonic seizures or asymmetric tonic seizures.

[0034] In some embodiments, the subject is a human.

[0035] BRIEF DESCRIPTION OF THE DRAWINGS

[0036] The accompanying drawings, which are incorporated in and constitute a part of this specification, illustrate certain embodiments, and together with the written description, serve to explain certain principles of the methods and devices disclosed herein.

[0037] FIG. 1A is an illustration of the dosing scheme for Part A (single ascending dose) of a phase 1 clinical trial to evaluate the safety, tolerability, pharmacokinetics and pharmacodynamics of single and multiple ascending doses of Compound 1 in healthy volunteers.

[0038] FIG. IB is an illustration of the dosing scheme for Part B (multiple ascending dose) of a phase 1 clinical trial to evaluate the safety, tolerability, pharmacokinetics and pharmacodynamics of single and multiple ascending doses of Compound 1 in healthy volunteers.

[0039] FIG. 1C is an illustration of the dosing scheme for Part C (optional food effect evaluation) of a phase 1 clinical trial to evaluate the safety, tolerability, pharmacokinetics and pharmacodynamics of single and multiple ascending doses of Compound 1 in healthy volunteers.

[0040] FIG. ID is a graph showing a composite change in qEEG score at different times post dose.

[0041] FIG. IE is a bar graph showing the period of time during which a therapeutic concentration is sustained after administration of 400 mg of cenobamate, 25 mg of XEN1101 and 30 mg of Compound 1 on day 1.

[0042] FIG. 2 is an illustration of the dosing scheme for a phase 2 trial to evaluate the photoparoxysmal electroencephalogram response, safety, tolerability, and pharmacokinetics of Compound 1 in participants with epilepsy and a photoparoxysmal electroencephalogram response to intermittent photic stimulation.

[0043] FIG. 3 is a schematic showing the design of the clinical trial described in Example 2.

[0044] FIG. 4 illustrates the concept of photoparoxysmal response, which pertains to an EEG anomaly precipitated by intermittent photic stimulation (IPS). A study participant is equipped with EEG recording equipment and is exposed to stray light of varying frequencies, allowing observation of the transition from normal EEG pattern to distinct PPR responses.

[0045] FIG. 5 is a flowchart illustrating disposition of subjects in the trial. 30 participants were screened, of which 10 met the inclusion criteria for the trial. In part A, which involved 15 mg dosing of Compound 1, 6 participants underwent safety assessment, and 5 of the 6 participants underwent PPR evaluations. In part B, which involved 45 mg dosing of Compound 1, 4 participants underwent safety assessment, and 3 participants underwent PPR evaluations.

[0046] FIG. 6 is a table showing demographic profile of study participants.

[0047] FIG. 7 is a table showing the incidence of adverse events in the study participants.

[0048] FIG. 8 is a table showing the response to treatment with Compound 1.

[0049] FIG. 9 shows an example of EEG recordings before (left panel) and after (right panel) administration of Compound 1.

[0050] FIG. 10A is a schematic illustrating the design of the ENERGY program, which is designed to demonstrate efficacy of Compound 1 and bring an improved therapy to focal and generalized epilepsy patients.

[0051] FIG 10B is a schematic illustrating the design of the EMPOWER observational study, which is designed to better understand patients’ joumies.

[0052] FIG. 10C is a schematic illustrating the design of the RADIANT phase 2 open label study, which is designed to evaluate the safety and efficacy of Compound 1 in epilepsy with focal and / or generalized seizures. FIG. 10D is a schematic illustrating the design of the P0WER1 study, which is designed to demonstrate efficacy of Compound 1 and the P0WER2 study, which is designed to evaluate a minimal dose of Compound 1.

[0053] FIG. 11 is a graph showing Placebo-corrected Change from Baseline QTcB (AAQTcB) Interval by Treatment and Timepoint (Safety Population) for Part A, SAD (FIG. 11 A) and Part B, MAD Day 10 (FIG. 11B). Data shown as mean ± 90% CI.

[0054] FIG. 12 is a bar graph showing clinically tolerated exposures in humans of cenobamate, XEN1101, and Compound 1, measured in multiple of predicted human ECso based on the rodent MES model (x MES ECso).

[0055] FIG. 13 is a graph showing Mean Plasma Concentration-Time Profile of Compound 1 by Dose (Part A, SAD). Data are shown as mean ± SD, with Compound 1 concentration-time profiles shown on a semi-log scale.

[0056] FIG. 14 is a Mean Plasma Concentration-Time Profile of Compound 1 on Day 1 and 10 (Part B, MAD). Data are shown as mean ± SD, with Compound 1 concentration -time profiles shown on a semi-log scale.

[0057] FIG. 15 is a table showing an in vitro non-GLP safety pharmacology study evaluating the ability of lOmM Compound 1 to modulate recombinant, human non-INacardiac channels, stably expressed in either CHO or HEK293 cells. Data are mean ± SEM (n=3). SEM=standard error of the mean. Superscript “a” indicates statistically significant differences from control group as determined by one-way ANOVA with Dunnett’s Multiple Comparison Test. CaV=voltage-gated calcium channel; hERG=human ether-a-go-go-related gene; HCN=hyperpolarization-activated cyclic nucleotide-gated channel; Kir=inwardly-rectifying potassium channel; KV=voltage-gated potassium channel. Superscript “b” indicates that the ratio to target values are based on primary pharmacology studies for hNaV1.6 UDB-lOHz (IC50 0.2mM).

[0058] FIG. 16 is a graph showing geometric mean plasma concentration-time profile of Compound 1 on Day 1 and 10 (Part B, MAD). Data are shown as mean ±SD, with Compound 1 concentration-time profiles shown on a semi-log scale. FIG. 17 is a boxplot showing model predicted steady state Cmax for Compound 1 administered under fasted and fed conditions (Part C). The results shown for modeling based on 30 mg and 45 mg doses.

[0059] FIG. 18 shows EMPOWER study respondent demographics. Of all respondents, 73% are female, and most are between the ages of 35 and 54.

[0060] FIG. 19 is a bar graph showing reported epilepsy diagnosis of the respondents.

[0061] FIG. 20 is a schematic showing respondents’ perception of their seizures.

[0062] FIG. 21 is a bar graph showing reported seizures over the last month.

[0063] FIG. 22 is a bar graph showing use of anti-seizure medications (ASMs).

[0064] FIG. 23 is a graphic showing data on respondents’ seizure tracking.

[0065] FIG. 24 is a bar graph showing impact of ASMs on quality of life and activities of daily living.

[0066] DETAILED DESCRIPTION THE DISCLOSURE

[0067] Reference will now be made in detail to various exemplary embodiments, examples of which are illustrated in the accompanying drawings. It is to be understood that the following detailed description is provided to give the reader a fuller understanding of certain embodiments, features, and details of aspects of the disclosure, and should not be interpreted as a limitation of the scope of the disclosure.

[0068] Definitions

[0069] In order for the present disclosure to be more readily understood, certain terms are first defined below. Additional definitions for the following terms and other terms may be set forth through the specification. If a definition of a term set forth below is inconsistent with a definition in an application or patent that is incorporated by reference, the definition set forth in this application should be used to understand the meaning of the term.

[0070] As used in this specification and the appended claims, the singular forms “a,” “an,” and “the” include plural references unless the context clearly dictates otherwise. Thus, for example, a reference to “a method” includes one or more methods, and / or steps of the type described herein and / or which will become apparent to those persons skilled in the art upon reading this disclosure and so forth.

[0071] The term “about” is used herein to mean within the typical ranges of tolerances in the art. For example, “about” can be understood as about 2 standard deviations from the mean. According to certain embodiments, when referring to a measurable value such as an amount and the like, “about” is meant to encompass variations of ±20%, ±10%, ±5%, ±1%, ±0.9%, ±0.8%, ±0.7%, ±0.6%, ±0.5%, ±0.4%, ±0.3%, ±0.2% or ±0.1% from the specified value as such variations are appropriate to perform the disclosed methods and / or to make and use the disclosed devices. When “about” is present before a series of numbers or a range, it is understood that “about” can modify each of the numbers in the series or range.

[0072] The terms “administer,” “administering” or “administration” as used herein refer to either directly administering a compound or pharmaceutically acceptable salt or ester of the compound or a composition comprising the compound or pharmaceutically acceptable salt or ester of the compound to a subject.

[0073] The term “and / or,” as used herein in the specification and in the claims, should be understood to mean “either or both” of the elements so conjoined, z.e., elements that are conjunctively present in some cases and disjunctively present in other cases. Other elements may optionally be present other than the elements specifically identified by the “and / or” clause, whether related or unrelated to those elements specifically identified unless clearly indicated to the contrary. Thus, as a non-limiting example, a reference to “A and / or B,” when used in conjunction with open-ended language such as “comprising” can refer, in one embodiment, to A without B (optionally including elements other than B); in another embodiment, to B without A (optionally including elements other than A); in yet another embodiment, to both A and B (optionally including other elements); etc.

[0074] The term “at least” prior to a number or series of numbers (e.g., “at least two”) is understood to include the number adjacent to the term “at least,” and all subsequent numbers or integers that could logically be included, as clear from context. When “at least” is present before a series of numbers or a range, it is understood that “at least” can modify each of the numbers in the series or range. The terms “disease,” “disorder,” and “condition” are used interchangeably herein.

[0075] As used herein, the term “in some embodiments” refers to embodiments of all aspects of the disclosure, unless the context clearly indicates otherwise.

[0076] As used herein, the term “clinically meaningful change” refers to a change in a measurable characteristic in a subject, e.g., a test result, which indicates a change in the subject’s clinical condition. In some embodiments, the test result comprises ECG parameters, such as heart rate (HR), PR interval, QRS, QT interval, or any combination thereof.

[0077] As used herein, the “effective amount” of a compound refers to an amount sufficient to elicit the desired biological response. As will be appreciated by those of ordinary skill in this art, the effective amount of a compound of the invention may vary depending on such factors as the desired biological endpoint, the pharmacokinetics of the compound, the disease being treated, the mode of administration, and the age, health, and condition of the subject. An effective amount encompasses therapeutic and prophylactic treatment.

[0078] As used herein, the term “partial suppression of PPR response” refers to a reduction, other than to zero, in the number of generalized photoparoxysmal EEG response (PPR) events in a subject following administration of Compound 1 or a pharmaceutically acceptable salt thereof, as compared to the number of generalized PPR events at baseline. The number of generalized PPR events may be measured in a subject as described, e.g., herein in Example 2. The term “baseline” refers to the number of generalized PPR events in a subject prior to administration of Compound 1. In some embodiments, partial suppression of PPR response may be achieved following administration of about 15 mg to about 45 mg of Compound 1 to the subject, e.g., once daily. In some embodiments, partial suppression of PPR response may be achieved in a subject following administration of about 15 mg to about 45 mg of Compound 1, or a pharmaceutically acceptable salt thereof, to a subject for at least 1 day, at least 2 days, at least 3 days, at least 4 days, at least 5 days, at least 6 days, at least 7 days, at least 14 days, at least 21 days, at least 28 days, at least 35 days or at least 42 days.

[0079] As used herein, the term “complete suppression of PPR response” refers to a reduction to zero in the number of generalized photoparoxysmal EEG response (PPR) events in a subject following administration of Compound 1 or a pharmaceutically acceptable salt thereof, as compared to the number of generalized PPR events at baseline. The number of generalized PPR events may be measured in a subject as described, e.g., herein in Example 1. The term “baseline” refers to the number of generalized PPR events in a subject prior to administration of Compound 1. In some embodiments, complete suppression of PPR response may be achieved following administration of about 15 mg to about 45 mg of Compound 1 to the subject, e.g., once daily. In some embodiments, complete suppression of PPR response may be achieved in a subject following administration of about 15 mg to about 45 mg of Compound 1, or a pharmaceutically acceptable salt thereof, to a subject for at least 1 day, at least 2 days, at least 3 days, at least 4 days, at least 5 days, at least 6 days, at least 7 days, at least 14 days, at least 21 days, at least 28 days, at least 35 days or at least 42 days.

[0080] As used herein, “pharmaceutically acceptable carrier” refers to a non-toxic carrier, adjuvant, or vehicle that does not destroy the pharmacological activity of the compound with which it is formulated. Pharmaceutically acceptable carriers, adjuvants or vehicles that may be used in the compositions described herein include, but are not limited to, ion exchangers, alumina, aluminum stearate, lecithin, serum proteins, such as human serum albumin, buffer substances such as phosphates, glycine, sorbic acid, potassium sorbate, partial glyceride mixtures of saturated vegetable fatty acids, water, salts or electrolytes, such as protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zinc salts, colloidal silica, magnesium trisilicate, polyvinyl pyrrolidone, cellulose-based substances, polyethylene glycol, sodium carboxymethylcellulose, polyacrylates, waxes, polyethylene-polyoxypropylene-block polymers, polyethylene glycol and wool fat.

[0081] As used herein, “pharmaceutically acceptable salt” refers to those salts which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of humans and lower animals without undue toxicity, irritation, allergic response and the like, and are commensurate with a reasonable benefit / risk ratio. Pharmaceutically acceptable salts are well known in the art. For example, Berge et al., describes pharmaceutically acceptable salts in detail in J. Pharmaceutical Sciences (1977) 66: 1-19. Pharmaceutically acceptable salts of the compounds of this invention include those derived from suitable inorganic and organic acids and bases. Examples of pharmaceutically acceptable, nontoxic acid addition salts are salts of an amino group formed with inorganic acids such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid and perchloric acid or with organic acids such as acetic acid, oxalic acid, maleic acid, tartaric acid, citric acid, succinic acid or malonic acid or by using other methods used in the art such as ion exchange. Other pharmaceutically acceptable salts include adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphorate, camphorsulfonate, citrate, cyclopentanepropionate, di gluconate, dodecyl sulfate, ethanesulfonate, formate, fumarate, glucoheptonate, glycerophosphate, gluconate, hemisulfate, heptanoate, hexanoate, hydroiodide, 2-hydroxy- ethanesulfonate, lactobionate, lactate, laurate, lauryl sulfate, malate, maleate, malonate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate, pamoate, pectinate, persulfate, 3 -phenylpropionate, phosphate, picrate, pivalate, propionate, stearate, succinate, sulfate, tartrate, thiocyanate, p-toluenesulfonate, undecanoate, valerate salts, and the like. Pharmaceutically acceptable salts derived from appropriate bases include alkali metal, alkaline earth metal, ammonium and N+(Ci-4alkyl)4 salts. Representative alkali or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium, and the like. Further pharmaceutically acceptable salts include, when appropriate, nontoxic ammonium, quaternary ammonium, and amine cations formed using counterions such as halide, hydroxide, carboxylate, sulfate, phosphate, nitrate, lower alkyl sulfonate, and aryl sulfonate.

[0082] As used herein, a “subject” to which administration is contemplated includes, but is not limited to, humans (z.e., a male or female of any age group, e.g., a fetus, a pediatric subject, such as an infant, a child, or an adolescent) or an adult subject (e.g., a young adult, a middle-aged adult or a senior adult) and / or a non-human animal, e.g., a mammal such as a primate (e.g., a cynomolgus monkeys or a rhesus monkeys), a cattle, a pig, a horse, a sheep, a goat, a rodent, a cat, or a dog. In certain embodiments, the subject is a human. In certain embodiments, the subject is a non-human animal.

[0083] As used herein, die terms “treat”, “treatment” or “treating” a condition or a disorder, e.g., epilepsy or an epilepsy syndrome, such as focal epilepsy, in a subject in need thereof includes achieving, partially, substantially or completely, one or more of the following: ameliorating, improving or achieving a reduction in the severity of at least one symptom or indicator associated with the condition or disorder; or arresting the progression or worsening of the condition or disorder.

[0084] As used herein, and unless otherwise specified, a “therapeutically effective amount” of a compound is an amount sufficient to provide a therapeutic benefit in the treatment of a disease, disorder or condition, or to delay or minimize one or more symptoms associated with the disease, disorder or condition. A therapeutically effective amount of a compound means an amount of therapeutic agent, alone or in combination with other therapies, which provides a therapeutic benefit in the treatment of the disease, disorder or condition. The term “therapeutically effective amount” can encompass an amount that improves overall therapy, reduces or avoids symptoms or causes of disease or condition, or enhances the therapeutic efficacy of another therapeutic agent.

[0085] The embodiments disclosed herein are not intended to be limited in any manner by the above exemplary listing of chemical groups and substituents. Those skilled in the art will recognize that several embodiments are possible within the scope and spirit of the present disclosure. The following description illustrates the disclosure and, of course, should not be construed in any way as limiting the scope of the inventions described herein.

[0086] Compounds and Compositions

[0087] In some aspects, methods provided by the present disclosure comprise administering to a subject Compound 1, or a pharmaceutically acceptable salt thereof, wherein Compound 1 is represented by the following formula:

[0088] In some embodiments, Compound 1 is in a crystalline form. In some embodiments, the crystalline form may be characterized by an X-ray powder diffraction pattern comprising X-ray powder diffraction peaks at the following diffraction angles (° 29): 12.6±0.2, 15.8±0.2, and 18.6±0.2. In some embodiments, the crystalline form may be characterized by an X-ray powder diffraction pattern comprising X-ray powder diffraction peaks at the following diffraction angles (° 29): 19.7±9.2, 12.3±9.2, 12.6±9.2, 15.8±9.2, 18.6±9.2, and 22.6±9.2. In some embodiments, the crystalline form may be characterized by an X-ray powder diffraction pattern comprising X-ray powder diffraction peaks at the following diffraction angles (° 29): 10.7±0.2, 12.3±9.2, 12.6±9.2, 14.9±9.2, 15.8±9.2, 16.6±9.2, 16.8±9.2, 18.6±9.2, 21.9±9.2 and 22.6±9.2. The crystalline form of Compound 1 is described, e.g., in WO 2919 / 232299, the entire contents of which are hereby incorporated herein by reference. In some embodiments, Compound 1, or a pharmaceutically acceptable salt thereof, may be administered to a subject in the context of the present disclosure as a part of a pharmaceutical composition comprising Compound 1 or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier.

[0089] Methods of Treatment

[0090] In some aspects, the present disclosure provides methods for modulating the activity of sodium channels and treating conditions relating to aberrant function of a sodium channel ion channel, e.g., abnormal late sodium (I\aL) current. In some embodiments, Compound 1, or a pharmaceutically acceptable salt thereof, is effective in the treatment of epilepsy or an epilepsy syndrome. Compound 1, or a pharmaceutically acceptable salt thereof, or composition comprising the same may also modulate all sodium ion channels, or may be specific to only one or a plurality of sodium ion channels, e.g., Navl.l, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, and / or 1.9. In some embodiments, a compound of the disclosure has specificity to sodium ion channel Navi .6.

[0091] In typical embodiments, the disclosure is intended to encompass the compounds disclosed herein, and the pharmaceutically acceptable salts, pharmaceutically acceptable esters, tautomeric forms, polymorphs, and prodrugs of such compounds. In some embodiments, the disclosure includes a pharmaceutically acceptable addition salt, a pharmaceutically acceptable ester, a solvate (e.g., hydrate) of an addition salt, a tautomeric form, a polymorph, an enantiomer, a mixture of enantiomers, a stereoisomer or mixture of stereoisomers (pure or as a racemic or non-racemic mixture) of Compound 1.

[0092] Compound 1 or a pharmaceutically acceptable salt thereof disclosed herein, and compositions described herein, can be used to treat a neurological disorder, a disorder associated with excessive neuronal excitability, or a disorder associated with de novo gain-of- function or loss-of-function mutations in central nervous system sodium channel genes, such as for example, SCN1A, SCN2A, and SCN8A.

[0093] In some aspects, provided are methods of treating a neurological disorder, a disorder associated with excessive neuronal excitability, or a disorder associated with de novo gain-of- function or loss-of-function mutations in the major central nervous system sodium channel genes, comprising administering to a subject in need thereof an effective amount of Compound 1 or a pharmaceutically acceptable salt thereof disclosed herein, or pharmaceutical compositions comprising the same.

[0094] Exemplary diseases, disorders, or conditions include epilepsy and other encephalopathies (e.g., malignant migrating focal seizures of infancy (MMFSI) or epilepsy of infancy with migrating focal seizures (EIMFS), autosomal dominant nocturnal frontal lobe epilepsy (ADNFLE), West syndrome, infantile spasms, epileptic encephalopathy, developmental and epileptic encephalopathy (DEE), early infantile epileptic encephalopathy (EIEE), generalized epilepsy, focal epilepsy, multifocal epilepsy, temporal lobe epilepsy, Ohtahara syndrome, early myoclonic encephalopathy, Lennox-Gastaut syndrome), and drug resistant epilepsy, seizures (e.g., frontal lobe seizures, generalized tonic clonic seizures, asymmetric tonic seizures, focal seizures).

[0095] Epilepsy is a CNS disorder in which nerve cell activity in the brain becomes disrupted, causing seizures or periods of unusual behavior, sensations and sometimes loss of consciousness. Seizure symptoms will vary widely, from a simple blank stare for a few seconds to repeated twitching of their arms or legs during a seizure. Epilepsy may involve a generalized seizure or a partial or focal seizure. All areas of the brain are involved in a generalized seizure. A person experiencing a generalized seizure may cry out or make some sound, stiffen for several seconds to a minute a then have rhythmic movements of the arms and legs. The eyes are generally open, the person may appear not to be breathing and may actually turn blue. The return to consciousness is gradual and the person may be confused from minutes to hours. There are six main types of generalized seizures: tonic-clonic, tonic, clonic, myoclonic, absence, and atonic seizures. In a partial or focal seizure, only part of the brain is involved, so only part of the body is affected. Depending on the part of the brain having abnormal electrical activity, symptoms may vary.

[0096] Epilepsy, as described herein, includes a generalized, partial, complex partial, tonic clonic, clonic, tonic, refractory seizures, status epilepticus, absence seizures, febrile seizures, or temporal lobe epilepsy.

[0097] In some embodiments, the epilepsy syndrome is early-onset DEE. In certain embodiments, the epilepsy syndrome is DEE, including, for example, Ohtahara Syndrome; epilepsy with migrating focal seizures of infancy (EIMFS); infantile and childhood DEE, for example West Syndrome and Lennon-Gastaut Syndrome; Dravet Syndrome; Idiopathic / Generic Generalized Epilepsies (IGE / GGE); Temporal Lobe Epilepsy; Myoclonic Astatic Epilepsy (MAE); Migrating Partial Epilepsy of Infancy (MMPSI); and familial hemiplegic migraines, with or without epilepsy. In certain embodiments, the epilepsy syndrome is late seizure onset epileptic encephalopathy.

[0098] In some embodiments, the epilepsy syndrome is focal epilepsy, including, for example, idiopathic location-related epilepsies (ILRE), frontal lobe epilepsy, temporal lobe epilepsy, parietal lobe epilepsy and occipital lobe epilepsy. In some embodiments, the epilepsy syndrome is adult focal epilepsy.

[0099] In some embodiments, Compound 1 or a pharmaceutically acceptable salt thereof disclosed herein, or pharmaceutical compositions comprising the same may be used in the treatment of epilepsy syndromes. Severe syndromes with diffuse brain dysfunction caused, at least partly, by some aspect of epilepsy, are also referred to as epileptic encephalopathies. These are associated with frequent seizures that are resistant to treatment and severe cognitive dysfunction, for instance West syndrome. In some embodiments, the epilepsy syndrome comprises an epileptic encephalopathy, such as Dravet syndrome, Angelman syndrome, CDKL5 disorder, frontal lobe epilepsy, infantile spasms, West’s syndrome, Juvenile Myoclonic Epilepsy, Landau-Kleffner syndrome, Lennox-Gastaut syndrome, Ohtahara syndrome, PCDH19 epilepsy, or Glutl deficiency.

[0100] In some embodiments, Compound 1 or a pharmaceutically acceptable salt thereof disclosed herein, or pharmaceutical compositions comprising the same may be used in the treatment of focal epilepsy, including, for example, idiopathic location-related epilepsies (ILRE), frontal lobe epilepsy, temporal lobe epilepsy, parietal lobe epilepsy and occipital lobe epilepsy. In some embodiments, the epilepsy syndrome is adult focal epilepsy. Focal epilepsy is a neurological condition in which the predominant symptom is recurring seizures that affect one hemisphere (half) of the brain. Thus, focal epilepsies are generally characterized by seizures arising from a specific part (lobe) of the brain.

[0101] In some embodiments, the epilepsy or epilepsy syndrome is a genetic epilepsy or a genetic epilepsy syndrome. In some embodiments, epilepsy or an epilepsy syndrome comprises epileptic encephalopathy, epileptic encephalopathy with SCN1A, SCN2A, SCN8A mutations, early infantile epileptic encephalopathy, Dravet syndrome, Dravet syndrome with SCN1A mutation, generalized epilepsy with febrile seizures, intractable childhood epilepsy with generalized tonic-clonic seizures, infantile spasms, benign familial neonatal-infantile seizures, SCN2A epileptic encephalopathy, focal epilepsy with SCN3 A mutation, cryptogenic pediatric partial epilepsy with SCN3 A mutation, SCN8A epileptic encephalopathy, sudden unexpected death in epilepsy (SUDEP), Rasmussen encephalitis, malignant migrating partial seizures of infancy, autosomal dominant nocturnal frontal lobe epilepsy, KCNQ2 epileptic encephalopathy, or KCNT1 epileptic encephalopathy.

[0102] In some embodiments, the methods described herein further comprise identifying a subject having epilepsy or an epilepsy syndrome (e.g., epileptic encephalopathy, epileptic encephalopathy with SCN1A, SCN2A, SCN8A mutations, early infantile epileptic encephalopathy, Dravet syndrome, Dravet syndrome with SCN1A mutation, generalized Epilepsy with febrile seizures, intractable childhood epilepsy with generalized tonic-clonic seizures, infantile spasms, benign familial neonatal-infantile seizures, SCN2A epileptic encephalopathy, focal epilepsy with SCN3 A mutation, cryptogenic pediatric partial epilepsy with SCN3 A mutation, SCN8A epileptic encephalopathy, sudden unexpected death in epilepsy (SUDEP), Rasmussen encephalitis, malignant migrating partial seizures of infancy, autosomal dominant nocturnal frontal lobe epilepsy, KCNQ2 epileptic encephalopathy, or KCNT1 epileptic encephalopathy) prior to administration of Compound 1 or a pharmaceutically acceptable salt thereof disclosed herein, or pharmaceutical compositions comprising the same.

[0103] In one aspect, the disclosure features a method of treating epilepsy or an epilepsy syndrome (e.g., epileptic encephalopathy, epileptic encephalopathy with SCN1A, SCN2A, SCN8A mutations, early infantile epileptic encephalopathy, developmental and epileptic encephalopathy, Dravet syndrome, Dravet syndrome with SCN1A mutation, generalized epilepsy with febrile seizures, intractable childhood epilepsy with generalized tonic-clonic seizures, infantile spasms, benign familial neonatal-infantile seizures, SCN2A epileptic encephalopathy, focal epilepsy with SCN3 A mutation, cryptogenic pediatric partial epilepsy with SCN3 A mutation, SCN8A epileptic encephalopathy, sudden unexpected death in epilepsy (SUDEP), Rasmussen encephalitis, malignant migrating partial seizures of infancy, autosomal dominant nocturnal frontal lobe epilepsy, KCNQ2 epileptic encephalopathy, or KCNT1 epileptic encephalopathy) comprising administering to a subject in need thereof Compound 1 or a pharmaceutically acceptable salt thereof disclosed herein, or pharmaceutical compositions comprising the same. Compound 1 or a pharmaceutically acceptable salt thereof disclosed herein, or pharmaceutical compositions comprising the same may also be used to treat an epileptic encephalopathy, wherein the subject has a mutation in one or more of the following genes: ALDH7A1, ALG13, ARHGEF9, ARX, ASAHI, CACNA1G, CDKL5, CHD2, CHRNA2, CHRNA4, CHRNB2, CLN8, CNTNAP2, CPA6, CSTB, DEPDC5, DNM1, EEF1A2, EPM2A, EPM2B, GABRA1, GABRA2, GABRB3, GABRG2, GNA01, GOSR2, GRIK1, GRIN1, GRIN2A, GRIN2B, HCN1, IER3IP1, KCN1A, KCNA2, KCNB1, KCNC1, KCNMA1, KCNN2, KCNQ2, KCNQ3, KCNT1, KCTD7, LGI1, MEF2C, NHLRC1, PCDH7, PCDH19, PLCB1, PNKP, PNPO, PRICKLEI, PRICKLE2, PRRT2, RELN, SCARB2, SCN1A, SCN1B, SCN2A, SCN8A, SCN9A, SHANK3, SIAT9, SIK1, SLC13A5, SLC25A22, SLC2A1, SLC35A2, SLC6A1, SNIP1, SPTAN1, SRPX2, ST3GAL3, STRADA, STX1B, STXBP1, SYN1, SYNGAP1, SZT2, TBC1D24, TRIM3, UNC79, and WWOX.

[0104] In some embodiments, the methods described herein further comprise identifying a subject having a mutation in one or more of ALDH7A1, ALG13, ARHGEF9, ARX, ASAHI, CACNA1G, CDKL5, CHD2, CHRNA2, CHRNA4, CHRNB2, CLN8, CNTNAP2, CPA6, CSTB, DEPDC5, DNM1, EEF1A2, EPM2A, EPM2B, GABRA1, GABRA2, GABRB3, GABRG2, GNA01, GOSR2, GRIK1, GRIN1, GRIN2A, GRIN2B, HCN1, IER3IP1, KCN1A, KCNA2, KCNB1, KCNC1, KCNMA1, KCNN2, KCNQ2, KCNQ3, KCNT1, KCTD7, LGH, MEF2C, NHLRC1, PCDH7, PCDH19, PLCB1, PNKP, PNPO, PRICKLEI, PRICKLE2, PRRT2, RELN, SCARB2, SCN1A, SCN1B, SCN2A, SCN8A, SCN9A, SHANK3, SIAT9, SIK1, SLC13A5, SLC25A22, SLC2A1, SLC35A2, SLC6A1, SNIP1, SPTAN1, SRPX2, ST3GAL3, STRADA, STX1B, STXBP1, SYN1, SYNGAP1, SZT2, TBC1D24, TRIM3, UNC79, and WWOX prior to administration of Compound 1 or a pharmaceutically acceptable salt thereof disclosed herein, or pharmaceutical compositions comprising the same.

[0105] Compound 1 or a pharmaceutically acceptable salt thereof disclosed herein, or pharmaceutical compositions comprising the same may also be used in methods for ameliorating at least one symptom or hallmark of epilepsy or epilepsy syndrome, including, for example, early-onset DEE, in a subject in need thereof. In certain embodiments, the symptom or hallmark includes one or more of seizures, hypotonia, sensory issues, such as sensory integration disorders, motor dysfunctions, intellectual and cognitive dysfunctions, movement and balance dysfunctions, such as choreoathetosis, dystonia, and ataxia, anxiety, sensory issues, urinary retention problems, irritability, behavior issues, visual dysfunctions, delayed language and speech, gastrointestinal disorders (for example, gastroesophageal reflux, diarrhea, constipation, dysmotility, and the like), neurodevelopmental delays, sleep problems, sudden unexpected death in epilepsy (SUDEP), motor development delays, delayed social milestones, repetitive actions, uncoordinated oral movements. In certain embodiments, the seizures include focal, clonic, tonic, and generalized tonic and clonic seizures, prolonged seizures (often lasting longer than 10 minutes), and frequent seizures (for example, convulsive, myoclonic, absence, focal, obtundation status, and tonic seizures).

[0106] In one aspect, the disclosure provides a method of ameliorating at least one symptom or hallmark of epilepsy or epilepsy syndrome, including, for example, focal epilepsy, the method comprising administering to a subject in need thereof Compound 1, or a pharmaceutically acceptable salt thereof disclosed herein, or pharmaceutical compositions comprising the same. In certain embodiments, the symptom or hallmark includes one or more of seizures, hypotonia, sensory issues, such as sensory integration disorders, motor dysfunctions, intellectual and cognitive dysfunctions, movement and balance dysfunctions, such as choreoathetosis, dystonia, and ataxia, anxiety, sensory issues, urinary retention problems, irritability, behavior issues, visual dysfunctions, delayed language and speech, gastrointestinal disorders (for example, gastroesophageal reflux, diarrhea, constipation, dysmotility, and the like), neurodevelopmental delays, sleep problems, sudden unexpected death in epilepsy (SUDEP), motor development delays, delayed social milestones, repetitive actions, uncoordinated oral movements. In certain embodiments, the seizures include focal, clonic, tonic, and generalized tonic and clonic seizures, prolonged seizures (often lasting longer than 10 minutes), and frequent seizures (for example, convulsive, myoclonic, absence, focal, obtundation status, and tonic seizures).

[0107] In some aspects, the present disclosure provides a method of reducing severity, number and / or frequency of seizures in a subject in need thereof that comprises administering to the subject an effective amount of Compound 1, or a pharmaceutically acceptable salt thereof. In some embodiments, the subject has epilepsy or an epilepsy syndrome. In some embodiments, the subject has focal epilepsy.

[0108] In some embodiments, provided herein is a method of treating a neurological disorder or a psychiatric disorder, wherein the method comprises administering to a subject in need thereof Compound 1 or a pharmaceutically acceptable salt thereof disclosed herein, or pharmaceutical compositions comprising the same.

[0109] Compound was previously shown to preferentially inhibit persistent sodium current (iNa) over peak sodium current (IN3) in neurons. Specifically, as described in PCT / US2024 / 017962, the entire contents of which are hereby incorporated herein by reference, Compound 1 exhibited preference for inhibiting persistent over peak sodium current Specifically, Compound 1 inhibited persistent Ixa in hNavl.6, and exhibited preference for the inhibition of persistent Ixaas compared to the inhibition of peak IN3, with the ratio of peak IN3to persistent Ixabeing 68. In contrast, standard-of-care anti-epileptic drugs (AEDs) exhibited less preference for the inhibition of persistent Ixaas compared to the inhibition of peak IN3, with the ratio of peak IN3to persistent Ixabeing less than 68. Specifically, the ratio of peak to persistent Ixafor various AEDs was 24 (cenobamate), 30 (carbamazepine), 8 (oxcarbazepine) and 16 (lamotrigine). Preferential inhibition of persistent Ixa over peak I may be associated with improved tolerability of Compound 1.

[0110] In various embodiments, a method of treatment provided herein yields benefits over any other therapy, such as for example benefits over a standard-of-care therapy. In some embodiments, a method herein provides increased selectivity for a hyperexcitable neuronal state, spares normal neuronal function, or provides a wider therapeutic window than another therapy.

[0111] In some embodiments, methods of treating a condition relating to aberrant function of a sodium ion channel in a subject, such as epilepsy or an epilepsy syndrome, provided by the present disclosure achieve at least a partial suppression of PPR response in the subject. Suppression of PPR has emerged over the past several decades as a valuable translation tool in early clinical development for the assessment of potential anti-seizure drugs (ASDs) with a variety of mechanisms of action.

[0112] Visual sensitive epilepsy is a reflex type of epilepsy; the epileptogenic reaction can be evoked systematically at any time in response to flashing lights (Kasteleijn et al., Adv Neurol. 1998;75:99-121). Photosensitivity, defined as a generalized epileptiform reaction elicited by IPS, is found in approximately 5% of all epileptic patients. Although most prevalent in idiopathic generalized epilepsies, photosensitivity may also be present in other types of epilepsy and most notably in specific genetically determined syndromes, like Dravet syndrome (Wolf et al., J Neurol Neurosurg Psychiatry, 1986;49: 1386-91; Verbeek el al., Clin Neurophysiol. 2017;128:323-30, Verbeek et al., Epilepsy Behav . 2015;47:39-44). Markedly visual sensitive patients are usually sensitive to IPS within clearly defined limits of flash frequency (mostly between 10-30 Hz). This photosensitivity range, the difference between the highest and lowest flash rates that consistently elicit a PPR, can be used as a quantitative measure of photosensitivity and, therefore, epileptogenicity (Jeavons and Harding, Photosensitive epilepsy. London: Heinemann. 1975). The photosensitivity range is related to the liability of visually induced seizures in daily life and is remarkably stable under controlled conditions. Previous studies show that the administration of marketed and experimental ASD, either in a single or repeated dose regimen, can have an impact on the PPR, diminishing or even abolishing the response to IPS (Kasteleijn et al., Epilepsia 1992;33 : 135-41). In summary, valuable preliminary information can be obtained using the PPR model.

[0113] In some embodiments, Compound 1, or a pharmaceutically acceptable salt thereof, may be administered to a subject in the context of the present disclosure at a dose of about 10 mg to about 45 mg, e.g., about 10 mg, about 15 mg, about 20 mg, about 25 mg, about 30 mg, about 35 mg, about 40 mg or about 45 mg. In some embodiments, Compound 1, or a pharmaceutically acceptable salt thereof, may be administered to a subject in the context of the present disclosure at a dose of about 10 mg to about 30 mg. In some embodiments, Compound 1, or a pharmaceutically acceptable salt thereof, may be administered to a subject once daily at a dose of about 10 mg to about 45 mg, e.g., about 10 mg, about 15 mg, about 20 mg, about 25 mg, about 30 mg, about 35 mg, about 40 mg or about 45 mg. In some embodiments, Compound 1, or a pharmaceutically acceptable salt thereof, may be administered to a subject once daily at a dose of about 10 mg to about 30 mg.

[0114] In some embodiments, Compound 1, or a pharmaceutically acceptable salt thereof, may be administered to a subject once daily with or without titration at a dose of about 10 mg to about 45 mg, e.g., about 10 mg, about 15 mg, about 20 mg, about 25 mg, about 30 mg, about 35 mg, about 40 mg or about 45 mg. In some embodiments, Compound 1, or a pharmaceutically acceptable salt thereof, may be administered to a subject once daily with or without titration at a dose of about 10 mg to about 30 mg.

[0115] In some embodiments, administration of Compound 1, or a pharmaceutically acceptable salt thereof, to a subject allows achieving therapeutic concentrations of Compound 1 about 4 hours, about 8 hours, about 12 hours, about 16 hours, about 20 hours or about 24 hours after first administration, e.g., when Compound 1, or a pharmaceutically acceptable salt thereof, is administered at a dose of about 10 mg to about 45 mg, e.g., about 10 mg, about 15 mg, about 20 mg, about 25 mg, about 30 mg, about 35 mg, about 40 mg or about 45 mg. In some embodiments, administration of Compound 1, or a pharmaceutically acceptable salt thereof, to a subject allows achieving therapeutic concentrations of Compound 1 about 4 hours, about 8 hours, about 12 hours, about 16 hours, about 20 hours or about 24 hours after first administration, e.g., when Compound 1, or a pharmaceutically acceptable salt thereof, is administered at a dose of about 10 mg to about 30 mg.

[0116] In some embodiments, administration of Compound 1, or a pharmaceutically acceptable salt thereof, allows exceeding therapeutic concentrations of Compound 1, or a pharmaceutically acceptable salt thereof, in a subject, while Compound 1, or a pharmaceutically acceptable salt thereof, is well tolerated by the subject. In some embodiments, administration of Compound 1, or a pharmaceutically acceptable salt thereof, allows exceeding therapeutic concentrations of Compound 1, or a pharmaceutically acceptable salt thereof, in a subject, while Compound 1, or a pharmaceutically acceptable salt thereof, is well tolerated by the subject with titration or without titration.

[0117] In some embodiments, Compound 1, or a pharmaceutically acceptable salt thereof, is administered to a subject at a dose of about 10 mg to about 45 mg, e.g., about 10 mg, about 15 mg, about 20 mg, about 25 mg, about 30 mg, about 35 mg, about 40 mg or about 45 mg, e.g., once daily, with titration or without titration. In some embodiments, Compound 1, or a pharmaceutically acceptable salt thereof, is administered to a subject at a dose of about 10 mg to about 30 mg, e.g., once daily, with titration or without titration.

[0118] In some embodiments, Compound 1, or a pharmaceutically acceptable salt thereof, is administered to a subject, e.g., once daily, without titration. In some embodiments, Compound 1, or a pharmaceutically acceptable salt thereof, is administered to a subject, e.g., at a dose of about 10 mg to about 45 mg, e.g., about 10 mg, about 15 mg, about 20 mg, about 25 mg, about 30 mg, about 35 mg, about 40 mg or about 45 mg, without titration. In some embodiments, Compound 1, or a pharmaceutically acceptable salt thereof, is administered to a subject, e.g., at a dose of about 10 mg to about 30 mg, without titration. In some embodiments, Compound 1, or a pharmaceutically acceptable salt thereof, is administered to a subject, e.g., once daily at a dose of about 10 mg to about 45 mg, e.g., about 10 mg, about 15 mg, about 20 mg, about 25 mg, about 30 mg, about 35 mg, about 40 mg or about 45 mg, without titration. In some embodiments, Compound 1, or a pharmaceutically acceptable salt thereof, is administered to a subject, e.g., once daily at a dose of about 10 mg to about 30 mg, without titration.

[0119] In any of the methods disclosed herein, Compound 1 or a pharmaceutically acceptable salt thereof disclosed herein, or pharmaceutical compositions comprising the same, is administered to the subject in an effective amount, which is an amount sufficient to elicit the desired biological response. An effective amount encompasses a therapeutically effective amount, which is an amount sufficient to provide a therapeutic benefit in the treatment of a disease, disorder or condition, or to delay or minimize one or more symptoms associated with the disease, disorder or condition. An effective amount also encompasses a prophylactically effective amount. In some embodiments, Compound 1 or a pharmaceutically acceptable salt thereof disclosed herein, or pharmaceutical compositions comprising the same is administered to the subject in an amount ranging from about 0.1 mg / kg to about 1 g / kg, such as from about 0.1 mg / kg to about 10 mg / kg, from about 0.1 mg / kg to about 5 mg / kg, from about 0.1 mg / kg to about 2.5 mg / kg, from about 0.1 mg / kg to about 1.5 mg / kg, from about 0.2 mg / kg to about 15 mg / kg, from about 0.2 mg / kg to about 5 mg / kg, from about 0.5 mg / kg to about 20 mg / kg, from about 0.5 mg / kg to about 10 mg / kg, or from about 0.5 mg / kg to about 5 mg / kg. In some embodiments, Compound 1 or a pharmaceutically acceptable salt thereof disclosed herein, or pharmaceutical compositions comprising the same is administered to the subject in an amount ranging from about 10 mg / kg to about 100 mg / kg, such as about 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95 or 100 mg / kg.

[0120] In some embodiments, Compound 1 or a pharmaceutically acceptable salt thereof disclosed herein, or pharmaceutical compositions comprising the same is administered to the subject as a single dose in an amount ranging from about 1 mg to about 180 mg or from about 2.5 mg to about 150 mg, such as about 1 mg, about 2 mg, about 3 mg, about 5 mg, about 10 mg, about 15 mg, about 20 mg, about 25 mg, about 30 mg, about 35 mg, about 40 mg, about 45 mg, about 50 mg, about 55 mg, about 60 mg, about 65 mg, about 70 mg, about 75 mg, about 80 mg, about 85 mg, about 90 mg, about 95 mg, about 100 mg, about 105 mg, about 110 mg, about 115 mg, about 120 mg, about 125 mg, about 130 mg, about 135 mg, about 140 mg, about 145 mg, or about 150 mg. In some embodiments, Compound 1 or a pharmaceutically acceptable salt thereof disclosed herein, or pharmaceutical compositions comprising the same is administered to the subject as a single dose in an amount of about 0.1 mg to about 500 mg (e.g., from about 0.5 mg to about 200 mg, from about 1 mg to about 150 mg, from about 5 mg to about 130 mg, or from about 10 mg to about 120 mg). In some embodiments, Compound 1 or a pharmaceutically acceptable salt thereof disclosed herein, or pharmaceutical compositions comprising the same is administered to the subject as a single dose in an amount of up to 150 mg, such as from about 30 mg to about 120 mg, such as about 30 mg, about 35 mg, about 40 mg, about 45 mg, about 50 mg, about 55 mg, about 60 mg, about 65 mg, about 70 mg, about 75 mg, about 80 mg, about 85 mg, about 90 mg, about 95 mg, about 100 mg, about 105 mg, about 110 mg, about 115 mg, or about 120 mg. In some embodiments, Compound 1 or a pharmaceutically acceptable salt thereof disclosed herein, or pharmaceutical compositions comprising the same is administered to the subject as a single dose in an amount of about 90 mg or about 120 mg. In some embodiments, the dose is an oral dose.

[0121] In some embodiments, Compound 1 or a pharmaceutically acceptable salt thereof disclosed herein, or pharmaceutical compositions comprising the same is administered to the subject as multiple doses, with a maximum dose in an amount ranging from about 10 mg to about 150 mg, such as about 10 mg, 15 mg, 20 mg, 25 mg, 30 mg, about 35 mg, about 40 mg, about 45 mg, about 50 mg, about 55 mg, about 60 mg, about 65 mg, about 70 mg, about 75 mg, about 80 mg, about 85 mg, about 90 mg, about 95 mg, about 100 mg, about 105 mg, about 110 mg, about 115 mg, about 120 mg, about 125 mg, about 130 mg, about 135 mg, about 140 mg, about 145 mg, or about 150 mg. In some embodiments, Compound 1 or a pharmaceutically acceptable salt thereof disclosed herein, or pharmaceutical compositions comprising the same is administered to the subject as multiple doses, with a maximum dose in an amount of about 10 mg, about 15 mg, about 20 mg, about 25 mg, about 30 mg, about 35 mg, about 40 mg, about 45 mg, about 50 mg, about 55 mg, 60 mg, about 75 mg, about 90 mg or about 120 mg.

[0122] In some embodiments, Compound 1 or a pharmaceutically acceptable salt thereof disclosed herein, or pharmaceutical compositions comprising the same is administered to the subject orally. In some embodiments, Compound 1 or a pharmaceutically acceptable salt thereof disclosed herein, or pharmaceutical compositions comprising the same is administered to the subject every day. In some embodiments, Compound 1 or a pharmaceutically acceptable salt thereof disclosed herein, or pharmaceutical compositions comprising the same is administered to the subject every day for at least 14 days. In some embodiments, Compound 1 or a pharmaceutically acceptable salt thereof disclosed herein, or pharmaceutical compositions comprising the same is administered to the subject in ascending doses, with a starting dose of about 5 mg to about 150 mg., e.g., about 5 mg to about 25 mg, about 20 mg to about 100 mg, such as about 5 mg, about 10 mg, about 15 mg, about 20 mg, about 25 mg, about 30 mg, about 35 mg, about 40 mg, about 45 mg, about 50 mg, about 55 mg, about 60 mg, about 65 mg, about 70 mg, about 75 mg, about 80 mg, about 85 mg, about 90 mg, about 95 mg, about 100 mg, about 105 mg, about 110 mg, about 115 mg, about 120 mg, about 125 mg, about 130 mg, about 135 mg, about 140 mg, about 145 mg or about 150 mg.

[0123] In some embodiments, Compound 1 or a pharmaceutically acceptable salt thereof disclosed herein, or pharmaceutical compositions comprising the same is administered to the subject in a fasted state, such as more than about 10 hours after the last meal and / or at least about 4 hours before the next meal. In some embodiments, Compound 1 or a pharmaceutically acceptable salt thereof disclosed herein, or pharmaceutical compositions comprising the same is administered to the subject in a fed state, such as after a meal normally consumed by the subject, including but is not limited to a high-fat and high calorie meal. In other embodiments, Compound 1 or a pharmaceutically acceptable salt thereof disclosed herein, or a pharmaceutical composition comprising the same is administered to a subject in either a fasted or fed state without regard to a food effect. In some embodiments, Compound 1 may have no food effect. In other embodiments, Compound 1 may have a minimal food effect, such that administration is without regard to food.

[0124] In some embodiments, Compound 1 or a pharmaceutically acceptable salt thereof disclosed herein, or pharmaceutical compositions comprising the same is administered without regard to any concomitant condition or medication affecting a subject’s heart. In other embodiments, Compound 1 or a pharmaceutically acceptable salt thereof disclosed herein, or pharmaceutical compositions comprising the same is administered without regard to any condition or medication affecting HR, PR, QRS or QT interval.

[0125] In some embodiments, Compound 1 or a pharmaceutically acceptable salt thereof disclosed herein, or pharmaceutical compositions comprising the same is orally administered to the subject in an amount effective to achieve a maximum plasma concentration (tmax) between about 1.5 to about 5 hours, such as about 1.5 to about 4 hours, about 2.5 to about 5 hours, about 2.5 to about 4 hours, about 2 to about 4 hours, or about 2 to about 3 hours.

[0126] In some embodiments, Compound 1 or a pharmaceutically acceptable salt thereof disclosed herein, or pharmaceutical compositions comprising the same is orally administered to the subject in an amount effective to achieve plasma TCso (time to 50% of Compound 1 plasma concentration at plateau) of from about 1500 ng / g to about 800 ng / g, such as from about 1400 ng / g to about 900 ng / g, from about 1300 ng / g to about 1000 ng / g, from about 1200 ng / g to about 1100 ng / g, or from about 1150 ng / g to about 1100 ng / g. In some embodiments, Compound 1 or a pharmaceutically acceptable salt thereof disclosed herein, or pharmaceutical compositions comprising the same is orally administered to the subject in an amount effective to achieve plasma TCso of about 1500 ng / g, about 1400 ng / g, about 1350 ng / g, about 1300 ng / g, about 1250 ng / g, about 1200 ng / g, about 1150 ng / g, about 1100 ng / g, about 1050 ng / g, about 1000 ng / g, about 900 ng / g, about 950 ng / g, about 900 ng / g, about 850 ng / g, or about 800 ng / g.

[0127] In some embodiments, Compound 1 or a pharmaceutically acceptable salt thereof disclosed herein, or pharmaceutical compositions comprising the same is orally administered to the subject in an amount effective to achieve brain EC so (half maximal effective concentration of Compound 1) of from about 85 ng / g to about 50 ng / g, such as from about 85 ng / g to about 60 ng / g, from about 80 ng / g to about 65 ng / g, from about 75 ng / g to about 60 ng / g, from about 70 ng / g to about 60 ng / g, or from about 70 ng / g to about 65 ng / g. In some embodiments, Compound 1 or a pharmaceutically acceptable salt thereof disclosed herein, or pharmaceutical compositions comprising the same is orally administered to the subject in an amount effective to achieve brain ECso of about 85 ng / g, 80 ng / g, 75 ng / g, 70 ng / g, 65 ng / g, 60 ng / g, 55 ng / g, or 50 ng / g.

[0128] Combination Therapy

[0129] Compound 1 or a pharmaceutically acceptable salt thereof disclosed herein, or pharmaceutical compositions comprising the same may be administered in combination with another agent or therapy. A subject to be administered a compound disclosed herein may have a disease, disorder, or condition, or a symptom thereof, that would benefit from treatment with another agent or therapy. These diseases or conditions can relate to epilepsy or an epilepsy syndrome. In some embodiments, Compound 1 or a pharmaceutically acceptable salt thereof disclosed herein, or pharmaceutical compositions comprising the same is administered in combination with an anti -epilepsy agent. Anti-epilepsy agents include, but not limited to, brivaracetam, carbamazepine, clobazam, clonazepam, diazepam, divalproex, eslicarbazepine, ethosuximide, ezogabine, felbamate, gabapentin, lacosamide, lamotrigine, levetiracetam, lorazepam, oxcarbezepine, permpanel, phenobarbital, phenytoin, pregabalin, primidone, rufinamide, tigabine, topiramate, valproic acid, vigabatrin, zonisamide, and cannabidiol. In some embodiments, Compound 1 or a pharmaceutically acceptable salt thereof disclosed herein, or pharmaceutical compositions comprising the same is administered in combination with carbamazepine.

[0130] In some embodiments, the disclosed methods comprise administering to the subject in need thereof Compound 1 or a pharmaceutically acceptable salt thereof disclosed herein, or pharmaceutical compositions comprising the same in combination with an anti-epilepsy agent. In some embodiments, the disclosed methods comprise administering to the subject in need thereof Compound 1 or a pharmaceutically acceptable salt thereof disclosed herein, or pharmaceutical compositions comprising the same in combination with carbamazepine.

[0131] Accordingly, one aspect of the disclosure provides for a composition comprising Compound 1 or a pharmaceutically acceptable salt thereof disclosed herein and at least one additional therapeutic agent. In some embodiments, the composition comprises Compound 1 or a pharmaceutically acceptable salt thereof disclosed herein and at least two additional therapeutic agents. In some embodiments, the composition comprises Compound 1 or a pharmaceutically acceptable salt thereof disclosed herein and at least three additional therapeutic agents, Compound 1 or a pharmaceutically acceptable salt thereof disclosed herein and at least four additional therapeutic agents, or Compound 1 or a pharmaceutically acceptable salt thereof disclosed herein and at least five additional therapeutic agents.

[0132] The methods of combination therapy include co-administration of a single formulation containing Compound 1 or a pharmaceutically acceptable salt thereof disclosed herein and additional therapeutic agent or agents, essentially contemporaneous administration of more than one formulation comprising Compound 1 or a pharmaceutically acceptable salt thereof disclosed herein and additional therapeutic agent or agents, and consecutive administration of Compound 1 or a pharmaceutically acceptable salt thereof disclosed herein and therapeutic agent or agents, in any order, wherein preferably there is a time period where Compound 1 or a pharmaceutically acceptable salt thereof disclosed herein and additional therapeutic agent or agents simultaneously exert a therapeutic effect.

[0133] Dosage Forms and Compositions

[0134] In one aspect, the disclosure provides dosage forms or compositions useful for treating a disease, disorder, or condition described herein, e.g., a neurological disorder, a disorder associated with excessive neuronal excitability, or a disorder associated with de novo gain-of-function or loss-of-function mutations in major central nervous system sodium channel genes, such as for example, SCN1A, SCN2A, and SCN8A.

[0135] Accordingly, the disclosure provides pharmaceutical compositions that contain, as the active ingredient, Compound 1 or a pharmaceutically acceptable salt thereof disclosed herein and one or more pharmaceutically acceptable excipients, carriers, including inert solid diluents and fillers, diluents, including sterile aqueous solution and various organic solvents, permeation enhancers, solubilizers and adjuvants. The pharmaceutical compositions may be administered alone or in combination with other therapeutic agents. Such compositions are prepared in a manner well known in the pharmaceutical art (see, e.g., Remington’s Pharmaceutical Sciences, Mace Publishing Co., Philadelphia, Pa. 17th Ed. (1985); and Modem Pharmaceutics, Marcel Dekker, Inc. 3rd Ed. (G. S. Banker & C. T. Rhodes, Eds.).

[0136] The pharmaceutical compositions may be administered in either single or multiple doses by any of the accepted modes of administration of agents having similar utilities, for example as described in those patents and patent applications incorporated by reference, including rectal, buccal, intranasal and transdermal routes, by intra-arterial injection, intravenously, intraperitoneally, parenterally, intramuscularly, subcutaneously, orally, topically, as an inhalant, or via an impregnated or coated device such as a stent, for example, or an artery-inserted cylindrical polymer. In some embodiments, the compounds or pharmaceutical compositions of the disclosure are administered orally.

[0137] One mode for administration is parenteral, particularly by injection. The forms in which the compositions of the disclosure may be incorporated for administration by injection include aqueous or oil suspensions, or emulsions, with sesame oil, corn oil, cottonseed oil, or peanut oil, as well as elixirs, mannitol, dextrose, or a sterile aqueous solution, and similar pharmaceutical vehicles. Aqueous solutions in saline are also conventionally used for injection, but less preferred in the context of the present invention. Ethanol, glycerol, propylene glycol, liquid polyethylene glycol, and the like (and suitable mixtures thereof), cyclodextrin derivatives, and vegetable oils may also be employed. The proper fluidity can be maintained, for example, by the use of a coating, such as lecithin, by the maintenance of the required particle size in the case of dispersion and by the use of surfactants. The prevention of the action of microorganisms can be brought about by various antibacterial and antifungal agents, for example, parabens, chlorobutanol, phenol, sorbic acid, thimerosal, and the like.

[0138] Sterile injectable solutions are prepared by incorporating a compound according to the present invention in the required amount in the appropriate solvent with various other ingredients as enumerated above, as required, followed by filtered sterilization. Generally, dispersions are prepared by incorporating the various sterilized active ingredients into a sterile vehicle which contains the basic dispersion medium and the required other ingredients from those enumerated above. In the case of sterile powders for the preparation of sterile injectable solutions, the preferred methods of preparation are vacuum-drying and freeze- drying techniques which yield a powder of the active ingredient plus any additional desired ingredient from a previously sterile-filtered solution thereof.

[0139] Oral administration is another route for administration of compounds in accordance with the present disclosure. Administration may be via capsule or tablets, or the like. In making the pharmaceutical compositions that include at least one compound described herein, the active ingredient is usually diluted by an excipient and / or enclosed within such a carrier that can be in the form of a capsule, sachet, paper or other container. When the excipient serves as a diluent, it can be in the form of a solid, semi-solid, or liquid material (as above), which acts as a vehicle, carrier or medium for the active ingredient. Thus, the compositions can be in the form of tablets, pills, powders, lozenges, sachets, cachets, elixirs, suspensions, emulsions, solutions, syrups, aerosols (as a solid or in a liquid medium), ointments containing, for example, up to 10% by weight of the active compound, soft and hard gelatin capsules, sterile injectable solutions, and sterile packaged powders.

[0140] Some examples of suitable excipients include lactose, dextrose, sucrose, sorbitol, mannitol, starches, gum acacia, calcium phosphate, alginates, tragacanth, gelatin, calcium silicate, microcrystalline cellulose, polyvinylpyrrolidone, cellulose, sterile water, syrup, and methyl cellulose. The formulations can additionally include lubricating agents such as talc, magnesium stearate, and mineral oil; wetting agents; emulsifying and suspending agents; preserving agents such as methyl and propylhydroxy-benzoates; sweetening agents; and flavoring agents.

[0141] The compositions of the disclosure can be formulated so as to provide quick, sustained or delayed release of the active ingredient after administration to the patient by employing procedures known in the art. Controlled release drug delivery systems for oral administration include osmotic pump systems and dissolutional systems containing polymer- coated reservoirs or drug-polymer matrix formulations. Examples of controlled release systems are given in U.S. Pat. Nos. 3,845,770; 4,326,525; 4,902,514; and 5,616,345. Another formulation for use in the methods of the present invention employs transdermal delivery devices (“patches”). Such transdermal patches may be used to provide continuous or discontinuous infusion of the compounds of the present invention in controlled amounts. The construction and use of transdermal patches for the delivery of pharmaceutical agents is well known in the art. See, e.g., U.S. Pat. Nos. 5,023,252, 4,992,445 and 5,001,139. Such patches may be constructed for continuous, pulsatile, or on demand delivery of pharmaceutical agents.

[0142] The compositions are preferably formulated in a unit dosage form. The term “unit dosage forms” refers to physically discrete units suitable as unitary dosages for human subjects and other mammals, each unit containing a predetermined quantity of active material calculated to produce the desired therapeutic effect, in association with a suitable pharmaceutical excipient (e.g., a tablet, capsule, ampoule). The compounds are generally administered in a pharmaceutically effective amount. Preferably, for oral administration, each dosage unit contains from about 1 mg to about 2 g of a compound described herein, and for parenteral administration, preferably from about 0.1 to about 700 mg of a compound described herein. It will be understood, however, that the amount of the compound actually administered usually will be determined by a physician, in the light of the relevant circumstances, including the condition to be treated, the chosen route of administration, the actual compound administered and its relative activity, the age, weight, and response of the individual subject, the severity of the subject's symptoms, and the like.

[0143] For preparing solid compositions such as tablets, the principal active ingredient is mixed with a pharmaceutical excipient to form a solid preformulation composition containing a homogeneous mixture of a compound of the present invention. When referring to these preformulation compositions as homogeneous, it is meant that the active ingredient is dispersed evenly throughout the composition so that the composition may be readily subdivided into equally effective unit dosage forms such as tablets, pills and capsules.

[0144] The tablets or pills of the present disclosure may be coated or otherwise compounded to provide a dosage form affording the advantage of prolonged action, or to protect from the acid conditions of the stomach. For example, the tablet or pill can comprise an inner dosage and an outer dosage component, the latter being in the form of an envelope over the former. The two components can be separated by an enteric layer that serves to resist disintegration in the stomach and permit the inner component to pass intact into the duodenum or to be delayed in release. A variety of materials can be used for such enteric layers or coatings, such materials including a number of polymeric acids and mixtures of polymeric acids with such materials as shellac, cetyl alcohol, and cellulose acetate.

[0145] Compositions for inhalation or insufflation include solutions and suspensions in pharmaceutically acceptable, aqueous or organic solvents, or mixtures thereof, and powders. The liquid or solid compositions may contain suitable pharmaceutically acceptable excipients as described supra. Preferably, the compositions are administered by the oral or nasal respiratory route for local or systemic effect. Compositions in preferably pharmaceutically acceptable solvents may be nebulized by use of inert gases. Nebulized solutions may be inhaled directly from the nebulizing device or the nebulizing device may be attached to a facemask tent, or intermittent positive pressure breathing machine. Solution, suspension, or powder compositions may be administered, preferably orally or nasally, from devices that deliver the formulation in an appropriate manner.

[0146] In one aspect, provided herein is a dosage form or a composition in a dosage form comprising: from about 0.1 mg to about 500 mg (e.g., from about 0.5 mg to about 200 mg, from about 1 mg to about 150 mg, from about 10 mg to about 120 mg) of Compound 1 or a pharmaceutically acceptable salt thereof disclosed herein and a pharmaceutically acceptable excipient.

[0147] In some embodiments, the dosage form or a composition in a dosage form comprises from about 2.5 mg to about 150 mg (e.g., from about 10 mg to about 150 mg, from about 20 mg to about 150 mg, from about 40 mg to about 150 mg, from about 60 mg to about 150 mg, from about 80 mg to about 150 mg, from about 100 mg to about 150 mg, from about 10 mg to about 120 mg, from about 20 mg to about 120 mg, from about 40 mg to about 120 mg, from about 60 mg to about 120 mg, from about 80 mg to about 120 mg, from about 100 mg to about 120 mg, from about 10 mg to about 100 mg, from about 20 mg to about 100 mg, from about 40 mg to about 100 mg, from about 60 mg to about 100 mg, from about 80 mg to about 100 mg, from about 10 mg to about 80 mg, from about 20 mg to about 80 mg, from about 40 mg to about 80 mg, from about 60 mg to about 80 mg, from about 10 mg to about 60 mg, from about 20 mg to about 60 mg, from about 40 mg to about 60 mg, from about 70 mg to about 120 mg, from about 70 mg to about 100 mg, from about 50 mg to about 120 mg, from about 50 mg to 90 mg, from about 30 mg to about 120 mg, from about 30 mg to about 60 mg, from about 30 mg to about 80 mg, from about 30 mg to about 100 mg) of Compound 1 or a pharmaceutically acceptable salt thereof disclosed herein. In some embodiments, the dosage form is an oral dosage form.

[0148] In some embodiments, the dosage form or a composition in a dosage form comprises from about 1 mg to about 100 mg (e.g., 1 from about 1 mg to about 80 mg, from about 1 mg to about 50 mg, from about 1 mg to about 20 mg, from about 1 mg to about 10 mg, from about 1 mg to about mg, from about 5 mg to about 100 mg, from about 5 mg to about 80 mg, from about 5 mg to about 50 mg, from about 5 mg to about 20 mg) of Compound 1 or a pharmaceutically acceptable salt thereof disclosed herein.

[0149] In some embodiments, the dosage form or a composition in a dosage form comprises about 200 mg, 190 mg, 180 mg, 170 mg, 160 mg, 150 mg, 140 mg, 130 mg, 120 mg, 110 mg, 100 mg, about 99 mg, about 98 mg, about 97 mg, about 96 mg, about 95 mg, about 94 mg, about 93 mg, about 92 mg, about 91 mg, about 90 mg, about 85 mg, about 80 mg, about 75 mg, about 70 mg, about 69 mg, about 68 mg, about 67 mg, about 66 mg, about 65 mg, about 64 mg, about 63 mg, about 62 mg, about 61 mg, about 60 mg, about 59 mg, about 58 mg, about 57 mg, about 56 mg, about 55 mg, about 54 mg, about 53 mg, about 52 mg, about 51 mg, about 50 mg, about 45 mg, about 40 mg, about 35 mg, about 30 mg, about 25 mg, about 20 mg, about 15 mg, about 10 mg, about 7 mg, about 5 mg, about 2.5 mg, about 2 mg, about 1.5 mg, or about 1 mg of Compound 1 or a pharmaceutically acceptable salt thereof disclosed herein. In some embodiments, the dosage form or a composition in a dosage form is for oral administration.

[0150] In another aspect, the present disclosure provides a dosage form or a composition in a dosage form comprising: a plurality of particles of Compound 1 or a pharmaceutically acceptable salt thereof disclosed herein and a pharmaceutically acceptable excipient, wherein the amount of the plurality of particles of Compound 1 or a pharmaceutically acceptable salt thereof disclosed herein in the dosage form is from about 0.1 mg to about 500 mg (e.g., from about 0.5 mg to about 200 mg, from about 1 mg to about 150 mg, from about 10 mg to about 120 mg).

[0151] In some embodiments, the plurality of particles of Compound 1 or a pharmaceutically acceptable salt thereof disclosed herein in the dosage form or composition is from about 2.5 mg to about 150 mg (e.g., from about 10 mg to about 150 mg, from about 20 mg to about 150 mg, from about 70 mg to about 120 mg, from about 30 mg to about 60 mg, about 100 mg, about 50 mg).

[0152] In some embodiments, the dosage form or the composition is configured for oral administration. In some embodiments, the dosage form is a solid form. In some embodiments, the dosage form is in the form of a capsule. In some embodiments, the pharmaceutical excipient in the capsule is a filler (e.g., cellulose derivatives (e.g., microcrystalline cellulose), starches (e.g., hydrolyzed starches, and partially pregelatinized starches), anhydrous lactose, lactose monohydrate, sugar alcohols (e.g., sorbitol, xylitol, and mannitol).

[0153] In some embodiments, the dosage form is a liquid form. In some embodiments, the dosage form is in the form of a solution. In some embodiments, the pharmaceutical excipient in the solution is selected from the group consisting of a filler (e.g., polymer (e.g., PEG 400)), an emulsifier (e.g., a castor oil derivative (e.g., Kolliphor RH40), a surfactant (e.g., a glyceride (e.g., Labrafil M2125 CS), a vitamin derivative (e.g., Vitamin ETPGS)), a solvent (e.g., propylene glycol, ethanol, di ethylene glycol monoethyl ether (or Transcutol HP)).

[0154] In some embodiments, the concentration of Compound 1 or a pharmaceutically acceptable salt thereof disclosed herein in the solution is from about 0.1 mg / mL to about 10 mg / mL (e.g., from about 0.5 mg / mL to about 10 mg / mL, from about 1 mg / mL to about 10 mg / mL, from about 2 mg / mL to about 10 mg / mL, from about 3 mg / mL to about 10 mg / mL, from about 4 mg / mL to about 10 mg / mL, from about 5 mg / mL to about 10 mg / mL, from about 6 mg / mL to about 10 mg / mL, from about 0.1 mg / mL to about 8 mg / mL, from about 0.5 mg / mL to about 8 mg / mL, from about 1 mg / mL to about 8 mg / mL, from about 2 mg / mL to about 8 mg / mL, from about 3 mg / mL to about 8 mg / mL, from about 4 mg / mL to about 8 mg / mL, from about 5 mg / mL to about 8 mg / mL, from about 6 mg / mL to about 8 mg / mL, from about 0.5 mg / mL to about 6 mg / mL, from about 1 mg / mL to about 6 mg / mL, from about 2 mg / mL to about 6 mg / mL, from about 3 mg / mL to about 6 mg / mL, from about 4 mg / mL to about 6 mg / mL, from about 0.5 mg / mL to about 4 mg / mL, from about 1 mg / mL to about 4 mg / mL, or from about 2 mg / mL to about 4 mg / mL).

[0155] In some embodiments, the concentration of Compound 1 or a pharmaceutically acceptable salt thereof disclosed herein in the solution is about 0.1 mg / mL, about 0.5 mg / mL, about 1 mg / mL, about 2 mg / mL, about 3 mg / mL, about 4 mg / mL, about 5 mg / mL, about 6 mg / mL, about 7 mg / mL, about 8 mg / mL, about 9 mg / mL, or about 10 mg / mL.

[0156] In some embodiments, the dosage form is in the form of a suspension. In some embodiments, the concentration of Compound 1 or a pharmaceutically acceptable salt thereof disclosed herein in the suspension is about 0.1 mg / mL, about 0.5 mg / mL, about 1 mg / mL, about 1.5 mg / mL, about 2 mg / mL, about 2.5 mg / mL, about 3 mg / mL, about 3.5 mg / mL, about 4 mg / mL, about 4.5 mg / mL, about 5 mg / mL, about 6 mg / mL, about 7 mg / mL, about 8 mg / mL, about 9 mg / mL, about 10 mg / mL, about 11 mg / mL, about 12 mg / mL, about 13 mg / mL, about 14 mg / mL, about 15 mg / mL, about 20 mg / mL, about 25mg / mL.

[0157] In some embodiments, the concentration of Compound 1 or a pharmaceutically acceptable salt thereof disclosed herein in the suspension is from about 0.1 mg / mL to about 10 mg / mL (e.g., from about 0.5 mg / mL to about 10 mg / mL, from about 1 mg / mL to about 10 mg / mL, from about 2 mg / mL to about 10 mg / mL, from about 3 mg / mL to about 10 mg / mL, from about 4 mg / mL to about 10 mg / mL, from about 5 mg / mL to about 10 mg / mL, from about 6 mg / mL to about 10 mg / mL, from about 0.1 mg / mL to about 8 mg / mL, from about 0.5 mg / mL to about 8 mg / mL, from about 1 mg / mL to about 8 mg / mL, from about 2 mg / mL to about 8 mg / mL, from about 3 mg / mL to about 8 mg / mL, from about 4 mg / mL to about 8 mg / mL, from about 5 mg / mL to about 8 mg / mL, from about 6 mg / mL to about 8 mg / mL, from about 0.5 mg / mL to about 6 mg / mL, from about 1 mg / mL to about 6 mg / mL, from about 2 mg / mL to about 6 mg / mL, from about 3 mg / mL to about 6 mg / mL, from about 4 mg / mL to about 6 mg / mL, from about 0.5 mg / mL to about 4 mg / mL, from about 1 mg / mL to about 4 mg / mL, or from about 2 mg / mL to about 4 mg / mL).

[0158] EXAMPLES In order that the embodiments described herein may be more fully understood, the following examples are set forth. The examples described in this application are offered to illustrate the compounds, pharmaceutical compositions, and methods provided herein and are not to be construed in any way as limiting their scope.

[0159] Example 1. A phase 1 clinical trial to evaluate the safety, tolerability, pharmacokinetics and pharmacodynamics of single and multiple ascending doses of Compound 1 in healthy volunteers

[0160] This is a trial to assess the safety, tolerability, pharmacokinetics (PK), and pharmacodynamics (PD) of Compound 1 in healthy participants aged 18 to 55 years (inclusive). The trial is initially comprised of 2 parts, with 1 additional optional part, as follows:

[0161] • Part A is randomized, double-blinded, and placebo-controlled. Part A is designed to investigate the safety, PK, and PD of single ascending doses of Compound 1.

[0162] • Part B is randomized, double-blinded, and placebo-controlled. Part B is designed to investigate the safety, PK, and PD of multiple ascending doses (selected based on the results from Part A) of Compound 1.

[0163] • Part C is a randomized, open-label, crossover design food effect evaluation to investigate the PK of a single 30 mg dose of Compound 1 in the fasted and fed state.

[0164] Part B will commence following the completion of at least Cohort A3 in Part A. Parts A, B, and C may be conducted concurrently. Parts A and B are double blinded. Parts A, B, and C consist of 3 periods: Screening / Baseline, Intervention, and Safety Follow-up.

[0165] Safety and tolerability assessments for Parts A, B, and C will include vital signs, 12- lead ECGs, physical examinations, clinical laboratory tests, and the C-SSRS (for Part B).

[0166] Number of Participants

[0167] The planned number of participants is as follows:

[0168] Part A: Approximately 32, up to 56 participants (8 per cohort)

[0169] Part B: Approximately 24, up to 40 participants (8 per cohort) Part C: Approximately 16 participants being administered 30 mg of Compound 1 (3x 10 mg capsules).

[0170] The total number of planned participants across Parts A, B, and C is approximately 72, up to 112 depending on optional cohorts. Participants in Parts A and B may also participate in Part C provided there is sufficient washout between participation in study parts.

[0171] Duration of the clinical trial is outlined in the table below.

[0172] Objectives and endpoints for Part A of the clinical trial (single ascending dose) is outlined in the table below.

[0173] Baseline for PD measurements is defined as the average value prior to dosing in the morning of Day 1 for each treatment period.

[0174] Objectives and endpoints for Part C of the clinical trial (food effect) is outlined in the table below.

[0175] Screening / Baseline Period

[0176] The Screening period for all 3 parts will be up to 42 days in duration (Day -43 to Day -2). Prior to any clinical trial procedures, participants will provide written informed consent to participate in the trial. A full medical screening will be performed to assess a subject’s eligibility for this study. Following confirmation of continued eligibility, participants will check-in to the clinic at Baseline (Day -1; the day before study drug administration).

[0177] Intervention Period

[0178] In Parts A and B participants will remain in the unit from Baseline (Day -1) to Discharge (Day 3 in Part A, Day 11 in Part B). In Part C, participants will remain in the unit from Baseline (Day -1) to Day 3 (first dosing period) and Day 6 to Day 9 (second dosing period). In Part A, participants will return to the clinical research unit for safety and PK assessments on Day 4 and Day 6. In Part B, participants will return to the clinical research unit for safety and PK assessments on Day 13. In part C, participants will return to the clinical research unit for safety and PK assessments on Day 4 through Day 11. If participants experience any clinically significant AEs during the confinement period, they may remain in the clinical facility for further observation at the discretion of the principal investigator (PI), following consultation with the sponsor.

[0179] Part A (Single Ascending Dose)

[0180] Healthy participants will be enrolled to receive single ascending oral doses of Compound 1 or placebo on Day 1. FIG. 1A is an illustration of the dosing scheme for Part A (single ascending dose) of the trial. Dose escalation in Part A will initially be conducted in up to a total of 4 planned cohorts (Cohorts Al to A4). Following completion of Cohort A4, up to an additional 3 escalation cohorts may be added. Increment-based escalation will be used in these additional 3 cohorts, with a maximum increment of 3 -fold the highest prior dose tested (note: if the projected concentrations of Compound 1 are to exceed 415 ng / mL, the mouse sLMA ECso, a measure of tolerability, the dose increase increment will be <1.5-fold). Doses may be adjusted upward or downward based on safety, tolerability, and PK data from the preceding cohorts. Cohorts after A4 will be numbered sequentially (A5, A6, etc.). Dose escalation will be stopped if the mean AUCinf of the next dose is predicted to exceed an AUCinf of 7500 hr.ng / mL (half of the rat NOAEL) unless otherwise justified via a substantial amendment. Eight participants will be enrolled in each cohort and will be randomized to receive either Compound 1 or placebo in a 3: 1 ratio.

[0181] The dosing regimen for Part A is summarized in the table below. Compound 1 will be administered to Cohort Al participants at the starting dose of 5 mg. Dosing in all cohorts will start with 2 sentinel participants with 1 of the 2 participants randomized to receive Compound 1 and the other participant randomized to receive placebo. The safety and tolerability of each sentinel participant will be monitored until Day 2 and will be reviewed prior to dosing the remainder of participants in the cohort. The PI will review safety / tolerability information available on the sentinel participants on Day 2 and, with agreement from the sponsor, will make the decision to dose the remaining 6 participants in the cohort.

[0182] Cohorts will be dosed in an escalating order. After at least 6 out of 8 participants in each dose cohort has completed dosing, blinded cumulative safety data collected up to Day 4 (72 hours post-dose) and available blinded PK data will be reviewed by the safety review committee (SRC) to determine the safety and tolerability of the study drug. If the current dose level is determined to be safe and tolerated by the SRC, the next dose cohort will be randomized to receive the selected dose of active Compound 1 or placebo. Additional cohorts may be considered to accommodate dose repetition, dose reduction, or slower dose escalation than planned.

[0183] Part B (Multiple Ascending Dose)

[0184] Following evaluation of Compound 1 administered as a single dose through cohort A3 at a minimum in Part A, the study will commence evaluation of the safety, tolerability, PK and PD of Compound 1 in a multiple dosing schedule. FIG. IB is an illustration of the dosing scheme for Part B (multiple ascending dose) of the trial. The starting dose level in Part B will be determined based on safety, tolerability, and PK data obtained in Part A. Compound 1 dose levels to be evaluated in Part B will not exceed doses evaluated in Part A.

[0185] Cohorts will be numbered sequentially (Bl, B2, etc.) with a minimum of 3 cohorts and up to 2 additional cohorts (a maximum of 5 cohorts). Eight participants will be enrolled in each cohort and will be randomized to receive either Compound 1 or placebo in a 3 : 1 ratio.

[0186] The dosing regimen for Part B is summarized in the table below.

[0187] Healthy participants will be enrolled to receive multiple ascending oral doses of Compound 1 or placebo once daily. Dosing will commence on Day 1 and will continue until Day 10. The last dose will be administered on the morning of Day 10. Participants will be discharged from the clinical research unit 24 hours after the last dose administration.

[0188] After at least 6 out of 8 participants in each dose cohort in Part B have been dosed through Day 10, the blinded safety data (including safety assessments performed on Day 10) and available blinded PK data will be reviewed to determine the safety and tolerability of the study drug. If the current dose level is determined to be safe and tolerated, the next dose cohort will be randomized to receive the selected dose of active Compound 1 or placebo. Additional cohorts may be considered to accommodate dose repetition, dose reduction, or slower dose escalation than planned. In addition, the SRC may also consider additional cohorts in the event that the maximum exposure has not been reached with any of the planned dose levels and no stopping criteria have been met.

[0189] Part C (Food Effect Evaluation)

[0190] Initiation of Part C is optional, based on the results of Parts A and B. Part C may commence once the safety and PK of Compound 1 have been adequately evaluated in Part A (note: Parts A, B and C may be conducted concurrently). FIG. 1C is an illustration of the dosing scheme for Part C (food effect evaluation) of the trial. Approximately 16 participants will receive 2 oral doses of Compound 1, one dose after a minimum of 10 hours fasting and one after (dosing within 30 minutes) the consumption of a high-fat, high calorie meal in a randomized crossover design. Participants will stay in the clinical research unit from Day -1 to Day 3 for each separate dosing visit with a 7 day wash out. The 7-day wash out period is dependent on the PK data of Part A and B. Additional days of washout may be added between fasted and fed dosing based on the observed half-life in Part A. The dose to be used in Part C will not exceed 50% of the maximum dose achieved in Part A. Part C is not blinded and not placebo controlled. Safety Follow-up Period

[0191] Part A: Day 9 (±2 days)

[0192] Part B: Day 18 (±2 days)

[0193] Part C: Day 16 (±2 days)

[0194] Number of Participants

[0195] Eight participants per cohort are planned in Parts A and B. The total number of participants required will depend upon the number of escalation steps. The clinical trial is anticipated to include approximately 72, or up to 112 participants across all 3 parts (Parts A, B, and C). In Part A, approximately 32, or up to 56 participants are planned to be administered Compound 1 or placebo. In Part B, approximately 24, or up to 40 participants are planned to be administered Compound 1 or placebo. In Part C, up to 16 participants are planned to be administered Compound 1.

[0196] Clinical Trial Intervention

[0197] In part A of the trial, on the dosing day, a single ascending dose of Compound 1 (starting at 5 mg) or matching placebo will be administered orally (fasted) and provided in single dose containers to the participants.

[0198] In part B of the trial, on all dosing days, multiple ascending doses of Compound 1 (starting at a dose selected from Part A and up to the maximum dose studied in Part A) or matching placebo will be administered once daily orally (fasted) and provided in single dose containers to the participants.

[0199] In part C of the trial, on all dosing days, a 30 mg dose (3x 10 mg) of Compound 1 (dose selected from Part A) will be administered orally (either fasted or fed) and provided in single dose containers to the participants.

[0200] Preliminary Findings

[0201] Participants were randomized 3 : 1 to receive either Compound 1 or placebo in the fasted state, with SAD cohorts receiving single oral doses (5-45 mg) and MAD cohorts receiving multiple doses (20 and 30 mg for 10 days). Blood samples were collected for PK analysis. Safety and tolerability assessments included AE incidence and severity, vital signs, physical examinations, clinical lab tests and 12-lead ECGs including PK time-matched recordings up to 24h post-dose. ECG parameters included HR, PR, QRS, and QT. QTcF (calculated using Fridericia's method)6 and Bazett’s-corrected QT interval (QTcB)7 were derived.

[0202] A total of 40 participants completed the study (n=30 Compound 1, n=10 placebo). All 40 participants were included in safety and PK analysis sets. Demographics and other baseline characteristics were generally similar across groups. Overall, the majority of participants were white, and not Hispanic or Latino. Part B (MAD) had a higher percentage of males, while in Part A (SAD), the Compound 1 15-mg group had more males. Subsequently, 52 healthy participants completed Parts A (n=18), B (n=18) and C (n=16).

[0203] Compound 1 was observed to be safe and generally well tolerated in healthy participants at all single doses up to 45 mg tested in Part A of the trial. All treatment- emergent adverse events (TEAEs) reported thus far have been mild in severity, mostly transient and resolved without administration of concomitant medication. No severe TEAEs were reported. The most frequently reported TEAEs were headache and fatigue. No deaths or TEAEs leading to study drug discontinuation have been reported. No SAEs, clinically meaningful findings on laboratory test results, vital signs or neurological examination were observed. No safety findings were observed with regards to clinical laboratory test results, electrocardiograms (ECGs), and vital signs.

[0204] Specifically, cardiac safety assessments showed no clinically meaningful change in ECG parameters across all doses, with no dose-related trends observed. Concentration-QTc analysis demonstrated no discernible effect on the QT interval in SAD or MAD cohorts. Any reports of dizziness had no apparent temporal correlation with point of maximum change in QTcB, based on QTc interval categorical analyses. Cardiac safety assessments showed no clinically meaningful change in ECG parameters across all doses, with no dose-related trends. By-timepoint QTc analysis demonstrated no discernible effect on the QT interval in SAD or MAD cohorts (FIGs. 11A-11B).

[0205] Compound 1 was also observed to affect brain activity and to rapidly achieve therapeutic concentration. FIG. ID is a graph showing a composite change in qEEG score at different times post dose. The composite endpoint from qEEG showed separation of drug versus placebo in the SAD and MAD cohorts. The difference between Compound 1 and placebo was significant for all doses at the first point measured. The effect was consistent with known pharmacokinetic profile of Compound 1.

[0206] It was also observed that therapeutic concentrations of Compound 1 were achieved and sustained for a longer period of time, as compared to other anti-epileptic drugs. FIG. IE is a bar graph showing the period of time during which a therapeutic concentration is sustained after administration of 400 mg of cenobamate, 25 mg of XEN1101 and 30 mg of Compound 1 on day 1. The results shown in FIG. IE indicate that after administration of 30 mg of Compound 1 on day 1, therapeutic concentration is maintained for 23 hours. In contrast, therapeutic concentration is maintained for 0 hours after administration of 400 mg of cenobamate, and for 5 hours after administration of 25 mg of XEN1101.

[0207] Dosing of an additional 45 mg MAD cohort was also completed. The results from this cohort showed a dose proportional increase in exposure with excellent tolerability, similar to the 20 mg and 30 mg MAD cohorts.

[0208] Pharmacokinetic Findings

[0209] Pharmacokinetic data demonstrate dose-dependent exposure. Compound 1 rapidly appeared in plasma with median tmax 1.5-2.3 hours and a geometric mean half-life of 45-66 hours (MAD). In Part A (SAD), following single doses of 5 to 45 mg Compound 1, plasma concentrations were quantifiable throughout the dosing interval in all participants (FIG. 13). In Part B (MAD), following multiple oral doses of Compound 1 20 and 30 mg QD, there was an increase in exposure from Day 1 to Day 10 in all participants (FIG. 14). Concentrations which exceeded the human equivalent of mouse MES ECso were reached in all cohorts (FIGS. 13-14) In the SAD cohorts, average concentrations 2-4x the human equivalent MES ECso were maintained for 8 hours with a single dose of 15 mg. In the MAD cohorts, concentrations in excess of 15x the human equivalent MES EC50 were achieved at Cmax with average Ctrough around 3-5x the MES EC50 at steady-state.

[0210] Food Effect

[0211] The Part C (food effect) study demonstrated that food intake does not affect Compound 1 absorption and therefore there is no need to take Compound 1 with food, which increases flexibility in dosing and ease of use. As such, Compound 1 may be administered without regard to food intake, i.e., Compound 1 may be administered with food or without food.

[0212] In vitro Findings

[0213] FIG. 15 is a table showing an in vitro non-GLP safety pharmacology study evaluating the ability of lOmM Compound 1 to modulate recombinant, human non-INacardiac channels, stably expressed in either CHO or HEK293 cells. Data are mean ± SEM (n=3). SEM=standard error of the mean. Superscript “a” indicates statistically significant differences from control group as determined by one-way ANOVA with Dunnett’s Multiple Comparison Test. CaV=voltage-gated calcium channel; hERG=human ether-a-go-go-related gene; HCN=hyperpolarization-activated cyclic nucleotide-gated channel; Kir=inwardly-rectifying potassium channel; KV=voltage-gated potassium channel. Superscript “b” indicates that the ratio to target values are based on primary pharmacology studies for hNaV1.6 UDB-lOHz (IC50 0.2mM).

[0214] Conclusions

[0215] Compound 1 demonstrated a favorable safety and tolerability profile in healthy participants. Specifically, Compound 1 demonstrated consistent safety, tolerability and PK profiles, with no significant food effect. Food effect analysis revealed no clinically significant impact to Cmax or AUC at steady state. Preliminary cardiac safety findings show no adverse ECG effects. These results support flexible dosing regimes up to 45 mg in the ongoing Compound 1 ENERGY trial.

[0216] Building on preclinical work, these findings support once-daily dosing of Compound 1 without titration to achieve multiples of the predicted therapeutically effective concentrations based on MES. First-in-human results demonstrate that Compound 1 is effective for treating patients with focal onset seizures and generalized epilepsy.

[0217] Updated Findings

[0218] These updated findings are from Part B up to 45 mg, including food effect data from Part C.

[0219] Demographics Summary Compound 1 has been administered to 52 healthy participants in Parts A (n=18), B (n=18) and C (n=16). All participants were included in the Safety and PK analysis sets. Overall, the majority of participants were white, and not Hispanic or Latino. Demographics and other baseline characteristics were generally similar across treatment groups, except for a slightly higher percentage of males in Part B, and the majority of the Compound 1 15-mg group in Part A (SAD) being male.

[0220] PK Update: Part B (MAD), up to 45 mg

[0221] FIG. 16 is a graph showing geometric mean plasma concentration-time profile of Compound 1 on Day 1 and 10 (Part B, MAD). Data are shown as mean ±SD, with Compound 1 concentration-time profiles shown on a semi-log scale. Exposure data from Part B (MAD) in FIG. 16 shows a dose-dependent increase of exposure up to 45 mg.

[0222] The 45 mg dose Cmax showes a modest increase on Day 1 (1.1-fold) and a more pronounced increase on Day 10 (1.3-fold), suggesting a less than proportional increase in Cmax from 30 mg to 45 mg. AUCo-inf and AUCo-tau demonstrate a consistent and linear dose proportional increase on Day 1 and 10 respectively, indicating that drug exposure is proportional to increasing dose up to 45 mg.

[0223] Consistent with data from Part B 20 and 30 mg cohorts, concentrations exceeding the predicted efficacious level based on the mouse MES ECso were reached in the 45 mg cohort. These findings support the use of up to the 45 mg dose to achieve optimal therapeutic levels.

[0224] Compound 1 Continues to Be Well Tolerated

[0225] Compound 1 remains well tolerated at tested doses: single doses up to 45 mg (Part A), at multiple doses of up to 45 mg QD for 10 days (Part B), and at 30 mg for 2 doses separated by a 7-day washout (Part C). No deaths, SAEs, AESIs or adverse event related discontinuations were reported. TEAEs were mostly mild, transient, and self-resolving. No severe TEAEs were reported. No safety findings were observed on clinical lab test results, ECGs, physical exam, or vital signs and no participants exhibited suicidal ideation and behavior, as determined from the C-SSRS. The tolerability summary for Compound 1 is shown in the table below.

[0226] Compound 1 Has No Clinically Significant Food Effect

[0227] Food effect analysis revealed no clinically significant impact to Cmax or AUC at steady state. The 90% CI for the ratio of the population geometric means between fed and fasted states was contained within the equivalence limits of 80%-125% for AUCiast and AUCinf (table below). Table below shows geometric mean (%CV) for single doses of Compound 1 30 mg administered under fasted and fed conditions (Part C).

[0228] AUCmf=area under the plasma concentration-time curve from time zero extrapolated to infinity;

[0229] CI=confidence interval; Cmax=maximum plasma drug concentration; Tmax=time to reach maximum observed concentration following drug administration.aMixed-effects model analysis with food (fasted / fed), period and sequence as fixed effects and participants as random effects.

[0230] While the 90% CI of the analogous ratio for Cmax was slightly outside the equivalence limits and Tmax was shifted to a longer time in fed state, such statistical / numerical differences are not expected to translate to clinically significant differences in efficacy or safety of Compound 1. Modeling and simulation with a population PK model of the effect of fed / fasted states on drug exposure at steady state showed that the decrease in fed Cmax is within the bioequivalence range, as shown in the table below and in FIG. 17, which is a boxplot showing model predicted steady state Cmax for Compound 1 administered under fasted and fed conditions (Part C). The results shown for modeling based on 30 mg and 45 mg doses.

[0231] The table below shows model predicted steady state Cmax for Compound 1 administered under fasted and fed conditions (Part C).

[0232] The effectiveness and safety profile of vormatrigine are thus likely to remain unchanged, regardless of whether vormatrigine is taken with or without respect to food.

[0233] Conclusions

[0234] Compound 1 demonstrated consistent safety, tolerability, and PK profiles, with no significant food effect. These results support flexible dosing regimens up to 45 mg in the ongoing vormatrigine ENERGY program.

[0235] Example 2. A Phase 2 trial to evaluate the photoparoxysmal electroencephalogram response, safety, tolerability, and pharmacokinetics of Compound 1 in participants with epilepsy and a photoparoxysmal electroencephalogram response to intermittent photic stimulation

[0236] Compound l is a novel inhibitor of persistent and peak sodium current (Ka) that is differentiated from currently available sodium channel (Nav) blockers and is being developed for the treatment of adult focal onset epilepsy. Focal epilepsy is characterized by focal onset seizures, which are localized (focal) areas of neuronal / network hyperexcitability that disrupt normal brain function by causing periods of abnormal network synchronization (seizure). Nav blockers are commonly used to treat focal epilepsy whereby they reduce pathologic neuronal hyperexcitability to prevent the development of seizures or terminate a seizure state. However, approved Nav blockers are not well tolerated, possibly due to an inability to selectively target hyperexcitable states.

[0237] Background and Clinical Trial Rationale

[0238] There is a significant need for better tolerated Nav blockers for patients with focal epilepsy (focal onset seizures, or FOS). Compound 1 has the potential to be a safe and effective treatment for patients with this condition and has shown efficacy in rodent models of epilepsy. Currently available standard-of-care Nav blockers used to treat epilepsy are limited by a low therapeutic index and a requirement to titrate to an efficacious concentration while managing tolerability. Significant class-related adverse effects are central nervous system (CNS)-related, including ataxia, drowsiness, and dizziness, which may be due to the excessive and long-lasting inhibition of peak Ha resulting in an inability of existing Nav blockers to selectivity reduce hyperexcitability while sparing normal brain function.

[0239] Preclinical data demonstrate that Compound 1 differentiates from approved Nav blockers in several ways leading to an increased preclinical protective index (range between exposures that are efficacious in the maximal electroshock assay MES seizure model and exposures that reduce spontaneous movement in the spontaneous locomotor activity assay model). This increased protective index may predict greater clinical tolerability for Compound 1. Features of Compound 1 that may support this increased protective index are proposed to be an increase in the potency for persistent and peak Ha, rapid Ha inhibition kinetics, increase in activity-dependent inhibition of peak Ha, and increased selectivity against non-Nav mediated activity.

[0240] The safety, tolerability, pharmacokinetics (PK), and pharmacodynamics (PD) of Compound 1 are currently being evaluated in healthy volunteers in an ongoing first-in-human trial (see Example 1). Compound 1 was observed to be safe and generally well tolerated in healthy participants at all single doses up to 45 mg tested in Part A of the trial. All treatment- emergent adverse events (TEAEs) reported thus far have been mild in severity and resolved without administration of concomitant medication. No severe TEAEs were reported. The most frequently reported TEAEs were headache and fatigue. No deaths or TEAEs leading to study drug discontinuation have been reported. No safety findings were observed with regards to clinical laboratory test results, electrocardiograms (ECGs), and vital signs.

[0241] The primary objective of this trial is to evaluate the pharmacodynamic effect of Compound 1 compared with placebo on the intermittent photic stimulation (IPS)-induced photoparoxysmal electroencephalogram response (IPS induced PPR) in participants with epilepsy and IPS-induced PPR.

[0242] Scientific Rationale for Clinical Trial Design

[0243] The assessment of potential new drugs for the treatment of epilepsy continues to be challenging. Epilepsy is characterized by different aetiologies and pathophysiological mechanisms. This leads to unpredictable electroencephalographic expressions and clinical manifestations for the disease. Clinical assessments that can be simply and reproducibly performed are useful in determining the potential of new treatments in development. Suppression of photoparoxysmal EEG response (PPR) has emerged over the past several decades as a valuable translation tool in early clinical development for the assessment of potential anti-seizure drugs (ASDs) with a variety of mechanisms of action.

[0244] Visual sensitive epilepsy is a reflex type of epilepsy; the epileptogenic reaction can be evoked systematically at any time in response to flashing lights.

[0245] Photosensitivity, defined as a generalized epileptiform reaction elicited by intermittent photonic stimulation (IPS), is found in approximately 5% of all epileptic patients. Although most prevalent in idiopathic generalized epilepsies, photosensitivity may also be present in other types of epilepsy and most notably in specific genetically determined syndromes, like Dravet syndrome.

[0246] Markedly visual sensitive patients are usually sensitive to IPS within clearly defined limits of flash frequency (mostly between 10-30 Hz). This photosensitivity range, the difference between the highest and lowest flash rates that consistently elicit a PPR, can be used as a quantitative measure of photosensitivity and, therefore, epileptogenicity. The photosensitivity range is related to the liability of visually induced seizures in daily life and is remarkably stable under controlled conditions. Previous studies show that the administration of marketed and experimental ASD, either in a single or repeated dose regimen, can have an impact on the PPR, diminishing or even abolishing the response to IPS. As measured by the EEG response to IPS, the pharmacodynamic effects are also not necessarily time-locked to the drug's pharmacokinetic profile, as was demonstrated in a single dose of valproic acid, levetiracetam and carisbamate. Combined with blood level monitoring, this study design offers information about the time of onset and the duration of the anti-epileptic action and some effects of tolerability of the drug.

[0247] Using a standardized, meticulously performed IPS procedure (short delivery of flashes, determination of threshold frequencies, for which the patient shows an epileptiform EEG response and simultaneous recording of the EEG and observation of the patient) brings the likelihood of provoking prominent clinical seizures to extremely low. Furthermore, IPS is a standard procedure in any routine EEG recording, like hyperventilation.

[0248] In summary, valuable preliminary information can be obtained using the PPR model. These studies are usually of short duration and are conducted in a limited number of patients under maximally standardized and controlled conditions. Positive results indicate target engagement and would support further clinical development of the drug that is investigated.

[0249] A single-blind, placebo-controlled, fixed-sequence design has been used by many others to successfully evaluate the IPS-induced PPR as a proof of principle for anti-epileptic drugs. This study design is preferred for 3 key reasons. First, this is the first in-patient study for Compound 1. Therefore, allowing it to only be blinded to the participant and the EEG reader provides for more diligent safety oversight during the Intervention Period. Second, each participant can serve as its own placebo control, which enables fewer participants to be exposed to study drug to achieve the study objectives. Reducing the total sample size allows for more efficient study conduct considering the rare prevalence of the patient population. Third, a PD effect can be observed after a limited number of participants are exposed to a single dose of an anti-epileptic drug. Therefore, if no PD effect is observed after administration of a lower dose of study drug to a limited number of participants, then escalation of the dose should be considered.

[0250] Rationale for allowing participants who are taking an existing sodium channel blocker (SCB) to be included in the trial

[0251] The purpose of this clinical trial is to explore the efficacy of Compound 1 as a treatment for epileptic seizures and to understand its safety and tolerability in patients. SCBs represent one of the most prescribed therapeutic options within the standard of care for this population. This clinical trial is expected to provide a benefit to patients during the trial and inform additional elements of the future clinical development program for Compound 1.

[0252] The inclusion of participants currently on sodium channel blocking drugs would also expand the eligible pool of patients exhibiting a measurable photoparoxysmal electroencephalogram response (PPR). While this is a rare epileptiform abnormality, it is anticipated to be responsive to this mechanism of action. This is inferred by the stable treatment of these patients with SCBs in an effort to provide anti-seizure benefit. The presence of a PPR would signify continued, abnormal cortical excitability even in the presence of stable SCB treatment and the PPR would provide an opportunity to observe an effect of Compound 1. Demonstration of an effect would also provide evidence for how Compound 1 and other ASDs are used in routine clinical practice.

[0253] Pharmacology studies have demonstrated that Compound l is a pan-Nav inhibitor with potent, voltage-dependent activity against CNS NaV isoforms. Compound 1 has been shown to be active in three models of acute seizure at exposures below those which were active in the sLMA tolerability model. Compound 1 protected mice from generalized seizures in the MES and pentylenetetrazole (PTZ)-induced models and from focal psychomotor seizures in the 6Hz model. The separation between exposures that were efficacious from those which were not tolerated is defined as the preclinical protective index (PI). There was a 3-fold PI between plasma exposures that were effective in the PTZ and 6Hz models compared to the mouse sLMA assay. The PI between the MES and sLMA assays was larger (15-fold). Importantly, this separation between MES and sLMA was wider than both carbamazepine and lamotrigine (Pls of ~6 and ~5, respectively). These data indicate that Compound 1 exhibits greater anti-convulsant efficacy at exposures that are better tolerated as compared to available SCBs. In addition, due to the higher PI observed with Compound 1 those patients who already receive a SCB at the maximum tolerated dose but still exhibit significant seizures, due to insufficient NaV blockade, could benefit from using Compound 1 as an add-on therapy due to its potentially greater tolerability as a way of improving outcomes. For this reason, patients who are taking an existing SCB will be included in the study. This will allow both the potential benefit and tolerability of Compound 1 to be established in patients with epilepsy on SCBs in addition to other ASDs. Justification for Dose

[0254] A single dose will be sufficient to observe a suppression of the IPS-induced PPR.

[0255] Dose levels for this first-in-patient trial have been determined based on results from an ongoing first-in-human trial designed to investigate the safety, tolerability, PK, and PD of single ascending doses and multiple ascending doses of Compound 1 in healthy volunteers.

[0256] All single doses evaluated to date (5 mg, 15 mg, and 45 mg) have been safe and generally well tolerated. At their peak, mean Compound 1 plasma concentrations for the 15 mg and 45 mg doses exceeded the estimated human equivalent exposure of the mouse MES ECso, the concentration predicted to be required for modulation of sodium channels and the intended biological effect in patients. Based on the MES model, doses of 15 mg and 45 mg of Compound 1 are expected to produce maximum concentrations that approximate the EC70 and EC90, respectively. Given these data, the dose level of 15 mg in Part A is expected to be able to suppress the PPR response in participants.

[0257] Trial Objectives The primary objective of this trial is to evaluate the pharmacodynamic effect of

[0258] Compound 1 compared with placebo on the intermittent photic stimulation (IPS)-induced photoparoxysmal electroencephalogram response (IPS-induced PPR) in participants with epilepsy and IPS-induced PPR.

[0259] Overall Design

[0260] This is a Phase 2, single-blind, placebo-controlled, fixed-sequence design trial to evaluate the photoparoxysmal EEG-response, safety, tolerability, and pharmacokinetics of Compound 1 in participants aged 18 to 65 years (inclusive) with epilepsy and IPS-induced PPR. The trial initially comprises 1 part (Part A), with 1 additional optional part (Part B). Both parts have identical design and will only differ in the dose of Compound 1.

[0261] The trial consists of 3 periods: Screening / Baseline, Intervention, and Safety Follow- Up. FIG. 2 is an illustration of the dosing scheme for the trial. Screening / Baseline Period

[0262] The Screening period will be up to 42 days in duration (Day -42 to Day -2). Prior to any clinical trial procedures, participants will provide written informed consent to participate in the trial. Following confirmation of continued eligibility, participants will check in to the clinic at Baseline (Day -1; the day before study drug administration). Participants who participated in Part A will only be re-screened for a PPR if that assessment was conducted 120 days (4 months) prior to the screening for Part B.

[0263] Intervention Period

[0264] Participants will remain in the unit from Baseline (Day -1) to Discharge (Day 3). If participants experience any clinically significant AEs during their in-patient stay, they may remain in the clinical facility for further observation at the discretion of the principal investigator (PI), following consultation with the sponsor.

[0265] Participants will undergo quantitative EEG (qEEG) at Baseline (Day -1) to establish a baseline measurement. Participants with epilepsy and an IPS-induced PPR will receive a single dose of placebo on the morning of Day 1 and a single dose of Compound 1 on the morning of Day 2. On Days 1 and 2, IPS-induced PPR will be measured pre-dose and at 1, 2, 3, 4, 6, and 8 hours post-dose. The Day 3 assessment will occur 24 hours after the Day 2 dose. On Days 1 and 2, quantitative EEG (qEEG) will be performed predose and before the IPS assessment at predose and at 1, 2, 3, 4, 6, and 8 hours postdose. On Day 3, qEEG assessment will also be performed before the IPS assessment (24 hours after the Day 2 dose). Predose qEEG will be performed twice to calculate a baseline measurement. Blood collection for PK parameters will be collected 30 minutes after the assessment of IPS-induced PPR.

[0266] In Part A, up to 12 participants will receive 15 mg of Compound 1. The sponsor may recommend proceeding to an optional Part B if less than 75% of the participants cumulatively evaluated in Part A have demonstrated a sufficient reduction on PPR, namely a standardized photosensitivity range (SPR) reduced by equal or more than 3 points while not leading to a complete abolishment of a generalized PPR in >1 eye conditions (eyes open, eye closure, eyes closed and / or eyes open with diffusor) over >3 testing times within 1 day, compared to the range at the same time points on Day 1. The minimum number of participants for both Part A and optional Part B will be 4 to allow for a proper evaluation of each dose. The dose for Part B, if needed, will be established based on ongoing unblinded review of emerging data from Part A and results from the trial described in Example 1. Participants from Part A will have the option of participating in Part B.

[0267] On every dosing day, safety assessments will include a neurological exam (including cranial nerves, coordination, and gait) and symptom-directed physical examination to be conducted pre-dose (within 2 hours before dosing) and 4 hours post-dose. Additionally, clinical laboratory parameters, including chemistry and hematology, will be evaluated on Baseline Day -1, pre-dose on Day 2, and at any time for all the other visits. Vital signs will be performed pre-dose (within 2 hours before dosing) and then 2, 4, 6, and 8 hours (±15 minutes) post-dose. ECG will be performed pre-dose (within 2 hours before dosing) and then 2, 4, and 6 hours (±15 minutes) post-dose. Participants will be discharged on Day 3 after a satisfactory safety review and completion of trial-related procedures. If a participant discontinues the Intervention Period early, an Early Termination (ET) visit will be conducted.

[0268] Safety follow-up period

[0269] A Safety Follow-Up visit will be conducted on Day 8 (±2 days).

[0270] Number of participants

[0271] This trial will enroll up to 12 participants (up to 12 participants total across both Part A and the optional Part B). Participants from Part A will have the option of participating in Part B. Participants who withdraw or are withdrawn from the study prior to completion of the nominal clinical conduct for reasons other than the occurrence of a serious adverse event (SAE) may be replaced.

[0272] Clinical trial intervention

[0273] For Part A and Part B, each study participant will receive placebo capsule(s) on Day 1 and Compound 1 capsule(s) on Day 2. On each dosing day, a single dose of Compound 1 (15 mg for Part A, to be determined for Part B) or matching placebo will be administered orally (fasted) and provided in single dose containers to the participants.

[0274] Topline Results

[0275] FIG. 3 is a schematic showing the design of the clinical trial described herein. Patients had to demonstrate PPR response during screening and baseline periods to be evaluable. Over a detailed 24-hour observation period, assessments were conducted focusing on participants displaying a baseline Photo Paroxysmal Response (PPR), a metric for gauging treatment efficacy. The observed suppression of PPR response was characterized either as a partial suppression of PPR response or a complete suppression of PPR response. A partial suppression of the PPR response was a reduction, other than to zero, in the number of generalized PPR events at any assessment period vs. baseline. A complete suppression of the PPR response was a reduction to zero in the number of generalized PPR events at any assessment period vs. baseline. Safety was monitored and PK samples were collected during the entire observation period. FIG. 4 illustrates the concept of photoparoxysmal response, which pertains to an EEG anomaly precipitated by intermittent photic stimulation (IPS). A study participant is equipped with EEG recording equipment and is exposed to stray light of varying frequencies, allowing observation of the transition from normal EEG pattern to distinct PPR responses.

[0276] FIG. 5 is a flowchart illustrating disposition of subjects in the trial. 30 participants were screened, of which 10 met the inclusion criteria for the trial. In part A, which involved 15 mg dosing of Compound 1, 6 participants underwent safety assessment, and 5 of the 6 participants underwent PPR evaluations. In part B, which involved 45 mg dosing of Compound 1, 4 participants underwent safety assessment, and 3 participants underwent PPR evaluations.

[0277] FIG. 6 is a table showing demographic profile of study participants.

[0278] FIG. 7 is a table showing the incidence of adverse events in the study participants. The results indicate that all adverse events were mild in severity and that the adverse event profile for Compound 1 was comparable to that of placebo.

[0279] FIG. 8 is a table showing the response to treatment with Compound 1. The results indicate that the majority of participants achieved a complete response to treatment, with only a single subject experiencing a partial response in the 15 mg dosing group. Every participant who was evaluated responded favorably to treatment with Compound 1, and all individuals who were taking concurrent medications experienced an enhanced benefit from coadministration of Compound 1.

[0280] FIG. 9 shows an example of EEG recordings before (left panel) and after (right panel) administration of Compound 1. The results indicate an elimination of PPR response upon administration of Compound 1.

[0281] The topline results indicate that Compound 1 is effective at suppressing PPR response in subjects with epilepsy. Summary of Results

[0282] Population of Subjects

[0283] Included in the trial were 7 unique participants: 6 participants participated in study part A (15 mg dose level of Compound 1), of which 3 participants proceeded to study part B (45 mg dose level). One participant was newly recruited and participated only in study part B. The participants were epilepsy patients between 18 and 65 years of age, both males and females.

[0284] Subject Disposition

[0285] At the 15 mg dose level (z.e., study part A), a total of 20 participants were screened, 6 were randomized and 6 participants completed the study. At the 45 mg dose level (z.e., study part B), a total of 10 participants were screened, 4 were randomized and 3 participants completed the study.

[0286] Administration of Compound 1

[0287] Participants received a single dose of placebo capsule(s) on Day 1 and a single dose of Compound 1 capsule(s) on Day 2 for Part A and Part B. In Part A, participants received 15 mg of Compound 1 and placebo orally (fasted). In Part B, participants received 45 mg of Compound 1 and placebo orally (fasted). The capsule(s) were provided to participants in single dose containers. The study included one treatment period of 4 days (Day -1 to Day 3) and a safety follow-up visit on Day 8 (±2 days).

[0288] Trial Results

[0289] The study was comprised of 2 parts, Part A and Part B, with identical designs, and only differed in the dose of Compound 1. The study was conducted in male and female participants ranging in age from 18 to 61 years old. At the 15 mg dose level, Part A, a total of 20 participants were screened, 6 were randomized and 6 participants completed the study. Of the 6 participants randomized, 2 of them were male and 4 were female. Participants in Part A of the study ranged in age from 19 to 61 years old and were white and not of Hispanic or Latino descent. At the 45 mg dose level, Part B, a total of 10 participants were screened, 4 were randomized and 3 participants completed the study. Of the 4 participants randomized, 1 was male and 3 were female. Participants in Part B of the study ranged in age from 18 to 61 years old and were white and not of Hispanic or Latino descent. All participants were diagnosed with epilepsy with sensitivity to light.

[0290] In Part A, 6 participants were exposed to Compound 1. Of those 6, 2 participants had at least 1 treatment-related TEAE following administration of placebo and Compound 1, respectively. The most frequently reported TEAE that occurred in >2 participants was fatigue (3 participants following administration of placebo and 3 participants following administration of Compound 1). Other treatment-related TEAEs reported after administration of Compound 1 were feelings of relaxation, muscle spasm, disturbance in attention, involuntary muscle contractions, sleep paralysis, insomnia, and nightmares (each in 1 participant). TEAEs were considered related to study drug for 1 and 6 participants following administration of placebo and Compound 1, respectively. In Part A, the time to AE onset for 10 of the 14 individual TEAEs during the Compound 1 treatment period was less than 24 hours following Compound 1 administration, with 6 of these TEAEs, fatigue, involuntary muscle contractions, nightmares, sleep paralysis, headaches, and feeling of relaxation, occurring within 6 hours of administration. The onset of the remaining 4 TEAEs in the Compound 1 treatment period occurred more than 4 days after Compound 1 administration. Most TEAEs in the Compound 1 treatment period following Compound 1 administration resolved on the same day, within 8 hours of onset. All TEAEs reported were mild in severity.

[0291] In Part B of the trial, 4 participants were exposed to study drug. Of the 4 participants, 1 participant had at least 1 treatment-related TEAE following administration of placebo and of the 3 participants exposed to Compound 1, all participants had at least 1 treatment-related TEAE. The most frequently reported TEAE that occurred in >2 participants was fatigue (3 participants following administration of placebo and 2 participants following administration of Compound 1), somnolence (2 participants following administration of Compound 1), and headache (2 participants following administration of placebo). Other treatment-related TEAEs reported after administration of Compound 1 were nausea, oral paraesthesia, tongue discomfort, feeling drunk, dizziness, headache, and nasal discomfort (each in 1 participant). In Part B, the time to AE onset for all 12 individual TEAEs during the Compound 1 treatment period was within 24 hours following Compound 1 administration. Time to AE onset for 9 of these TEAEs was within 6 hours of administration. Ten out of 12 TEAEs occurring during the Compound 1 treatment period resolved within 24 hours of onset. All TEAEs reported were mild in severity.

[0292] Compound 1 was administered to 3 participants with previously prescribed and stable concomitant antiseizure medications. One participant received 50 mg twice daily administration (BID) brivaracetam, 1 participant received 250 mg BID lamotrigine, and 1 participant received 500 mg BID valproic acid. TEAEs following administration of Compound 1 in the participant on concomitant brivaracetam included insomnia, nightmare, and sleep paralysis in Part A. TEAEs following administration of Compound 1 in the participant receiving lamotrigine included disturbance in attention and muscle contractions involuntary in Part A, and nausea, dizziness, fatigue, and headache in Part B. TEAEs following administration of Compound 1 in the participant on concomitant valproic acid included feeling of relaxation and constipation in Part A.

[0293] All TEAEs resolved without any treatment intervention except for headache in one participant in Part B following Compound 1 administration that was treated with a single dose of paracetamol. The participant had experienced headaches following placebo administration that did not require treatment. No participants had a TEAE that led to study drug discontinuation, no SAEs, AESI or deaths were reported and all TEAEs reported were mild in severity. Compound 1 was well tolerated in participants when Compound 1 was coadministered with previously prescribed and stable concomitant antiseizure medications. There were no significant Compound 1 related AEs indicative of potential CNS toxicity or excessive sodium channel blockade when co-administered with antiseizure medications.

[0294] Efficacy results showed that all participants responded favorably to treatment with Compound 1. Of the eight participants with epilepsy evaluated, seven achieved a complete response to treatment, while one participant in the 15 mg dosage group exhibited a partial response. All participants already undergoing treatment experienced an additional therapeutic benefit with the co-administration of Compound 1. In conclusion, Compound 1 significantly reduced or abolished IPS-induced PPR in all participants whereas no change was observed in the placebo group.

[0295] The following pharmacokinetic parameters were determined: maximum observed concentration (Cmax), time to Cmax (tmax), area under the concentration-time curve from 0 to 24 hours (AUC24), AUC from 1.5 to 24 hours (AUC1.5-24), and AUC from 0 to the last measurable concentration at 24.5 hours (AUCiast). The results summarized in the table below, indicate that after a single dose, Compound 1 achieves or exceeds therapeutic concentrations sufficient to reduce or eliminate PPR , while maintaining a favorable tolerability profile.

[0296] %CV = percent coefficient of variation.aFirst measured time point and not necessarily the actual tmax

[0297] Example 3. A Double-Blind, Randomized, Multicenter Phase 2 / 3 Study Evaluating the

[0298] Efficacy and Safety of Compound 1 in Adults with Focal Onset Seizures

[0299] Rationale

[0300] Focal epilepsy is characterized by focal onset seizures (FOS) which, in turn, are characterized by localized neuronal hyperexcitability. The current standard-of-care for FOS is limited by tolerability issues and need for titration to avoid side effects, possibly due to inability to selectively target hyperexcitable states. Compound l is a next-generation functional state modulator targeting the hyperexcitable state of sodium channels in the brain, currently in development for adult FOS.

[0301] Compound 1 has presented with a superior preclinical profile relative to current standard-of-care and has shown favorable tolerability in healthy volunteers, including preliminary evidence of cardiac safety. Notably, emerging preclinical and clinical data demonstrate the ability of Compound 1 to significantly exceed therapeutic concentrations while being well tolerated, with recent Phase 2a findings of 100% response in epilepsy patients with photoparoxysmal response providing additional proof-of-concept. The current study aims to evaluate the efficacy, safety, and pharmacokinetics of Compound 1 as an adjunctive therapy in adult FOS.

[0302] Method

[0303] This global, multicenter, double-blind, randomized, parallel design Phase 2 / 3 study will enroll ~230 eligible male and female participants aged 18-75 years (inclusive) with FOS, currently taking 1-3 anti-seizure medications (ASMs). Participants will be randomized 1 : 1 to receive Compound 1 once daily (QD) or matching placebo for 12 weeks. The study will consist of the following periods: Screening, Observation, Treatment and Safety Follow-up.

[0304] Results

[0305] The primary endpoint will be median percent change in monthly (28 days) focal seizure frequency from the Observation Period to the Treatment Period for subjects treated with Compound 1, as compared to subjects treated with placebo. Secondary endpoints will include the proportion of subjects treated with Compound 1 experiencing a >50% reduction in monthly (28 days) focal seizure frequency from the Observation Period to the Treatment Period (responder rate), as compared to subjects treated with placebo; plasma concentrations of Compound 1 and safety assessments. Further exploratory endpoints will examine the effect of Compound 1 on additional efficacy and safety outcomes.

[0306] Conclusions

[0307] Expanding on preclinical and preliminary clinical data, the study will examine the efficacy, safety and pharmacokinetics of Compound 1 as an ideal precision ASM for patients with FOS.

[0308] Example 4. Compound 1 Demonstrates Potent Antiseizure Activity Across Three Acute Models with Highest Predictive Validity for Focal Onset Seizures

[0309] Rationale

[0310] Approximately 3.5 million people in the United States have been diagnosed with epilepsy, with around 60% classified as focal onset seizures (FOS). Despite the availability of over 30 antiseizure medications (ASMs), 30-40% of patients remain refractory to current treatments, highlighting the urgent need for novel treatments. Compound l is a nextgeneration functional state modulator that targets the hyperexcitable state of CNS sodium channels. It is currently in development for adult FOS, with emerging preclinical and clinical data pointing to an ideal precision ASM profile.

[0311] An analysis framework was recently implemented to assess the translational concordance of common preclinical seizure models. Using this framework, a decision tree was developed for accelerated FOS drug discovery that includes three acute seizure models with high predictive validity: audiogenic, maximal electroshock (MES) and 6-Hz (32mA). In this study, antiseizure efficacy of Compound 1 across these models was assessed, providing robust support for its accelerated development as a treatment for FOS.

[0312] Methods

[0313] Male and female juvenile DBA / 2J mice were used to assess the antiseizure activity of Compound 1 in the audiogenic seizure model. MES and 6-Hz experiments were conducted in adult male CD-I mice. Mice were pre-treated with either vehicle or Compound 1 by oral gavage 30 minutes prior to audio or electrical stimulus. For audiogenic seizure experiments, mice were exposed to 110 dB of white noise for 60 seconds and observed for the presence or absence of full tonic hindlimb extension. Electroshocks for MES experiments were 50 Hz, 0.8 s, 10 ms square pulse width, 50 mA, and for 6-Hz experiments were 6 Hz, 3 s, 0.2 ms rectangular pulse width, 32 mA. Mice were observed for the presence or absence of full tonic hindlimb extension (MES), or psychomotor seizures defined as stun / immobility, forelimb clonus, Straub tail and lateral head movement (6-Hz).

[0314] Results

[0315] Mice were completely protected from audiogenic-induced tonic hindlimb extension, with an ED50 value of 0.55 mg / kg. In the MES acute seizure model, Compound 1 (3 mg / kg and 10 mg / kg) completely protected mice from tonic hindlimb extension, with an ED50 value of 0.42 mg / kg. Compound 1 also significantly reduced incidence of psychomotor seizures induced by 6-Hz (32mA).

[0316] Conclusions

[0317] Compound 1 exhibited potent antiseizure activity across three acute seizure models shown to have the highest predictive validity for FOS within our PAC framework.

[0318] Example 5. Additional Studies of Compound 1

[0319] FIG. 10A is a schematic illustrating the design of the ENERGY program with the goal to demonstrate efficacy of Compound 1 and bring an improved therapy to focal and generalized epilepsy patients. As illustrated in FIG. 10A, the ENERGY program consists of four studies: the EMPOWER study, the RADIANT study, the POWER1 study and the POWER2 study.

[0320] FIG 10B is a schematic illustrating the design of the EMPOWER observational study, designed to better understand patient journey. This study will be conducted in partnership with The Epilepsy Study Consortium (TESC).

[0321] FIG. 10C is a schematic illustrating the design of the RADIANT phase 2 open label study to evaluate the safety and efficacy of Compound 1 in epilepsy with focal and / or generalized seizures. The study will involve up to 50 subjects and will include a 4-week screening observation period; followed by an 8-week intervention period during which the subjects will be administered 30 mg of Compound 1 once daily; followed by a 2-week safety follow-up period. During the study, seizure frequency, seizure freedom, safety and pharmacokinetics will be assessed.

[0322] FIG. 10D is a schematic illustrating the design of the POWER1 study to demonstrate efficacy of Compound 1 and POWER2 study to evaluate a minimal dose of Compound 1. The POWER1 study will involve approximately 200 subjects. The study will include a screening, observation and randomization period, followed by an intervention period, followed by a safety follow-up period. During the intervention period, subjects will receive either placebo for 12 weeks, or Compound 1 at a dose of 20 mg for 6 weeks, and a dose of 30 mg for 6 weeks. The intervention period will be followed by a safety follow-up period. The P0WER2 study will involve approximately 300 subjects. The study will include a screening, observation and randomization period, followed by an intervention period, followed by a safety follow-up period or an open label extension (OLE) period. During the intervention period, subjects will receive either placebo for 12 weeks, or Compound 1 at a dose of 10 mg for 12 weeks, or compound 1 at a dose of 20 mg for 6 weeks, followed by a dose of 30 mg for 6 weeks.

[0323] Example 6. Epilepsy Monitoring of Prospective Seizure Observations with Electronic Records (EMPOWER): An Observational Study Designed to Better Understand the Patient Journey

[0324] Rationale

[0325] Epilepsy is a complex neurological disease characterized by unprovoked, spontaneous seizures with a global prevalence of ~65 million people. In the United States, an estimated 3.5 million have an epilepsy diagnosis, almost a third of whom live with uncontrolled seizures. Associated with this is decreased quality of life and increased risk of overall mortality from sudden unexpected death in epilepsy (SUDEP) and seizure-related accidents.

[0326] Patient seizure counts do not reflect true seizure burden, with more than half of seizures not accurately reported. The development of tools to accurately characterize seizures requires direct patient input. This study aims to characterize seizure burden and ASM use patterns over time in epilepsy patients and is designed to empower patients to take an active part in their epilepsy journey.

[0327] Methods

[0328] The EMPOWER is an ongoing observational study consisting of participant-elected enrollment into a patient registry followed by a prospective observational period up to 24 months. No intervention is being provided. EMPOWER aims to recruit -3,000 participants aged >18 years in the US with a confirmed epilepsy diagnosis, according to ILAE classifications.

[0329] Prospective participants will be engaged via a dedicated website, social media channels, and patient-facing materials. Eligible patients will be provided access to an electronic seizure diary to record their seizures, ASM use, and other self-reported data (e.g., quality of life). For those who have opted in during the registration period to share medical records, these linked medical records will prospectively track intercurrent event monitoring e.g., hospitalizations, infections, etc.). Study surveys will collect information including demographics, seizure types / counts and seizure tracking behavior. Periodically, summarized deidentified reports will be shared with participants to facilitate learning from others’ experiences. The end of the registration period will be three months prior to the study end (which study end is 24 months from study initiation date). This will allow the last participant at the last visit to record up to three months of seizure diaries prior to the end of the observation period.

[0330] A subset of patients may be contacted by a nurse navigator to help define their epilepsy and seizure types.

[0331] Inclusion Criteria

[0332] A participant must meet the following criteria (at registration, unless otherwise specified) for the participant to be eligible for this study:

[0333] I 1. Participant is willing to sign an informed consent document in accordance with ICH GCP guidelines, indicating that they understand the purpose of the study.

[0334] I 2. Is male or female aged >18 at the time of registry enrollment.

[0335] I 3. Has a diagnosis of epilepsy confirmed by a healthcare professional.

[0336] Inclusion criteria will be assessed prior to the observation period.

[0337] Exclusion Criteria

[0338] No exclusion criteria will be used.

[0339] Participant Withdrawal

[0340] A participant may withdraw from the study at any time at their own request. A participant may be withdrawn at any time at the discretion of the sponsor PI for behavioral, compliance, or administrative reasons, but should be reviewed with the sponsor prior to withdrawal. This is expected to be uncommon. If the participant withdraws consent for disclosure of future information, the sponsor will retain and continue to use all data collected before such withdrawal of consent

[0341] Concomitant Medications

[0342] During the registration period, medical records and medical claims will be used to determine prior and current use of antiseizure medications.

[0343] Any changes in prescribed antiseizure medication that the participant is receiving at the time of enrollment or receives during the observational period must be recorded within the seizure diary along with the following information:

[0344] • Dates of administration, including start and end dates

[0345] • Dosage information, including dose and frequency of administration

[0346] Use of rescue medication by the participant during the observational period of the study must be recorded within the seizure diary along with the following information:

[0347] • Date of administration

[0348] • Name, dose, and frequency

[0349] Data Collected

[0350] Demographic Data

[0351] Demographic data will be obtained at the time of signing of the informed consent. As part of the initial registration process, patients may opt into future communications.

[0352] Medical, Disease, and Medication History

[0353] Assessment of medical history via electronic medical records will include a detailed history of the participant’s epilepsy disease course relating to his / her seizures, including past and present data.

[0354] Data collected may include, but will not be limited to, age and type at initial seizure, age at epilepsy diagnosis, other seizure types experienced (if applicable), seizure frequency, EEG findings, CT (Computed Tomography) findings, magnetic resonance imaging findings, current and past ASMs (Anti-Seizure Medications), surgical interventions, number of hospitalizations (and reasons for hospitalization), rescue medications, and medications for other medical conditions.

[0355] At this time, prior and current ASMs taken from diagnosis through study period will also be recorded, including the type of medication, length of treatment, and response to treatment (e.g., efficacy and / or tolerability).

[0356] In addition, medical history will include other clinically significant diseases that resolved at or before signing of the informed consent, and prior surgeries. Ongoing conditions will be considered concurrent medical condition.

[0357] Survey Data

[0358] The surveys in the study will collect participant information including but not limited to:

[0359] • Additional demographic data.

[0360] • Seizure types (type and count) and seizure tracking behavior (use of diary, type of dairy, motivations to or not to track seizures)

[0361] • Awareness of clinical trials and motivation to participate in a clinical trial.

[0362] Seizure Diary

[0363] A seizure diary will be completed by the participant. Participants will record, at a minimum, the type and frequency of different seizures experienced. The participant will be educated on how to complete the diary prior to the start of the observational period through the use of a training guide.

[0364] Objective and Endpoint Results

[0365] Assessment of medical history via electronic medical records will include a detailed history of the participant’s epilepsy disease course relating to their seizures. Study surveys will collect participant information including, but not limited to: demographic data; seizure types / count and seizure tracking behavior (use of diary, type of dairy, motivations to track / not track). During the registration period, medical records and claims will be used to determine prior and current ASM use. Health economics / medical resource utilization will be captured through electronic medical records and medical claims (ICD-10 coding). Summarized deidentified reports will be shared periodically with patients.

[0366] Individual results may better inform a participant of his or her condition while aggregate results may help better understand the conditions under which patients are diagnosed and treated for their epilepsy.

[0367] Participants will receive access to interim data reports summarizing patient-reported survey findings at predetermined intervals. Eligible patients may be contacted for a short interview to share more information about their epilepsy. Furthermore, participants enrolled in this study may be considered for inclusion in an interventional clinical trial, provided they meet the entry criteria, and they are interested in participating.

[0368] Preliminary Data for 81 participants

[0369] Most participants were diagnosed with epilepsy by a neurologist over 2 years after their first seizure, with nearly half unaware of their epilepsy type. In the past 6 months, 68% reported at least 1 seizure per month, and nearly 75% described their seizures as moderate-to- severe. Over 50% of participants believe that their seizures are uncontrolled, despite 40% currently using 2 or more ASMs and over 50% having previously tried 3 or more ASMs. Half needed >2 ASMs, with higher usage among those seeing specialists or reporting recent seizures. All participants reported at least moderate impact on quality-of-life, and more than half considered an epilepsy clinical trial in the past year. Many patients with active seizures are not tracking their seizures, with both seizures and treatment side effects associated with significant quality of life impacts. Conclusions

[0370] EMPOWER will generate standardized, longitudinal data to support planned future interventional clinical trials, while providing a greater understanding of participant experiences of epilepsy. Eligible participants may be considered for inclusion in the POWER interventional trials investigating safety and efficacy of Compound 1, a precision ASM for focal onset seizures and generalized epilepsy. Preliminary findings reveal a significant disease burden compounded by persistent, uncontrolled seizures and profound psychosocial impact.

[0371] Update

[0372] EMPOWER is an ongoing study which aims to characterize seizure burden and antiseizure medication (ASM) use patterns over time in epilepsy patients; empowering them to actively participate in their epilepsy journey. Data is presented from 183 respondents, matched in open claims, with epilepsy ICD10 code.

[0373] Key Demographics and Seizure Experience

[0374] FIG. 18 shows EMPOWER study respondent demographics. Of all respondents, 73% are female, and most are between the ages of 35 and 54. Nearly two-thirds of respondents have self-reported a seizure in the last month and 89% are on at least one ASM.

[0375] FIG. 19 is a bar graph showing reported epilepsy diagnosis of the respondents. Most participants are unaware of their seizure type even when managed by a neurologist or epileptologist.

[0376] FIG. 20 is a schematic showing respondents’ perception of their seizures. More than 3 / 4 of respondents described their seizures as moderate to severe, with more than half believing they are uncontrolled.

[0377] FIG. 21 is a bar graph showing reported seizures over the last month. Despite available treatments, two-thirds of respondents reported experiencing a seizure in the last month. FIG. 22 is a bar graph showing use of anti-seizure medications (ASMs). Of the respondents, 53% need >2 ASMs, with higher usage among those seeing specialists or reporting recent seizures.

[0378] FIG. 23 is a graphic showing data on respondents’ seizure tracking. A significant gap in seizure tracking exists, with many patients with active seizures not tracking their seizures.

[0379] FIG. 24 is a bar graph showing impact of ASMs on quality of life and activities of daily living. Seizures and treatment side effects have a significant impact on respondents’ daily lives.

[0380] Conclusions

[0381] The EMPOWER observational study is ongoing with over 3,000 patients consented. EMPOWER continues to generate standardized, longitudinal data to support planned interventional trials and deepen understanding of patient experiences of epilepsy. Findings to date reveal a significant disease burden compounded by persistent, uncontrolled, often untracked seizures alongside profound psychosocial impact.

[0382] Example 7. An Open Label Clinical Trial to Evaluate the Efficacy and Safety of Compound 1 in Adult Patients with Focal Onset or Primary Generalized Tonic-Clonic Seizures (RADIANT)

[0383] Introduction

[0384] Compound l is a novel inhibitor of persistent and activity dependent sodium current (INa) that is differentiated from currently available voltage-gated sodium channel (NaV) modulators. Compound 1 is being developed for the treatment of adult focal onset epilepsy and primary generalized tonic-clonic seizures (PGTCS). Focal epilepsy is characterized by localized (focal) areas of neuronal or network hyperexcitability, which disrupts normal brain function by causing periods of abnormal network synchronization (seizures). Generalized seizures are characterized by widespread involvement of bilateral cortical regions at the onset. They are usually accompanied by impairment of consciousness. They can further be divided into absence, tonic clonic, clonic, tonic, atonic and myoclonic seizure types. NaV modulators are commonly used to treat focal epilepsy by reducing pathological neuronal hyperexcitability to prevent the onset of seizures or terminate ongoing seizure activity. However, existing NaV medications are not well tolerated, likely due to their inability to selectively target hyperexcitable states of sodium channel activity without affecting normal neuronal function. Compound 1 aims to overcome this limitation, offering a more targeted and better-tolerated treatment option for patients with focal onset epilepsy.

[0385] PGTCS represents a major concern for patients suffering from idiopathic generalized epilepsy. Evaluation of Compound 1 in this patient population, where sodium channel blockers (SCBs) are frequently used to treat, is an opportunity to evaluate a new, rapidly acting mechanism based on a relied upon target. Compound l’s differentiated mechanism of action may allow its use as an alternative to treat PGTCS.

[0386] Background and Clinical Trial Rationale

[0387] Epilepsy is a common condition characterized by recurrent seizures resulting from disturbances in the brain’s electrical activity, known as hyperexcitability. Epilepsy affects approximately 65 million individuals worldwide with at least one-third experiencing uncontrolled seizures due to the insufficient efficacy or dose-limiting intolerability of current medications.

[0388] In the United States, the Centers for Disease Control and Prevention report a prevalence of approximately 3 million adults with epilepsy, with an estimated 31,000 new cases diagnosed annually. The majority of these patients suffer from focal epilepsy. According to the World Health Organization, the estimated proportion of the general population with active epilepsy, defined as ongoing seizures or a need for treatment, ranges from 4 to 10 per 1000 individuals.

[0389] Focal epilepsy involves localized areas of neuronal or network hyperexcitability, disrupting normal brain function and daily activities by causing periods of abnormal network synchronization manifested clinically as seizures. These focal onset seizures may remain confined to one brain area within a single hemisphere, or they can spread to broader brain areas, leading to focal to bilateral tonic-clonic seizures. Each seizure event poses a significant threat to patients and can be fatal due to an increased risk of sudden unexpected death in epilepsy (SUDEP). Focal onset seizures, related to a focal brain dysfunction, occur in approximately 60% of cases and generalized seizures represent approximately 30% of cases while in the remaining 10% the classification is uncertain.

[0390] The current most effective treatments for focal onset seizures involves the use of NaV modulators. These medications work by reducing pathologic neuronal hyperexcitability associated with seizures, thereby preventing their initiation and / or attenuating their spread and severity. However, approved NaV drugs are not well tolerated, due to their inability to selectively target pathological, hyperexcitable states while sparing normal neuronal activity. This limitation restricts the efficacy of these treatments and introduces significant side effects.

[0391] Compound 1 offers a unique mechanism of action, allowing for the selective modulation of NaV channels. This selective targeting differentiates it from current sodium channel-based therapies, as it aims to allow dosing to higher efficacy by avoiding tolerability limitations of the existing medications. Nonclinical and clinical data, detailed in the Investigator’s Brochure (IB), support potential of Compound 1 as a breakthrough treatment for focal epilepsy.

[0392] This mechanism is fundamentally different from that of traditional sodium-channel blocking antiseizure medications (ASMs), which act through enhancement of voltage-gated sodium channel fast inactivation. Some ASMs that reduce focal seizures by enhancing fast inactivation of voltage-gated sodium channels have been shown to aggravate generalized seizures, particularly absence seizures and myoclonic seizures, thus Compound 1 has the potential not only to treat focal onset seizures (FOS) but also PGTCS.

[0393] To date, Compound 1 has been administered to approximately 40 clinical trial participants, at therapeutic dose levels up to 45 mg. Only mild treatment-emergent adverse events (TEAEs) were reported, with no serious adverse events (SAEs) or deaths. In the Phase 2 trial described in Example 2, patients with well-characterized photosensitive epilepsy demonstrated complete electroencephalogram (EEG) responses to intermittent photic stimulation (IPS) after receiving single doses of Compound 1. This strongly suggests that Compound 1 is likely to be effective in treating patients with FOS and PGTCS.

[0394] Novel ASMs are often first evaluated in adult patients with focal seizures because focal epilepsy is more common in adults, and is associated with seizures that are more frequent and more easily documented than primary generalized seizures. Evaluation of new ASMs for the treatment of primary generalized seizures is usually delayed until efficacy and safety have been first established in patients experiencing focal seizures. Of all of the ASMs that have demonstrated efficacy in the treatment of focal seizures, only valproate, lamotrigine, levetiracetam, topiramate, perampanel and lacosamide are currently approved for the treatment of seizures associated with primary generalized seizures in the United States or European Union, with some evidence also supporting the use of zonisamide.

[0395] The primary objective of this trial is to evaluate the frequency of FOS and PGTCS in participants administered Compound 1 over an 8-week treatment period.

[0396] This is a Phase 2, open label, single arm, multicenter clinical trial to evaluate the efficacy and safety of Compound 1 in adult patients with focal onset seizures or primary generalized tonic clonic seizures. In this trial, all participants will receive Compound 1 30 mg QD for 8 weeks. The primary objective of the trial is to evaluate the efficacy of Compound 1 in reducing the monthly focal or primary generalized tonic clonic seizure frequency from the Screening / Observation Period to the Treatment Period. The safety, tolerability, and pharmacokinetics (PK) of Compound 1 will also be assessed in this trial.

[0397] This trial consists of the Screening / Observation Period, the Treatment Period, and the Safety Follow-up Visit.

[0398] Scientific Rationale for Clinical Trial Design and Justification for Dose

[0399] This clinical trial is conducted in adult epileptic patients with focal onset seizures or primary generalized tonic clonic seizures in order to demonstrate the efficacy and safety of Compound 1 in this target patient population.

[0400] Aligned with trial’s main objective is the primary endpoint, which is the median percent change in monthly seizure frequency from the Screening / Observation Period to the Treatment Period for Compound 1, as reported by participants in the seizure diary. Safety and tolerability of Compound 1 will also be explored by assessing the incidence and severity of TEAEs in participants receiving Compound 1 and other ASMs.

[0401] The open-label, single-arm study design is selected for this trial to evaluate efficacy and safety of a 30 mg dose in a broader population of patients with a lower seizure burden than typically used in a double-blind placebo-controlled trial. Additionally, the open-label, non-placebo-controlled nature of this trial will allow adjustment of other background medication that patients are currently using to control seizures. In this design, every participant will serve as their own control based on the Screening / Baseline Observation Period before exposure to study drug.

[0402] The treatment duration of 8 weeks has been selected based on the ability of Compound 1 to rapidly reach therapeutic concentrations and should provide adequate time to see the effect based on the preclinical efficacy and the mechanism of action. All participants will have PK assessments at Visits 1, 2, 3, 4 and 5, and / or at the ET visit (if applicable) to correlate plasma concentrations to safety and efficacy in the trial population.

[0403] The participants will be allowed to maintain a stable treatment regimen of currently approved ASMs but must have at least 2 countable seizures during the Screening / Observation Period for focal onset patients, or 1 countable primary generalized tonic clonic seizure during the Screening / Observation Period for PGTCS patients.

[0404] The study drug, Compound 1, was designed with a fast-on, slow-off binding profile to selectively modulate the NaV current associated with hyperexcitability that generates seizures while sparing normal neuronal function. The nonclinical data generated with Compound 1 supports a profile that is differentiated from currently available ASMs in established efficacy models including audiogenic, maximal electroshock (MES), 6Hz 32mA, and spontaneous locomotion activity (SLMA) models with a remarkable therapeutic index and potency. Importantly, the potency of Compound 1 in the MES rodent model predicted a human equivalent half-maximal effective concentration (EC so) of 24 ng / mL.

[0405] PK and pharmacodynamic data generated in the Phase 1 clinical trial (see Example 1) have validated this profile in healthy participants. Data generated in the Phase 1 clinical trial demonstrated that repeat doses of 20 and 30 mg of Compound 1 during the multiple ascending dose (MAD) portion of the trial resulted in plasma levels 5 to 8 times greater than the MES predicted efficacious concentration on the first day of dosing and 5 to 15 times greater than the MES-predicted efficacious dose on Day 10 without tolerability issues. Following 10 days of Compound 1 administration, trough plasma concentration (Ctrough) levels were 2.6 to 4 times greater than the MES-predicted efficacious concentration. The data generated in the Phase 1 clinical trial demonstrated that Compound 1 can achieve established therapeutic ranges rapidly on the first day of dosing and safely maintain an efficacious concentration, in sharp contrast to nearly all currently approved ASMs. A comparison of EEG data between participants who were administered Compound 1 confirmed that Compound 1 rapidly penetrates the brain at all doses, at the first timepoint observed when compared to placebo. Any observed side effects in the study were typically associated with maximum plasma drug concentration (Cmax), mild in nature and resolved rapidly. The clinical data generated to date has confirmed that concentrations far in excess of the predicted therapeutic range can be rapidly accessed and sustained without any tolerability issues, further supporting the differentiated profile of Compound 1.

[0406] The first clinical trial in patients described in Example 2 demonstrated that Compound

[0407] 1 has an impact on hyperexcitability as measured by EEG in patients with photoparoxsymal response (PPR). Doses of 15 or 45 mg of Compound 1 administered to patients with PPR showed a partial or complete response by EEG analysis in all patients, confirming the potential for expected benefit of Compound 1, by impacting NaV hyperexcitability. Notably, Compound 1 was administered in 3 participants concomitantly with their existing ASMs (lamotrigine, brivaracetam, and valproate) with no impact on tolerability or exposure relative to the observed in healthy participants. Overall, the PK and tolerability profiles were similar to the data generated in the Phase 1 trial, with only mild side effects that quickly resolved. The exposures achieved with the single doses administered in the trial described in Example

[0408] 2 are anticipated to be maintained for the 30 mg doses throughout the entire treatment period in this clinical trial.

[0409] Objectives and Endpoints

[0410] Abbreviations: ASM=antiseizure medication; CGI-S=Clinical Global Impression of Severity; C- SSRS=Columbia-Suicide Severity Rating Scale; ECG=electrocardiogram; FOS=focal onset seizure(s); PGI- S=Patient Global Impression of Severity; PGTCS=primary generalized tonic-clonic Seizure(s);

[0411] PK=pharmacokinetics; TEAE=treatment-emergent adverse event.

[0412] Overall Design

[0413] This is a Phase 2, open-label, single-arm, multicenter clinical trial to evaluate the efficacy and safety of Compound 1 in adult patients with focal onset seizures or primary generalized tonic-clonic seizures. In this trial, all participants will receive Compound 1 30 mg once daily (QD) for 8 weeks. The primary objective of the trial is to evaluate the efficacy of Compound 1 in reducing the monthly focal or primary generalized tonic-clonic seizure frequency from the Screening / Observation Period to the Treatment Period. The safety, tolerability, and pharmacokinetics (PK) of Compound 1 will also be assessed in this trial.

[0414] This trial consists of the Screening / Observation Period, the Treatment Period, and the Safety Follow-up Visit. The Screening / Observation Period will be up to 4 weeks long (Day - 28 to Day -1). The Treatment Period will be 8 weeks in duration. At the in-clinic Visit 1 (Day 1), participants will be re-evaluated on all eligibility assessments and those who remain eligible will have their first dose of Compound 1 30 mg administered at the clinic. For all participants, a Follow-up (end of study; EOS) visit will be conducted 2 weeks after the last dose of study drug. This visit may be carried out in the clinic or as a home health visit.

[0415] Up to 50 participants will be enrolled in this clinical trial. Participants will selfadminister Compound 1 30 mg (3x10 mg capsule) QD for 8 weeks.

[0416] Efficacy Analyses

[0417] 1. Median percent change in monthly (28 days) seizure frequency from the Screening / Observation Period to the Treatment Period for Compound 1 (primary endpoint)

[0418] For each patient, the seizure data in the 8 weeks treatment period will be divided into blocks of 28 days (days 1-28, 29-56); the patient percent change in monthly seizure frequency from Screening / Observation Period will be calculated, for each block and the median will be derived. The difference in seizure frequencies from the Treatment Period to the Screening / Observation Period will be summarized descriptively. In addition, 2 sided 90% confidence intervals will be calculated by bootstrapping.

[0419] 2. Number of days after the first dosing with Compound 1 to reach the same or higher number of monthly seizures from the Screening / Observation Period to the Treatment Period

[0420] Monthly seizure frequency will be evaluated per-day using a 28-day, right-adjusted sliding window (e.g., for Day 28, the window will cover Days 1 through 28). The time-to- event will be defined as the time until the first day when the monthly seizure frequency becomes greater or equal to the baseline seizure frequency. This data will be fitted to a Kaplan-Meier estimator. The estimator will be used to estimate the median time-to-baseline as well as 2-sided 95% confidence interval. 3. Proportion of participants experiencing a >50% reduction in monthly (28 days) seizure frequency from the Screening / Observation Period to the Treatment Period (Responder Rate) for Compound 1.

[0421] For each 28-day block, the proportion of subjects with individual percent change in monthly seizure frequency less than 50% will be calculated together with the 95% confidence interval.

[0422] 4. Proportion of participants experiencing seizure freedom, 100% reduction in monthly (28 days) seizure frequency from the Screening / Observation Period to the Treatment Period for Compound 1.

[0423] For each 28-day block, the proportion of subjects with individual percent change in monthly seizure frequency equal to 100% will be calculated together with the 95% confidence interval.

[0424] 5. Impact of Compound 1 on PGI-S and CGI-S

[0425] The difference in PGI-S and CGI-S scores from the Treatment Period to the Screening / Observation Period will be summarized descriptively.

[0426] Safety Analyses

[0427] No formal hypothesis tests will be performed for any safety endpoint. In summaries of change from baseline safety variables, only participants with both baseline and postbaseline data will be included. Adverse event data will be coded using the Medical Dictionary for Regulatory Activities (MedDRA). The overall incidence of participants having at least 1 AE will be summarized by treatment. The incidence of treatment-emergent adverse events (TEAEs) will be summarized by treatment, System Organ Class (SOC), and preferred term. Each participant will be counted only once per SOC and preferred term. Additional AE summaries for severity and relationship to study drug may be produced.

[0428] Summary statistics for changes in vital sign measurements, changes in clinical laboratory results, changes in ECG parameters and change in C-SSRS will be calculated, by visits.

[0429] Pharmacokinetic Analyses Plasma concentrations per time point will be summarized using the following descriptive statistics: number of observations (N), arithmetic mean, geometric mean, median, maximum, standard deviation, coefficient of variation (CV%) and geometric CV%. The following PK parameters will be estimated via noncompartmental analysis: maximum plasma drug concentration (Cmax), time to maximum plasma drug concentrations (Tmax).

[0430] Screening / Observation Period

[0431] The Screening / Observation Period will be up to 4 weeks long (Day -28 to Day -1). Prior to any screening procedures, participants and caregiver (if applicable) will provide written informed consent. Screening assessments will be completed to check the participant’s eligibility to enter the trial, and will include medical and psychiatric history, demographics, height and weight measurements, vital signs measurements, physical and neurological examinations, pregnancy testing (females only), drug, and alcohol screen, clinical laboratory evaluations, ECGs, and C SSRS evaluation. The Screening visit may be performed in the clinic or at the participant’s home.

[0432] At the start of the Screening / Observation Period, a seizure diary will be deployed to the participant and caregiver (if applicable), and training on how to use it will be provided. Participants and caregiver (if applicable) are expected to record their seizures daily and must meet a seizure count over the 4-week period. The seizure diary must also be completed for a minimum of 80% of all days during the 4-week Screening / Observation Period in order to progress to the Treatment Period. If a participant has 4 weeks of acceptable seizure diary data (with approximately 80% compliance) for at least 4 weeks immediately prior to D-l, they may utilize their diary data to satisfy the study diary screening requirements.

[0433] Treatment Period

[0434] The Treatment Period will be 8 weeks in duration. At the in-clinic Visit 1 (Day 1), participants will be re-evaluated on all eligibility assessments and those who remain eligible will have their first dose of Compound 1 30 mg administered at the clinic. Participants are expected to remain on their stable pre-screening ASM dosing regimen and will continue to record all seizures in their seizure diary throughout the Treatment Period. Safety Follow-Up

[0435] For all participants, a Follow-up (end of study; EOS) visit will be conducted 2 weeks after the last dose of study drug. This visit may be carried out in the clinic or as a home health visit.

[0436] Efficacy Assessments

[0437] Seizure Frequency

[0438] All seizures are to be self-reported daily by participants, and / or caregiver (if applicable) in a seizure diary to be provided at Screening. Training will be provided on the seizure diary at Screening and throughout the Screening / Observation, and Treatment Period, as required. Training on the backup paper diary will be done ad-hoc via a telephone call and / or telehealth visit, if necessary. Seizure diaries will be reviewed for completeness and any discrepancies may be queried. The seizures will be classified by the PI and reviewed by an expert to ensure accuracy in their classification.

[0439] Clinical Global Impression - Severity

[0440] The Clinical Global Impression scales are commonly used measures of symptom severity and response in clinical trials. The CGI-S scale will be used in this clinical trial and assesses the clinician’s impression of the participant’s current illness state. The clinician should use their total clinical experience with this patient population and rate the current severity of the participant’s seizure condition on a 7-point scale from 1 (normal, not at all ill) to 7 (among the most extremely ill patients).

[0441] Patient Global Impression - Severity

[0442] The PGI-S assesses the participants’ impression of their current illness state. The participant is required to assess their condition on a 7-point scale from 1 (Not present) to 7 (extremely severe).

[0443] Safety Assessments

[0444] Physical and Neurological Examinations Physical (z.e., inspection, percussion, palpation, and auscultation) and neurological examinations (including cranial nerves, coordination, reflexes, and gait) will be performed. Clinically relevant findings that are present prior to the study drug initiation must be recorded with the participant’s medical history. Clinically relevant findings found after study drug initiation and meeting the definition of an AE (a new event or worsening of a previously existing condition) must be recorded as an AE.

[0445] Vital Sign Measurements

[0446] Body temperature, respiratory rate, pulse rate, and systolic and diastolic blood pressure will be assessed.

[0447] Hei ht Wei ht and BMI

[0448] Height (cm) and weight (kg) will be recorded and body mass index (BMI) will be calculated at Screening. Thereafter, body weight will be recorded, and BMI calculated using the height measured at Screening, as specified in the SoA.

[0449] Electrocardiograms

[0450] For each participant, ECGs will be obtained according to the SoA using an ECG machine that automatically calculates the heart rate and measures PR, QRS, and QT intervals, as well as QTcF. ECGs will be taken after at least a 5 minute rest in the supine position and participants must remain supine but awake during ECG collection.

[0451] Example 8. A Double-Blind, Randomized, Multicenter, Trial Evaluating the Efficacy and Safety of Compound 1 in Adults with Focal Seizures (POWER 1)

[0452] Introduction

[0453] Compound l is a novel inhibitor of persistent and activity dependent sodium current (iNa) that is differentiated from currently available voltage-gated sodium channel (Nav) modulators. Compound 1 is being developed for the treatment of adult focal onset epilepsy. Focal epilepsy is characterized by localized (focal) areas of neuronal or network hyperexcitability, which disrupts normal brain function by causing periods of abnormal network synchronization (seizures).

[0454] Nav modulators are commonly used to treat focal epilepsy by reducing pathological neuronal hyperexcitability to prevent the onset of seizures or terminate ongoing seizure activity. However, existing Nav medications are not well tolerated, likely due to their inability to selectively target hyperexcitable states of sodium channel activity without affecting normal neuronal function. Compound 1 aims to overcome this limitation, offering a more targeted and better-tolerated treatment option for patients with focal onset epilepsy.

[0455] Background and Clinical Rationale

[0456] Epilepsy is a common condition characterized by recurrent seizures resulting from disturbances in the brain’s electrical activity, known as hyperexcitability. Epilepsy affects approximately 65 million individuals worldwide with at least one-third experiencing uncontrolled seizures due to the insufficient efficacy or dose-limiting intolerability of current medications.

[0457] In the United States, the Centers for Disease Control and Prevention report a prevalence of approximately 3 million adults with epilepsy, with an estimated 31,000 new cases diagnosed annually. The majority of these patients suffer from focal epilepsy. According to the World Health Organization, the estimated proportion of the general population with active epilepsy, defined as ongoing seizures or a need for treatment, ranges from 4 to 10 per 1000 individuals.

[0458] Focal epilepsy involves localized areas of neuronal or network hyperexcitability, disrupting normal brain function and daily activities by causing periods of abnormal network synchronization manifested clinically as seizures. These focal onset seizures may remain confined to one brain area within a single hemisphere, or they can spread to broader brain areas, leading to focal to bilateral tonic-clonic seizures. Each seizure event poses a significant threat to patients and can be fatal due to an increased risk of sudden unexpected death in epilepsy (SUDEP).

[0459] The current most effective treatments for focal onset seizures involves the use of Nav modulators. These medications work by reducing pathologic neuronal hyperexcitability associated with seizures, thereby preventing their initiation and / or attenuating their spread and severity. However, approved Nav drugs are not well tolerated, due to their inability to selectively target pathological, hyperexcitable states while sparing normal neuronal activity. This limitation restricts the efficacy of these treatments and introduces significant side effects.

[0460] Compound 1 offers a unique mechanism of action, allowing for the selective modulation of Nav channels. This selective targeting differentiates it from current sodium channel-based therapies, as it aims to allow dosing to higher efficacy by avoiding tolerability limitations of the existing medications. Nonclinical and clinical data support potential of Compound 1 as a breakthrough treatment for focal epilepsy.

[0461] To date, Compound 1 has been administered to approximately 40 clinical trial participants, at therapeutic dose levels up to 45 mg. Only mild treatment-emergent adverse events (TEAEs) were reported, with no serious adverse events (SAEs) or deaths. In the Phase 2 proof-of-concept trial described in Example 2, patients with well-characterized photosensitive epilepsy demonstrated complete electroencephalogram (EEG) responses to intermittent photic stimulation (IPS) after receiving single doses of Compound 1. This strongly suggests that Compound 1 is likely to be effective in treating patients with focal onset seizures.

[0462] The primary objective of this trial is to evaluate the frequency of focal onset seizures in participants administered Compound 1 compared with placebo over a 12-week treatment period.

[0463] This trial (POWER 1) is a double-blind, randomized, multicenter, trial to evaluate the efficacy and safety of Compound 1 in adults who can attest to concurrently taking at least 1, but no more than 3 acceptable ASMs. Participants will be randomized 1 : 1 to receive daily Compound 1 or matching placebo. Those randomized to Compound 1 will receive 20 mg doses for the first 6 weeks and 30 mg doses for the second 6 weeks of the 12-week Treatment Period. The primary objective of the trial is to evaluate the effectiveness of Compound 1, compared to placebo, in reducing the monthly focal seizure frequency from the Screening / Observation Period to the Treatment Period. Changes in focal seizure frequency over time and by dose will be assessed as secondary endpoints. The safety, tolerability, and pharmacokinetics (PK) / pharmacodynamics (PD) of Compound 1 will also be assessed in this trial. Scientific Rationale for Clinical Trial Design and Justification of Dose

[0464] The objective of this double-blind clinical trial (POWER 1) is to demonstrate the efficacy and safety of Compound 1 in adults with focal onset epilepsy. Compound 1 was designed with a fast-on, slow-off binding profile to selectively modulate the Nav current associated with hyperexcitability that generates seizures while sparing normal neuronal function. The nonclinical data generated with Compound 1 supports a profile that is differentiated from currently available ASMs in established efficacy models including audiogenic, maximal electroshock (MES), 6Hz 32mA, and spontaneous locomotion activity (SLMA) models with a remarkable therapeutic index and potency. Importantly, the potency of Compound 1 in the MES rodent model predicted a human equivalent half-maximal effective concentration (EC so) of 24 ng / mL.

[0465] PK and pharmacodynamic data generated in the Phase 1 clinical trial described in Example 1 have validated this profile in healthy volunteers. Data generated in the Phase 1 clinical trial demonstrated that repeat doses of 20 and 30 mg of Compound 1 during the multiple ascending dose (MAD) portion of the study resulted in plasma levels 5 to 8 times greater than the MES-predicted efficacious concentration on the first day of dosing and 5 to 15 times greater than the MES-predicted efficacious dose on Day 10 without tolerability issues. Following 10 days of Compound 1 administration, trough plasma concentration (Ctrough) levels were 2.6 to 4 times greater than the MES-predicted efficacious concentration. The data generated in the Phase 1 clinical study demonstrated that Compound 1 can achieve established therapeutic ranges rapidly on the first day of dosing and safely maintain an efficacious concentration, in sharp contrast to nearly all currently approved ASMs. A comparison of EEG data between subjects who were administered Compound 1 confirmed that Compound 1 rapidly penetrates the brain at all doses, at the first timepoint observed when compared to placebo. Any observed side effects in the study were typically associated with maximum plasma drug concentration (Cmax), mild in nature and resolved rapidly. The clinical data generated to date has confirmed that concentrations far in excess of the predicted therapeutic range can be rapidly accessed and sustained without any tolerability issues, further supporting the differentiated profile of Compound 1.

[0466] The first clinical trial in patients described in Example 2 demonstrated that Compound 1 has an impact on hyperexcitability as measured by EEG in patients with photoparoxsymal response (PPR). Doses of 15 or 45 mg of Compound 1 administered to patients with PPR showed a partial or complete response by EEG analysis in all patients, confirming the potential for expected benefit of Compound 1, by impacting Nav hyperexcitability. Notably, Compound 1 was administered in 3 participants concomitantly with their existing ASMs (lamotrigine, brivaracetam, and valproate) with no impact on tolerability or exposure relative to the observed in healthy participants. Overall, the PK and tolerability profiles were similar to the data generated in the Phase 1 trial, with only mild side effects that quickly resolved. The exposures achieved with the single doses administered in the study described in Example 2 are anticipated to be maintained for the 20 and 30 mg doses in the POWER 1 study throughout the entire treatment period.

[0467] The purpose of the POWER 1 clinical trial is to demonstrate the efficacy and safety of Compound 1 in participants with refractory focal onset epilepsy. Participants will be screened for epilepsy and overall health, but the key criteria will be their seizure frequency as evidenced by seizure diary reporting, with at least an 80% compliance rate. Participants will be allowed to maintain a stable treatment regimen of up to 3 currently approved ASMs but must have at least 8 seizures over the Screening / Observation period, with no more than 21 consecutive seizure-free days in order to ensure that the frequency and distribution of seizures are appropriate to demonstrate the benefit of Compound 1. The endpoint for the study is the median percent change in monthly seizure frequency from the Screening / Observation Period to the Treatment Period for Compound 1 compared to placebo, as reported by participants and / or care giver in the seizure diary.

[0468] Following randomization to either the placebo control arm or the active arm, participants will enter the 12-week Treatment Period. The single active arm will be administered 20 mg QD of Compound 1 for 6 weeks followed by 30 mg QD of Compound 1 for 6 weeks. This design is expected to achieve average exposures of 4.5 times the MES- predicted efficacious dose for 6 weeks, and average exposures of 7.5 times the MES- predicted efficacious dose for the second 6-week period, therefore maximizing the ability to control seizures. The clinical data generated to date have not demonstrated an increase in TEAEs as the dose is escalated, and because titration is not required to achieve predicted efficacious doses, expected benefit should be achieved over the entire 12-week Treatment Period. The treatment duration of 12 weeks was selected to ensure adequate time to evaluate the effect of Compound 1 on seizure burden as well as its durability as compared to a placebo control arm. The overall duration of the treatment phase of 12 weeks is consistent with the regulatory guidelines for anti-seizure medications. All participants will have PK assessments on Day 1 and on the final day of the Treatment Period (or the Early Termination Visit) to correlate plasma concentrations to safety and efficacy in the study population and compare the effect of the drug between placebo and active arms. Objectives and Endpoints

[0469] Participants with focal seizures will be randomized into 1 of 2 arms to receive Compound 1 once daily (QD), at the same time every day, at 20 mg for the first 6 weeks and 30 mg for the second 6 weeks of the Treatment Period, or matching placebo.

[0470] The objectives and endpoints of the trial are listed below.

[0471] ASM=anti-seizure medication; CGI-S=Clinical Global Impression of Severity; PGI-S=Patient Global Impression of Severity; C-SSRS=Columbia-Suicide Severity Rating Scale; ECG=electrocardiogram; PD=pharmacodynamics; PK=pharmacokinetics; TEAE=treatment-emergent adverse event.

[0472] Overall design

[0473] This global, multicenter, double-blind, randomized, parallel design Phase 2 / 3 clinical trial is designed to establish the efficacy, safety, tolerability, and PK of Compound 1.

[0474] Eligible male and female participants aged 18 to 75 years (inclusive), with focal seizures, currently taking 1 to 3 anti-seizure medications (ASMs) will be enrolled and randomized into this clinical trial.

[0475] Clinical Trial Periods

[0476] This trial consists of the following periods: the Screening / Observation Period, the Treatment Period, and the Follow-up Period. Screening / Observation Period The Screening / Observation Period will be up to 64 days in duration. Prior to any clinical trial procedures to assess eligibility, participants will provide written informed consent to participate in the trial. A first telehealth visit (or telephone call) Screening Visit 1 (SCI) will be conducted for consent, medical history review, and seizure diary set-up and training. Participants will then be given 7 to 10 days within the Screening Period to achieve >80% seizure diary compliance. At telehealth (or telephone call) Screening Visit 2 (SC2) seizure diary compliance will be assessed and the SC3 visit will be scheduled. Participants with <80% seizure diary compliance will be retrained at the visit. At Screening Visit 3 (SC3), participants will complete their screening assessments, have the seizure diary compliance reviewed and will be assessed for eligibility. Participants who already have at least 4 weeks of acceptable seizure diary entries at SCI, with >80% compliance, will directly enter SC3 directly and skip SC2. These 4 weeks of data will count towards the total 9 weeks of the screening / observation seizure diary data.

[0477] Participants and / or caregiver are expected to continuously record their daily seizures in their seizure diary throughout the entire Screening / Observation Period.

[0478] Screening eligibility assessments at SC3 may be performed in-clinic or at a home health visit including telehealth (or telephone call).

[0479] Treatment Period

[0480] The Treatment Period will be 12 weeks in duration. At in-clinic Visit 1 (Day 1), participants will be reevaluated on all eligibility assessments and those who remain eligible will be randomized to receive either Compound 1 or placebo using an interactive response technology (IRT) system. Participants are permitted to be randomized with pending laboratory assessments if the laboratory assessments at screening are supportive of eligibility. Following all assessments and randomization, the first dose of study drug will be administered at the clinic. Participants are expected to remain on their stable pre-screening ASM dosing regimen and will continue to record all seizures in the seizure diary throughout the Treatment Period. Telehealth (or telephone call) visits may be conducted at Visit 2 and Visit 5. Visit 3 and Visit 4 may be home health visits or telehealth visits (or telephone call) and Visit 6 (end of treatment) will be an in-clinic visit. Participants who discontinue study drug before the end of the Treatment Period should have an Early Termination Visit on the last day of receiving study drug or as soon as possible thereafter. These participants should then have a final end of study (EOS) Telehealth Visit 2 weeks after the last dose of study drug.

[0481] Follow-Up Period

[0482] For all participants, a telephone call or telehealth EOS visit will be conducted 2 weeks after the last dose of study drug.

[0483] Study Drug(s) Administered

[0484] On each dosing day, a single dose of Compound 1 (20 mg for the first 6 weeks and 30 mg for the second 6 weeks of the Treatment Period) or matching placebo will be administered orally, around the same time every day, every morning (QAM) or every afternoon or evening (QPM), with or without food every day during the Treatment Period.

[0485] Efficacy Assessments

[0486] Seizure Frequency

[0487] All seizures are to be self-reported daily by participants or by their care giver in an electronic seizure diary to be provided at the initial screening visit (SCI) after all preliminary eligibility assessments have been conducted. Training will be provided on the electronic seizure diary at SCI and throughout the Screening / Observation, and Treatment Periods, as required. Training on the backup paper diary will be done ad-hoc via a telephone call or telehealth visit, if necessary. Seizure diaries will be reviewed for completeness and any discrepancies may be queried. The seizures will be classified by the PI and reviewed by an expert to ensure accuracy in their classification.

[0488] Clinical Global Impression - Severity

[0489] The Clinical Global Impression (CGI) scales are commonly used measures of symptom severity and response in clinical trials. The Clinical Global Impression of Severity (CGI-S) scale will be used in this clinical trial and assesses the clinician’s impression of the participant’s current illness state. The clinician should use their total clinical experience with this patient population and rate the current severity of the participant’s seizure condition on a 7-point scale from 1 (normal, not at all ill) to 7 (among the most extremely ill patients).

[0490] Patient Global Impression - Severity

[0491] The Patient Global Impression of Severity (PGI-S) assesses the participants’ impression of their current illness state. The participant is required to assess their seizure condition on a 7-point scale from 1 (Not present) to 7 (extremely severe).

[0492] Safety Assessments

[0493] Physical and Neurological Examinations

[0494] Physical examinations (i.e., inspection, percussion, palpation, and auscultation) will be performed during the course of the trial. Additionally, a neurological examination (including cranial nerves, coordination, reflexes, and gait) will also be conducted as specified in the SoA. Clinically relevant findings that are present prior to the study drug initiation must be recorded with the participant’s medical history. Clinically relevant findings found after study drug initiation and meeting the definition of an AE (new AE or worsening of previously existing condition) must be recorded as an AE.

[0495] Vital Sign Measurements

[0496] Body temperature, pulse rate, respiratory rate, and blood pressure will be assessed at all in-clinic and home health visits, as described in the study manual.

[0497] Hei ht Wei ht and BMI

[0498] Weight (kg) will be recorded at SC3, Visit 6, and the Early Termination Visit, as appropriate. Height (cm) will be recorded, and body mass index (BMI) will be calculated at SC3.

[0499] Electrocardiograms ECGs will be taken after at least 5 minutes in the supine position and participants must remain supine but awake during ECG collection. All recorded ECGs will be reviewed by the investigator or medical qualified designee, and the review will be documented in the source. A repeat ECG will be conducted if a participant shows an abnormal ECG. A cardiologist review of abnormal ECG tracings will be requested if deemed necessary by the investigator.

[0500] While the foregoing disclosure has been described in some detail by way of illustration and example for purposes of clarity and understanding, it will be clear to one of ordinary skill in the art from a reading of this disclosure that various changes in form and detail can be made without departing from the true scope of the disclosure and may be practiced within the scope of the appended claims. For example, all constructs, methods, and / or component features, steps, elements, or other aspects thereof can be used in various combinations.

[0501] Claims or descriptions that include “or” between one or more members of a group are considered satisfied if one, more than one, or all of the group members are present in, employed in, or otherwise relevant to a given product or process unless indicated to the contrary or otherwise evident from the context. The disclosure includes embodiments in which exactly one member of the group is present in, employed in, or otherwise relevant to a given product or process. The disclosure also includes embodiments in which more than one, or the entire group members are present in, employed in, or otherwise relevant to a given product or process. Furthermore, it is to be understood that the disclosure encompasses all variations, combinations, and permutations in which one or more limitations, elements, clauses, descriptive terms, etc., from one or more of the listed claims is introduced into another claim dependent on the same base claim (or, as relevant, any other claim) unless otherwise indicated or unless it would be evident to one of ordinary skill in the art that a contradiction or inconsistency would arise. Where elements are presented as lists, (e.g., in Markush group or similar format) it is to be understood that each subgroup of the elements is also disclosed, and any element(s) can be removed from the group. In general, where embodiments or aspects of the disclosure, is / are referred to as comprising particular elements, features, etc., certain embodiments or aspects consist, or consist essentially of, such elements, features, etc. For purposes of simplicity those embodiments have not in every case been specifically set forth in so many words herein. It should also be understood that any embodiment or aspect of the disclosure can be explicitly excluded from the claims, regardless of whether the specific exclusion is recited in the specification.

[0502] All patents, patent applications, websites, other publications or documents, accession numbers and the like cited herein are incorporated by reference in their entirety for all purposes to the same extent as if each individual item were specifically and individually indicated to be so incorporated by reference.

Claims

We claim:

1. A method of treating a condition relating to aberrant function of a sodium ion channel in a subject in need thereof, said method comprising administering to said subject Compound 1, or a pharmaceutically acceptable salt thereof, once daily at a dose of about 10 mg to about 45 mg, wherein Compound 1 is represented by the following structural formula:

2. The method of claim 1, wherein said subject experiences at least a partial suppression of PPR response.

3. A method of treating a condition relating to aberrant function of a sodium ion channel in a subject in need thereof, said method comprising administering to said subject Compound1, or a pharmaceutically acceptable salt thereof, at a dose of about 10 mg to about 45 mg; wherein Compound 1 is represented by the following structural formula:such that said subject experiences at least a partial suppression of PPR response.

4. The method of claim 3, wherein Compound 1 is administered once daily.

5. The method of any one of claims 1-4, wherein said subject experiences a partial suppression of PPR response.

6. The method of any one of claims 1-4, wherein said subject experiences a complete suppression of PPR response.

7. The method of any one of claims 1-6, wherein said subject experiences suppression of PPR response 1 or more hours following administration of the Compound 1, or a pharmaceutically acceptable salt thereof.

8. The method of claim 7, wherein said subject experiences suppression of PPR response about 1 hour following, about 2 hours following, about 3 hours following, about 4 hours following, about 5 hours following, about 6 hours following, about 7 hours following or about 8 hours following administration of Compound 1, or a pharmaceutically acceptable salt thereof.

9. The method of any one of claims 1-8, wherein said suppression of PPR response lasts for at least about 1 hour, at least about 2 hours, at least about 3 hours, at least about 4 hours, at least about 5 hours, at least about 6 hours, at least about 7 hours at least about 8 hours, at least about 9 hours, at least about 10 hours, at least about 11 hours, at least about 12 hours, at least about 13 hours, at least about 14 hours, at least about 15 hours, at least about 16 hours, at least about 17 hours, at least about 18 hours, at least about 19 hours, at least about 20 hours, at least about 21 hours, at least about 22 hours, at least about 23 hours or at least about24 hours following administration of Compound 1, or a pharmaceutically acceptable salt thereof.

10. The method of any one of claims 1-9, wherein said dose is about 10 mg to about 40 mg, about 10 mg to about 35 mg, about 10 mg to about 30 mg, about 15 mg to about 25 mg, about 20 mg to about 45 mg, about 20 mg to about 40 mg, about 25 mg to about 35 mg, about25 mg to about 30 mg, about 20 mg to about 35 mg, about 25 mg to about 40 mg, about 30 mg to about 45 mg, or about 30 mg to about 40 mg.

11. The method of claim 10, wherein said dose is about 10 mg, about 15 mg, about 20 mg, about 25 mg, about 30 mg, about 35 mg, about 40 mg or about 45 mg.

12. The method of any one of claims 1-11, wherein the dose is administered for at least 1 day, at least 2 days, at least 3 days, at least 4 days, at least 5 days, at least 6 days, at least 7 days, at least 14 days, at least 21 days, at least 28 days, at least 35 days or at least 42 days.

13. The method of any one of claims 1-12, wherein the subject does not experience adverse events.

14. The method of any one of claims 1-13, wherein the subject experiences mild adverse events.

15. The method of any one of claims 1-14, wherein the subject does not experience a clinically meaningful change in at least one ECG parameter.

16. The method of claim 15, wherein the at least one ECG parameter is selected from the group consisting of heart rate (HR), PR interval, QRS, QT interval and any combination thereof.

17. The method of claim 15 or claim 16, wherein the subject does not experience a clinically meaningful change in the QT interval.

18. The method of any one of claims 1-17, wherein said condition relating to aberrant function of a sodium ion channel is a neurological disorder.

19. The method of claim 18, wherein said neurological disorder is a disorder associated with excessive neuronal excitability.

20. The method of claim 18 or 19, wherein said neurological disorder is associated with one or more de novo gain-of-function or loss-of-function mutations in central nervous system sodium ion channel genes.

21. The method of any one of claims 18-20, wherein the condition is epilepsy or an epilepsy syndrome.

22. The method of claim 21, wherein the condition is a genetic epilepsy or a genetic epilepsy syndrome.

23. The method of claim 21, wherein the condition is a pediatric epilepsy or a pediatric epilepsy syndrome.

24. The method of any one of claims 18-23, wherein the condition is selected from the group consisting of malignant migrating focal seizures of infancy (MMFSI), epilepsy of infancy with migrating focal seizures (EIMFS), autosomal dominant nocturnal frontal lobe epilepsy (ADNFLE), West syndrome, infantile spasms, epileptic encephalopathy, focal epilepsy, Ohtahara syndrome, developmental and epileptic encephalopathy, Lennox-Gastautsyndrome, seizures, leukodystrophy, leukoencephalopathy, intellectual disability, multifocal epilepsy, drug-resistant epilepsy, temporal lobe epilepsy and cerebellar ataxia.

25. The method of claim 24, wherein the condition is epileptic encephalopathy.

26. The method of claim 24, wherein the condition is focal epilepsy.

27. The method of claim 26, wherein the focal epilepsy is adult focal epilepsy.

28. The method of claim 24, wherein the seizures are generalized tonic clonic seizures or asymmetric tonic seizures.

29. The method of any one of claims 1-28, wherein the subject is a human.

30. A method of achieving at least a partial suppression of PPR response in a subject with an epilepsy or an epilepsy syndrome, said method comprising administering to said subject Compound 1, or a pharmaceutically acceptable salt thereof, once daily at a dose of about 10 mg to about 45 mg, wherein Compound 1 is represented by the following structural formula:

31. The method of claim 30, wherein said method achieves a complete suppression of PPR response in said subject.

32. The method of claim 30 or 31, wherein said dose is about 10 mg to about 40 mg, about 10 mg to about 35 mg, about 15 mg to about 30 mg, about 15 mg to about 25 mg, about 20 mg to about 45 mg, about 20 mg to about 40 mg, about 25 mg to about 35 mg, about 25 mg to about 30 mg, about 20 mg to about 35 mg, about 25 mg to about 40 mg, about 30 mg to about 45 mg, or about 30 mg to about 40 mg.

33. The method of claim 32, wherein said dose is about 10 mg, about 15 mg, about 20 mg, about 25 mg, about 30 mg, about 35 mg, about 40 mg or about 45 mg.

34. The method of any one of claims 30-33, wherein the dose is administered for at least 1 day, at least 2 days, at least 3 days, at least 4 days, at least 5 days, at least 6 days, at least 7 days, at least 14 days, at least 21 days, at least 28 days, at least 35 days or at least 42 days.

35. The method of any one of claims 30-34, wherein said subject experiences suppression of PPR response about 1 or more hours following administration of the Compound 1, or a pharmaceutically acceptable salt thereof.

36. The method of claim 35, wherein said subject experiences suppression PPR response about 1 hour following, about 2 hours following, about 3 hours following, about 4 hours following, about 5 hours following, about 6 hours following, about 7 hours following or about 8 hours following administration of Compound 1, or a pharmaceutically acceptable salt thereof.

37. The method of any one of claims 30-36, wherein said suppression of PPR response lasts for at least about 1 hour, at least about 2 hours, at least about 3 hours, at least about 4 hours, at least about 5 hours, at least about 6 hours, at least about 7 hours at least about 8 hours, at least about 9 hours, at least about 10 hours, at least about 11 hours, at least about 12 hours, at least about 13 hours, at least about 14 hours, at least about 15 hours, at least about 16 hours, at least about 17 hours, at least about 18 hours, at least about 19 hours, at least about 20 hours, at least about 21 hours, at least about 22 hours, at least about 23 hours or at least about 24 hours following administration of Compound 1, or a pharmaceutically acceptable salt thereof.

38. The method of any one of claims 30-37, wherein the subject does not experience adverse events.

39. The method of any one of claims 30-37, wherein the subject experiences mild adverse events.

40. The method of any one of claims 30-39, wherein the subject does not experience a clinically meaningful change in at least one ECG parameter.

41. The method of claim 40, wherein the at least one ECG parameter is selected from the group consisting of heart rate (HR), PR interval, QRS, QT interval and any combination thereof.

42. The method of claim 40 or 41, wherein the subject does not experience a clinically meaningful change in QT interval.

43. The method of any one of claims 30-42, wherein the epilepsy or epilepsy syndrome is a genetic epilepsy or a genetic epilepsy syndrome.

44. The method of any one of claims 30-43, wherein the epilepsy or epilepsy syndrome is a pediatric epilepsy or a pediatric epilepsy syndrome.

45. The method of any one of claims 30-44, wherein the epilepsy or epilepsy syndrome is selected from the group consisting of malignant migrating focal seizures of infancy (MMFSI), epilepsy of infancy with migrating focal seizures (EIMFS), autosomal dominant nocturnal frontal lobe epilepsy (ADNFLE), West syndrome, infantile spasms, epileptic encephalopathy, focal epilepsy, Ohtahara syndrome, developmental and epileptic encephalopathy, Lennox-Gastaut syndrome, seizures, leukodystrophy, leukoencephalopathy, intellectual disability, multifocal epilepsy, drug-resistant epilepsy, temporal lobe epilepsy and cerebellar ataxia.

46. The method of claim 45, wherein the epilepsy or epilepsy syndrome is epileptic encephalopathy.

47. The method of claim 45, wherein the epilepsy or epilepsy syndrome is focal epilepsy.

48. The method of claim 47, wherein the focal epilepsy is adult focal epilepsy.

49. The method of claim 45, wherein the seizures are generalized tonic clonic seizures or asymmetric tonic seizures.

50. The method of any one of claims 30-49, wherein the subject is a human.

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