Methods of use of AMPA receptor modulators

Abstract

The present disclosure provides, in part, a method of treating a disease, disorder, or condition mediated by AMPA receptor activity in a subject in need thereof, the method comprising orally administering a daily dose of Compound 1 or a pharmaceutically acceptable salt thereof to the subject, wherein the daily dose is from about 0.1 mg to about 5 mg of Compound 1 or a pharmaceutically acceptable salt thereof.

Description

[0001]Attorney Docket No. PNP-008WO METHODS OF USE OF AMPA RECEPTOR MODULATORS CROSS-REFERENCE TO RELATED APPLICATIONS This application claims the benefit of and priority to U.S. Provisional Application No. 63 / 642,269, filed on May 3, 2024, the entire contents of which are hereby incorporated by reference its entirety for all purposes. BACKGROUND Glutamate is the primary excitatory neurotransmitter in the mammalian brain. Glutamatergic signaling participates in a wide range of neural functions including learning and memory, long-term potentiation and synaptic plasticity. α-Amino-3-hydroxyl-5-methyl- 4-isoxazole-propionic acid (AMPA) receptors are a subtype of glutamate receptors, which are glutamate-gated ion channels expressed primarily on postsynaptic membranes of excitatory synapses in the central nervous system (CNS). AMPA receptors mediate the majority of fast neurotransmission across synaptic gaps. Thus, inhibition or negative modulation of AMPA receptors is an attractive strategy for therapeutic intervention in CNS disorders characterized by excessive neuronal activity. However, since AMPA receptor activity is so ubiquitous within the CNS, general antagonism affects most areas of the CNS resulting in undesired and intolerable side effects, such as ataxia, sedation, and / or dizziness, which are shared by all known general AMPA receptor antagonists. Therefore, therapeutics comprising AMPA receptor modulators which are selective for specific targets (e.g., transmembrane AMPA receptor regulatory proteins γ8 (TARP γ8)-associated AMPA receptor complexes) are suitable for the treatment of CNS disorders. SUMMARY In one aspect, the present disclosure provides a method of treating a disease, disorder, or condition mediated by AMPA receptor activity in a subject in need thereof, the method comprising orally administering a daily dose of Compound 1 or a pharmaceutically acceptable salt thereof to the subject, wherein the daily dose is from about 0.1 mg to about 5 mg of Compound 1 or a pharmaceutically acceptable salt thereof. In some embodiments, the disease, disorder, or condition mediated by AMPA receptor activity is selected from the group consisting of epilepsy, seizure, pain, a cognitive disorder, neurodegenerative disorder, and a psychiatric disorder. 1 IPTS / 128949854.1 Attorney Docket No. PNP-008WO In some embodiments, the method does not result in a serious adverse event (SAE) in the subject. In some embodiments, the method does not result in a clinically meaningful change in laboratory values or electrocardiograms (ECG) or a relevant vital sign change in the subject. Also provided herein is an oral formulation comprising: from about 0.1 mg to about 5 mg of Compound 1 or a pharmaceutically acceptable salt thereof; and a pharmaceutically acceptable excipient; wherein the oral formulation is in the form of tablet. BRIEF DESCRIPTION OF THE DRAWINGS FIG.1 depicts a pharmacokinetic (PK) profile of Compound 1 from the single ascending dose (SAD) and first multiple ascending dose (MAD) trials. FIG.2 depicts a PK profile of Compound 1 from the SAD and two MAD trials. FIG.3 depicts mean full PK profiles of Compound 1 for all cohorts of the second MAD trial. FIG.4 provides brain positron emission tomography (PET) scan images showing that TARP^8-containing AMPA receptors were enriched in the hippocampus and cerebral cortex and minimal in the cerebellum and brain stem. DETAILED DESCRIPTION The present disclosure provides, in part, methods of treating a disease, disorder, or condition mediated by AMPA receptor activity in a subject in need thereof. In some embodiments, the methods of the present disclosure includes administering a compound described in the present disclosure to the subject. In some embodiments, the compound is Compound 1 or a pharmaceutically acceptable salt thereof. So that the disclosure may be more readily understood, certain technical and scientific terms used herein are specifically defined below. Unless specifically defined elsewhere in this document, all other technical and scientific terms used herein have the meaning commonly understood by one of ordinary skill in the art to which this disclosure belongs. I. DEFINITIONS The following terms are intended to have the meanings presented therewith below and are useful in understanding the description and intended scope of the present disclosure. In the claims, articles such as “a,” “an,” and “the” may mean one or more than one unless indicated to the contrary or otherwise evident from the context. Claims or descriptions 2 IPTS / 128949854.1 Attorney Docket No. PNP-008WO 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. Also contemplated are embodiments in which exactly one member of the group is present in, employed in, or otherwise relevant to a given product or process. Also contemplated are embodiments in which more than one, or all of the group members are present in, employed in, or otherwise relevant to a given product or process. Where the use of the term “about” is before a quantitative value, the present disclosure also includes the specific quantitative value itself, unless specifically stated otherwise. As used herein, the term “about” refers to a ±10% variation from the nominal value unless otherwise indicated or inferred. The term “pharmaceutically acceptable” refers to those compounds, materials, compositions, and / or dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit / risk ratio. The terms “pharmaceutically acceptable carrier” and “pharmaceutically acceptable excipient” are used interchangeably herein and refer to buffers, carriers, and excipients suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit / risk ratio. Pharmaceutically acceptable carriers include any of the standard pharmaceutical carriers, such as a phosphate buffered saline solution, water, emulsions (e.g., such as an oil / water or water / oil emulsions), and various types of wetting agents. The compositions also can include stabilizers and preservatives. For examples of carriers, stabilizers, and adjuvants, see e.g., Adeboye Adejare, Remington: The Science and Practice of Pharmacy (23rd ed.2020). The term “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, and Gould, Salt selection for basic 3 IPTS / 128949854.1 Attorney Docket No. PNP-008WO drugs, International Journal of Pharmaceutics, 33 (1986) 201-217. Pharmaceutically acceptable salts of the compounds of this disclosure 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, digluconate, dodecylsulfate, 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+(C1–4alkyl)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. As used herein, a “subject” to which administration is contemplated includes, but is not limited to, humans (e.g., a male or female of any age group, e.g., a pediatric subject (e.g., infant, child, adolescent) or adult subject (e.g., young adult, middle–aged adult or senior adult)) and / or a non-human animal, e.g., a mammal such as primates (e.g., cynomolgus monkeys, rhesus monkeys), cattle, pigs, horses, sheep, goats, rodents, cats, and / or dogs. In certain embodiments, the subject is a human. In certain embodiments, the subject is a non- human animal. The terms “human,” “patient,” and “subject” are used interchangeably herein. Disease, disorder, and condition are used interchangeably herein. As used herein, “treat”, “treating”, and “treatment” refer to the treatment of a disease, disorder, or symptom or manifestation of such in a subject, e.g., in a human. This includes (a) inhibiting the disease, disorder, etc., i.e., slowing or arresting its progress or development; 4 IPTS / 128949854.1 Attorney Docket No. PNP-008WO and (b) relieving the disease, disorder, etc., i.e., causing regression of the disease state. As used herein, “prevent”, “preventing” and “prevention” refer to causing a disease, disorder, or symptom or manifestation of such not to occur for at least a period of time in at least some subjects. The term “effective amount” as used herein refers to the amount of a compound, e.g., a compound or composition described herein, sufficient to elicit a beneficial or desired result or biological effect. As will be appreciated by those of ordinary skill in this art, the effective amount of a compound or composition described herein 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, weight, health, and condition of the subject. An effective amount can be administered in one or more administrations, applications, or dosages and is not intended to be limited to a particular formulation or administration route. For example, an effective amount may be an amount of a compound or composition sufficient to achieve one or more of the following: (i) modulate an activity of an AMPA receptor, or (ii) treat or prevent a disease, disorder, or condition mediated by AMPA receptor activity, e.g., epilepsy, seizure, pain, a cognitive disorder, or a psychiatric disorder, or a symptom or manifestation thereof. As used herein, and unless otherwise specified, a “therapeutically effective amount” of a compound or composition is an amount sufficient to provide a therapeutic benefit in the treatment of a disease or condition, or to delay or minimize one or more symptoms associated with the disease, disorder or condition. As will be appreciated by those of ordinary skill in this art, a therapeutically effective amount of a compound or composition described herein 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, weight, health, and condition of the subject. A therapeutically effective amount of a compound or composition can be administered in one or more administrations, applications, or dosages and is not intended to be limited to a particular formulation or administration route. A therapeutically effective amount of a compound or composition also includes 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. In addition, a therapeutically effective amount can encompass an amount of a compound or composition that improves overall therapy, reduces or avoids symptoms or causes of disease or condition, or enhances the therapeutic efficacy of another therapeutic agent. 5 IPTS / 128949854.1 Attorney Docket No. PNP-008WO The term “daily dose” as used herein refers to a dose administered within a 24 hour period. The daily dose can be administered to the subject in either a single administration step or in smaller amounts in multiple administration steps resulting in the total daily dose. The term “chronic administration” as used herein refers to repeated administration of a daily dose of the same medication (e.g., Compound 1 or a pharmaceutically acceptable salt thereof for a period of time (e.g., chronic administration for at least 5 days out of 7 days of treatment, chronic administration for at least 6 days out of 7 days of treatment). The term “adverse event” as used herein refers to the development of an undesirable medical condition or the deterioration of a preexisting medical condition after or during exposure to a pharmaceutical product, whether or not considered causally related to the product. The term “serious adverse event” as used herein refers to an adverse event occurring during any study phase (e.g., baseline, treatment, washout, or follow-up), and at any dose of the investigational product, comparator, or placebo, that fulfils 1 or more of the following: results in death, is immediately life-threatening, requires inpatient hospitalization or prolongation of existing hospitalization, results in persistent or significant disability or incapacity, results in a congenital abnormality or birth defect, or is an important medical event that many jeopardize the participant or may require medical intervention to prevent one of the outcomes listed above. The term “dose-limiting toxicity” as used herein refers to any adverse event or lab abnormality of CTCAE 5.0 Grade ≥ 3 determined to be treatment related. At various places in the present specification, variables or parameters are disclosed in groups or in ranges. It is specifically intended that the description include each and every individual subcombination of the members of such groups and ranges. For example, an integer in the range of 0 to 40 is specifically intended to individually disclose 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, and 40, and an integer in the range of 1 to 20 is specifically intended to individually disclose 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, and 20. Throughout the description, where compounds or compositions are described as having, including, or comprising specific components, or where processes and methods are described as having, including, or comprising specific steps, it is contemplated that, 6 IPTS / 128949854.1 Attorney Docket No. PNP-008WO additionally, there are compounds or compositions of the present disclosure that consist essentially of, or consist of, the recited components, and that there are processes and methods according to the present disclosure that consist essentially of, or consist of, the recited processing steps. Similarly, throughout the description, where compounds or compositions are described as consisting essentially of specific components, or where processes and methods are described as consisting essentially of specific steps, it is contemplated that, additionally, there are compounds or compositions of the present disclosure that consist of the recited components, and that there are processes and methods according to the present disclosure that consist of the recited processing steps. In the application, where an element or component is said to be included in and / or selected from a list of recited elements or components, it should be understood that the element or component can be any one of the recited elements or components, or the element or component can be selected from a group consisting of two or more of the recited elements or components. Further, it should be understood that elements and / or features of a composition or a method described herein can be combined in a variety of ways without departing from the spirit and scope of the present disclosure, whether explicit or implicit herein. For example, where reference is made to a particular compound, that compound can be used in various embodiments of compositions of the present disclosure and / or in methods of the present disclosure, unless otherwise understood from the context. In other words, within this application, embodiments have been described and depicted in a way that enables a clear and concise application to be written and drawn, but it is intended and will be appreciated that embodiments may be variously combined or separated without parting from the present teachings and disclosure(s). For example, it will be appreciated that all features described and depicted herein can be applicable to all aspects of the disclosure(s) described and depicted herein. It should be understood that the expression “at least one of” includes individually each of the recited objects after the expression and the various combinations of two or more of the recited objects unless otherwise understood from the context and use. The expression “and / or” in connection with three or more recited objects should be understood to have the same meaning unless otherwise understood from the context. 7 IPTS / 128949854.1 Attorney Docket No. PNP-008WO The use of the term “include,” “includes,” “including,” “have,” “has,” “having,” “contain,” “contains,” or “containing,” including grammatical equivalents thereof, should be understood generally as open-ended and non-limiting, for example, not excluding additional unrecited elements or steps, unless otherwise specifically stated or understood from the context. It should be understood that the order of steps or order for performing certain actions is immaterial so long as the present disclosure remain operable. Moreover, two or more steps or actions may be conducted simultaneously. The use of any and all examples, or exemplary language herein, for example, “such as” or “including,” is intended merely to illustrate better the present disclosure and does not pose a limitation on the scope of the disclosure unless claimed. No language in the specification should be construed as indicating any non-claimed element as essential to the practice of the present disclosure. The claims encompasses all variations, combinations, and permutations in which one or more limitations, elements, clauses, and descriptive terms from one or more of the listed claims is introduced into another claim. For example, any claim that is dependent on another claim can be modified to include one or more limitations found in any other claim that is dependent on the same base claim. Where elements are presented as lists, e.g., in Markush group format, each subgroup of the elements is also disclosed, and any element(s) can be removed from the group. “Administer”, “administering”, or “administration”, as used herein, refer to implanting, absorbing, ingesting, injecting, or otherwise introducing an entity described herein (e.g., polymeric complex described herein), or providing the same to a subject. Chemical Definitions Definitions of specific functional groups and chemical terms are described in more detail below. The chemical elements are identified in accordance with the Periodic Table of the Elements, CAS version, Handbook of Chemistry and Physics, 75thEd., inside cover, and specific functional groups are generally defined as described therein. Additionally, general principles of organic chemistry, as well as specific functional moieties and reactivity, are described in Thomas Sorrell, Organic Chemistry, University Science Books, Sausalito, 1999; Smith and March, March’s Advanced Organic Chemistry, 5thEdition, John Wiley & Sons, 8 IPTS / 128949854.1 Attorney Docket No. PNP-008WO Inc., New York, 2001; Larock, Comprehensive Organic Transformations, VCH Publishers, Inc., New York, 1989; and Carruthers, Some Modern Methods of Organic Synthesis, 3rdEdition, Cambridge University Press, Cambridge, 1987. The abbreviations used herein have their conventional meaning within the chemical and biological arts. The chemical structures and formulae set forth herein are constructed according to the standard rules of chemical valency known in the chemical arts. Compounds described herein may comprise one or more isotopic substitutions. For example, H may be in any isotopic form, including1H,2H (D or deuterium), and3H (T or tritium); C may be in any isotopic form, including12C,13C, and14C; O may be in any isotopic form, including16O and18O; and the like; F may be in any isotopic form, including18F and 19F; and the like. II. METHODS OF TREATMENT In one aspect, the present disclosure relates to methods of treating a disease, disorder, or condition mediated by AMPA receptor (AMPAR) activity in a subject in need thereof. In some embodiments, the method comprising administering to the subject a compound or a pharmaceutically acceptable salt thereof described herein. In some embodiments, the compound is Compound 1 or a pharmaceutically acceptable salt thereof. Compound 1 is 3-(7-Chloro-1H-indazol-5-yl)-2,5-bis(trifluoromethyl)imidazo[4,5- b]pyridine and represented by the following chemical formula: . Compound 1 inhibits TARP γ8-containing AMPARs with picomolar The compounds described in the present disclosure and methods of preparation thereof are disclosed in WO2016176460, which is incorporated by reference herein. Provided herein, in part, is a method of treating a disease, disorder, or condition mediated by AMPA receptor activity in a subject in need thereof, the method comprising orally administering a daily dose of Compound 1 or a pharmaceutically acceptable salt thereof to the subject, wherein the daily dose is from about 0.1 mg to about 5 mg of Compound 1 or a pharmaceutically acceptable salt thereof. 9 IPTS / 128949854.1 Attorney Docket No. PNP-008WO In some embodiments, the daily dose is administered to the subject for at least 2 consecutive days, at least 3 consecutive days, or at least 4 consecutive days. In some embodiments, the daily dose is administered to the subject for at least 5 consecutive days. In some embodiments, the daily dose is administered to the subject for chronic administration for at least 5 days out of 7 days of treatment. In some embodiments, the daily dose is administered to the subject for chronic administration for at least 6 days out of 7 days of treatment. In some embodiments, the method does not result in a breakthrough seizure or epilepsy. In some embodiments, the daily dose is administered to the subject daily. The disease, disorder, or condition mediated by AMPA receptor activity includes and is not limited to cerebral ischemia, head injury, spinal cord injury, Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis (ALS), Huntington's chorea, AIDS nervous disturbance, epilepsy, mental disorder, mobility disturbance, pain, spasticity, nervous disturbance by toxin in food, various neurodegenerative diseases, various mental diseases, chronic pain, migraine, cancer pain, diabetic neuropathy, encephalitis, acute disseminated encephalomyelitis, acute demyelinating polyneuropathy (Guillain Barre syndrome), chronic inflammatory demyelinating polyneuropathy, multiple sclerosis, Marchifava-Bignami disease, central pontine myelinolysis, Devic syndrome, Balo disease, HIV- or HTLV- myelopathy, progressive multifocal leukoencephalopathy, a secondary demyelinating disorder (for example, CNS lupus erythematodes, polyarteritis nodosa, Sjogren syndrome, sarcoidosis, isolated cerebral vasculitis, etc.), schizophrenia, depression, and bipolar disorder (e.g., bipolar mania). In some embodiments, the AMPA mediated disease, disorder or condition is depression, anxiety disorders, anxious depression, post-traumatic stress disorder, epilepsy, schizophrenia, prodromal schizophrenia, or a cognitive disorder. In some embodiments, the disease, disorder, or condition mediated by AMPA receptor activity or is a condition related to hippocampal hyperexcitability. In some embodiments, the disease, disorder, or condition mediated by AMPA receptor activity is selected from the group consisting of diabetic peripheral neuropathy, trigeminal neuralgia, post herpetic neuralgia, attention-deficit / hyperactivity disorder (ADHD), post-traumatic stress disorder (PTSD), essential tremors, major depressive disorder (MDD), anxiety, cognitive / negative symptoms in schizophrenia, absence epilepsy, clinical seizures associated with Alzheimer's disease, osteoarthritis, and developmental and epileptic encephalopathies (DEE). 10 IPTS / 128949854.1 Attorney Docket No. PNP-008WO In some embodiments, the disease, disorder, or condition mediated by AMPA receptor activity is a CNS disorder. In some embodiments, the disease, disorder, or condition mediated by AMPA receptor activity is selected from the group consisting of epilepsy, seizure, pain, a cognitive disorder, a neurodegenerative disorder, and a psychiatric disorder. In some embodiments, the neurodegenerative disorder or cognitive disorder is selected from the group consisting of mild cognitive impairment, amnesia, dementia, Alzheimer's disease, delirium, or cognitive impairment associated with a psychotic disorder (e.g., anxiety, mood disorder), essential tremors, or cognitive / negative symptoms in schizophrenia. In some embodiments, the neurodegenerative disorder is Alzheimer's disease. In some embodiments, the epilepsy is focal epilepsy. In some embodiments, the focal epilepsy is drug-resistant focal epilepsy. In some embodiments, the focal epilepsy is refractory focal epilepsy. In some embodiments, the seizure is focal seizure, e.g., focal onset seizure. In some embodiments, the seizure is refractory focal seizure. In some embodiments, the epilepsy is absence epilepsy. In some embodiments, the seizure is seizure (e.g., clinical seizure) associated with Alzheimer's disease. In some embodiments, the pain is peripheral neuropathic pain. In some embodiments, the peripheral neuropathic pain is selected from the group consisting of diabetic neuropathy (e.g., diabetic peripheral neuropathy), postherpetic neuralgia, trigeminal neuralgia, and idiopathic sensory polyneuropathy. In some embodiments, the pain is arthritis (e.g., osteoarthritis). In some embodiments, the psychiatric disorder is selected from the group consisting of bipolar disorder, anxiety, schizophrenia, depression, ADHD, PTSD, MDD. In some embodiments, the psychiatric disorder is bipolar disorder. In some embodiments, the bipolar disorder has acute mania. In some embodiments, the bipolar disorder is bipolar mania. In some embodiments, the daily dose is administered to the subject in a single administration. 11 IPTS / 128949854.1 Attorney Docket No. PNP-008WO In some embodiments, the daily dose is about 0.1 mg, about 0.125 mg, about 0.2 mg, about 0.25 mg, about 0.3 mg, about 0.4 mg, about 0.5 mg, about 0.6 mg, about 0.7 mg, about 0.75 mg, about 0.8 mg, about 0.9 mg, about 1 mg, about 1.1 mg, about 1.2 mg, about 1.25 mg, about 1.3 mg, about 1.4 mg, about 1.5 mg, about 1.6 mg, about 1.7 mg, about 1.75 mg, about 1.8 mg, about 1.9 mg, about 2 mg, about 2.1 mg, about 2.2 mg, about 2.25 mg, about 2.3 mg, about 2.4 mg, about 2.5 mg, about 2.6 mg, about 2.7 mg, about 2.75 mg, about 2.8 mg, about 2.9 mg, about 3 mg, about 3.1 mg, about 3.2 mg, about 3.25 mg, about 3.3 mg, about 3.4 mg, about 3.5 mg, about 3.6 mg, about 3.7 mg, about 3.75 mg, about 3.8 mg, about 3.9 mg, about 4 mg, about 4.1 mg, about 4.2 mg, about 4.25 mg, about 4.3 mg, about 4.4 mg, about 4.5 mg, about 4.6 mg, about 4.7 mg, about 4.75 mg, about 4.8 mg, about 4.9 mg, or about 5 mg of Compound 1 or a pharmaceutically acceptable salt thereof. In some embodiments, the daily dose is about 0.25 mg of Compound 1 or a pharmaceutically acceptable salt thereof. In some embodiments, the daily dose is about 0.5 mg of Compound 1 or a pharmaceutically acceptable salt thereof. In some embodiments, the daily dose is about 0.75 mg of Compound 1 or a pharmaceutically acceptable salt thereof. In some embodiments, the daily dose is about 1 mg of Compound 1 or a pharmaceutically acceptable salt thereof. In some embodiments, the daily dose is about 1.25 mg, 1.5 mg, or 1.75 mg of Compound 1 or a pharmaceutically acceptable salt thereof. In some embodiments, the daily dose is about 2 mg, 2.25 mg, 2.5 mg, or 2.75 mg of Compound 1 or a pharmaceutically acceptable salt thereof. In some embodiments, the daily dose is about 3 mg of Compound 1 or a pharmaceutically acceptable salt thereof. In some embodiments, the daily dose is about 4 mg of Compound 1 or a pharmaceutically acceptable salt thereof. In some embodiments, the subject is treated for at least 7 days, for at least 14 days, for at least 21 days, for at least 28 days, for at least 35 days, for at least 42 days, for at least 49 days, or for at least 56 days. In some embodiments, the subject is treated for at least 1 month, 2 months, 3 months, 4 months, 5 months or 6 months. In some embodiments, the subject is administered a lower daily dose for a first period of time and then the subject is administered a higher daily dose for a second period of time. Also provided herein is a method of treating a disease, disorder, or condition mediated by AMPA receptor activity in a subject in need thereof, the method comprising orally administering a lower daily dose of Compound 1 or a pharmaceutically acceptable salt 12 IPTS / 128949854.1 Attorney Docket No. PNP-008WO thereof to the subject for a first period of time and then a higher daily dose of Compound 1 or a pharmaceutically acceptable salt thereof to the subject for a second period of time. In some embodiments, the lower daily dose is about 0.125 mg, about 0.25 mg, about 0.5 mg, about 0.6 mg, about 0.7 mg, about 0.75 mg, about 0.8 mg, about 0.9 mg, or about 1 mg of Compound 1 or a pharmaceutically acceptable salt thereof. In some embodiments, the higher daily dose is about 0.75 mg, about 1 mg, about 1.1 mg, about 1.2 mg, about 1.25 mg, about 1.3 mg, about 1.4 mg, about 1.5 mg, or about 1.75 mg of Compound 1 or a pharmaceutically acceptable salt thereof. In some embodiments, the first period of time is 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 8 days, at least 9 days, at least 10 days, or at least 14 days. In some embodiments, the second period of time is at least 10 days, at least 20 days, at least 30 days, at least 40 days, at least 50 days, at least 60 days, at least 2 months, at least 3 months, at least 4 months, at least 5 months, or at least 6 months. In some embodiments, the subject is administered a first daily dose for a first period of time, then the subject is optionally administered a second daily dose for a second period of time, and then the subject is administered a final daily dose for a third period of time. In certain embodiments, the first daily dose is about 0.125 mg, about 0.25 mg, about 0.50 mg, or about 0.75 mg of Compound 1 or a pharmaceutically acceptable salt thereof. In other embodiments, the second daily dose is about 0.25 mg, about 0.50 mg, about 0.75 mg, about 1.0 mg, or about 1.25 mg of Compound 1 or a pharmaceutically acceptable salt thereof. In some embodiments, the final daily dose is about 0.75 mg, about 1.0 mg, about 1.25 mg, about 1.5 mg, or about 1.75 mg of Compound 1 or a pharmaceutically acceptable salt thereof. In certain embodiments, the first period of time is at least 2 days, at least 3 days, at least 4 days, or at least 5 days. In other embodiments, the second period of time is 1, 2, 3, 4, or 5 days. In some embodiments, the third period of time is at least 20 days, at least 30 days, at least 40 days, at least 50 days, at least 60 days, at least 3 months, at least 4 months, at least 5 months, or at least 6 months. In some embodiments, the method results in improved tolerability in the subject. In some embodiments, the method does not result in a serious adverse event (SAE) in the subject. In some embodiments, the serious adverse event is assessed by the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI-CTCAE). 13 IPTS / 128949854.1 Attorney Docket No. PNP-008WO In some embodiments, the method does not result in a clinically meaningful change in laboratory values or electrocardiograms (ECG) or a relevant vital sign change in the subject. In some embodiments, the method does not result in dose-limiting toxicities (DLT). In some embodiments, the subject is between 18 and 90 years old (e.g., between 18 and 80 years old, between 18 and 70 years old, between 18 and 60 years old, between 18 and 55 years old). In some embodiments, Compound 1 or pharmaceutically acceptable salt thereof can be administered to the subject without regard to food intake of the subject. In some embodiments, administration of a compound of the disclosure, or pharmaceutically acceptable salt thereof, is effective in preventing a disease, disorder, or condition mediated by AMPA receptor activity in an individual who may be predisposed to the disease, disorder, or condition but does not yet experience or display the pathology or symptomatology of the disease, disorder, or condition. III. PHARMACEUTICAL COMPOSITIONS AND ROUTES OF ADMINISTRATION The compounds of the present disclosure (e.g., Compound 1 or a pharmaceutically acceptable salt thereof) are used, alone or in combination with one or more additional active ingredients, to formulate pharmaceutical compositions. A pharmaceutical composition of the present disclosure comprises: (a) an effective amount of at least one compound in accordance with the present disclosure (e.g., Compound 1 or a pharmaceutically acceptable salt thereof) and (b) a pharmaceutically acceptable excipient. Delivery forms of the pharmaceutical compositions containing one or more dosage units of the active agents may be prepared using suitable pharmaceutical excipients and compounding techniques known or that become available to those skilled in the art. The compositions may be administered in the inventive methods by a suitable route of delivery, e.g., oral, parenteral, rectal, topical, or ocular routes, or by inhalation. The preparation may be in the form of tablets, capsules, sachets, dragees, powders, granules, lozenges, powders for reconstitution, liquid preparations, or suppositories. Preferably, the compositions are formulated for intravenous infusion, topical administration, or oral administration. 14 IPTS / 128949854.1 Attorney Docket No. PNP-008WO In one aspect, the present disclosure provides an oral formulation comprising: from about 0.1 mg to about 5 mg of Compound 1 or a pharmaceutically acceptable salt thereof; and a pharmaceutically acceptable excipient; wherein the oral formulation is in the form of tablet. In some embodiments, the oral formulation comprises about 0.1 mg, about 0.125 mg, about 0.2 mg, about 0.25 mg, about 0.3 mg, about 0.4 mg, about 0.5 mg, about 0.6 mg, about 0.7 mg, about 0.7 mg, about 0.8 mg, about 0.9 mg, about 1 mg, about 1.1 mg, about 1.2 mg, about 1.25 mg, about 1.3 mg, about 1.4 mg, about 1.5 mg, about 1.6 mg, about 1.7 mg, about 1.75 mg, about 1.8 mg, about 1.9 mg, about 2 mg, about 2.1 mg, about 2.2 mg, about 2.25 mg, about 2.3 mg, about 2.4 mg, about 2.5 mg, about 2.6 mg, about 2.7 mg, about 2.75 mg, about 2.8 mg, about 2.9 mg, about 3 mg, about 3.1 mg, about 3.2 mg, about 3.25 mg, about 3.3 mg, about 3.4 mg, about 3.5 mg, about 3.6 mg, about 3.7 mg, about 3.75 mg, about 3.8 mg, about 3.9 mg, about 4 mg, about 4.1 mg, about 4.2 mg, about 4.25 mg, about 4.3 mg, about 4.4 mg, about 4.5 mg, about 4.6 mg, about 4.7 mg, about 4.75 mg, about 4.8 mg, about 4.9 mg, or about 5 mg of Compound 1 or a pharmaceutically acceptable salt thereof. In some embodiments, the formulation comprises about 0.25 mg of Compound 1 or a pharmaceutically acceptable salt thereof. In some embodiments, the formulation comprises about 0.75 mg of Compound 1 or a pharmaceutically acceptable salt thereof. In some embodiments, the formulation comprises about 1.0 mg of Compound 1 or a pharmaceutically acceptable salt thereof. In some embodiments, the formulation comprises about 1.25 mg of Compound 1 or a pharmaceutically acceptable salt thereof. In some embodiments, the formulation comprises about 1.75 mg of Compound 1 or a pharmaceutically acceptable salt thereof. In some embodiments, the formulation comprises about 2.25 mg of Compound 1 or a pharmaceutically acceptable salt thereof. For oral administration, the compounds of the present disclosure can be provided in the form of tablets or capsules, or as a solution, emulsion, or suspension. Oral tablets may include a compound according to the present disclosure mixed with pharmaceutically acceptable excipients such as inert diluents, disintegrating agents, binding agents, lubricating agents, sweetening agents, flavoring agents, coloring agents and preservative agents. Suitable inert fillers include sodium and calcium carbonate, sodium and calcium phosphate, lactose, starch, sugar, glucose, methyl cellulose, magnesium stearate, mannitol, sorbitol, and the like. Exemplary liquid oral excipients include ethanol, glycerol, 15 IPTS / 128949854.1 Attorney Docket No. PNP-008WO water, and the like. Starch, polyvinyl-pyrrolidone (PVP), sodium starch glycolate, microcrystalline cellulose, and alginic acid are suitable disintegrating agents. Binding agents may include starch and gelatin. The lubricating agent, if present, may be magnesium stearate, stearic acid or talc. If desired, the tablets may be coated with a material such as glyceryl monostearate or glyceryl distearate to delay absorption in the gastrointestinal tract, or may be coated with an enteric coating. Capsules for oral administration include hard and soft gelatin capsules. To prepare hard gelatin capsules, compounds of the present disclosure may be mixed with a solid, semi- solid, or liquid diluent. Soft gelatin capsules may be prepared by mixing the compound of the present disclosure with water, an oil such as peanut oil or olive oil, liquid paraffin, a mixture of mono and di-glycerides of short chain fatty acids, polyethylene glycol 400, or propylene glycol. Liquids for oral administration may be in the form of suspensions, solutions, emulsions or syrups or may be lyophilized or presented as a dry product for reconstitution with water or other suitable vehicle before use. Such liquid compositions may optionally contain: pharmaceutically-acceptable excipients such as suspending agents (for example, sorbitol, methyl cellulose, sodium alginate, gelatin, hydroxyethylcellulose, carboxymethylcellulose, aluminum stearate gel and the like); non-aqueous vehicles, e.g., oil (for example, almond oil or fractionated coconut oil), propylene glycol, ethyl alcohol, or water; preservatives (for example, methyl or propyl p-hydroxybenzoate or sorbic acid); wetting agents such as lecithin; and, if desired, flavoring or coloring agents. The active agents of this disclosure may also be administered by non-oral routes. For example, the compositions may be formulated for rectal administration as a suppository. For parenteral use, including intravenous, intramuscular, intraperitoneal, or subcutaneous routes, the compounds of the present disclosure may be provided in sterile aqueous solutions or suspensions, buffered to an appropriate pH and isotonicity or in parenterally acceptable oil. Suitable aqueous vehicles include Ringer's solution and isotonic sodium chloride. Such forms will be presented in unit-dose form such as ampules or disposable injection devices, in multi-dose forms such as vials from which the appropriate dose may be withdrawn, or in a solid form or pre-concentrate that can be used to prepare an injectable formulation. Illustrative infusion doses may range from about 1 to 1000.mg / kg / minute of compound, admixed with a pharmaceutical carrier over a period ranging from several minutes to several days. 16 IPTS / 128949854.1 Attorney Docket No. PNP-008WO For topical administration, the compounds may be mixed with a pharmaceutical carrier at a concentration of about 0.1% to about 10% of drug to vehicle. Another mode of administering the compounds of the present disclosure may utilize a patch formulation to affect transdermal delivery. The compounds of the present disclosure may alternatively be administered in methods of this disclosure by inhalation, via the nasal or oral routes, e.g., in a spray formulation also containing a suitable carrier. EXAMPLES In order that the disclosure described herein may be more fully understood, the following examples are set forth. The examples described in this application are offered to illustrate the particles, compositions, and methods provided herein and are not to be construed in any way as limiting their scope. Example 1A. Single Ascending Dose and Food Effect, Safety, and Pharmacokinetic Study of Compound 1 in Healthy Participants This is a 2-part double-blinded, randomized, placebo-controlled single ascending dose (SAD) safety, tolerability, and pharmacokinetic (PK) study of Compound 1 in healthy participants (Part 1), with a separate cohort assessing the effect of a high-fat meal on the PK of Compound 1 (Part 2). In Part 1 SAD study, each healthy participant received a single dose of Compound 1 on Day 1 and was observed for 1 week following Compound 1 administration. In Part 2 food effect (FE) study, each participant received a dose of Compound 1 on Day 1 with a high-fat meal and was observed for 1 week following the dose. The objectives and endpoints of this study are summarized in Table 1. 17 IPTS / 128949854.1 Attorney Docket No. PNP-008WO Table 1. Objectives and Endpoints Objectives Endpoints d x Methodology Part 1 SAD Study Five or more dose levels of Compound 1 vs placebo were evaluated in Part 1 of this study, as shown below. 18 IPTS / 128949854.1 Attorney Docket No. PNP-008WO Table 2. Study design Part 1 Single Dose of Compound Compound 1 Number of Cohort 1 FormulationParticipantsao Part 2 FE Study One cohort of six healthy participants were enrolled to investigate the effect of food on the bioavailability of Compound 1. The dose of Compound 1 to be administered with food was determined based on the emerging safety, tolerability, and PK data from Part 1. Conduct of Part 2 was the same as Part 1 with the following differences: (1) study medication was administered in a fed condition and (2) this was an open-label study with all participants receiving Compound 1. Assessment of Safety Safety was assessed through the monitoring of AEs (including DLTs), clinical laboratory evaluations, electrocardiograms (ECGs), and physical and neurological examinations. Assessment of Pharmacokinetics Blood samples for PK were collected for pharmacokinetics assessment. Diagnosis and study population (key eligibility criteria): Inclusion Criteria ^ Healthy participants between 18 and 55 years old (inclusive) at Screening. ^ Medically healthy at Screening with no clinically significant or relevant diseases, abnormalities, or medical conditions as determined by the Investigator based on the participant’s medical history, physical and neurological exam, vital signs, ECG, or laboratory evaluations (hematology, chemistry, and urinalysis) 19 IPTS / 128949854.1 Attorney Docket No. PNP-008WO ^ Body weight ≥ 50 kg (110 lbs.) and a body mass index ≥ 18 and ≤ 32 kg / m2Exclusion Criteria ^ Any clinically significant abnormality on physical examination at Screening that, in the opinion of the Investigator, would require exclusion from the study ^ Abnormal resting vital signs prior to dosing ^ Clinically significant abnormal safety laboratory parameters at Screening (serum chemistry, hematology, or urinalysis) per Investigator ^ A history of cardiac abnormalities, including a family history of long QT syndrome ^ Abnormal and clinically relevant ECG changes at Screening. Example 1B. Randomized, Double-blind, Placebo-controlled, Multiple Ascending Dose, Safety, Tolerability, and Pharmacokinetic Study of Compound 1 in Healthy Participants This is a randomized double-blind, placebo-controlled, multiple ascending dose (MAD) study designed to evaluate the safety, tolerability, and PK profile of Compound 1 in healthy participants. The objectives and endpoints of this study are summarized in Table 3. Table 3. Objectives and Endpoints Objectives Endpoints ), 20 IPTS / 128949854.1 Attorney Docket No. PNP-008WO Exploratory ^ To evaluate the effect of ^ Analysis od ECG parameters M gy In Cohorts 1 and 2, each participant received once daily (QD) oral doses of Compound 1 or placebo for 14 days and was followed for 4 weeks after the last dose. In Cohorts 3 and 4, each participant received QD oral doses of Compound 1 or placebo for 28 days and were followed for 4 weeks after the last dose. Four dose levels were planned to be evaluated in this study (Table 4). Table 4. Study design Cohort Maximally Compound 1 Compound 1 Compound 1 Compound 1 Number of Targeted Formulation Formulation Formulation Formulation Evaluable Dose of Administered Administered Administered Administered Partici ants o aUp to two additional dose levels / cohorts were added depending upon the emerging adverse events and PK data frompreceding doses.In Cohort 5 (optional), each participant received 0.75 mg QD of Compound 1 or placebo for 5 days followed by 1.25 mg QD of Compound 1 for 23 days. Assessment of Safety Safety was assessed through the monitoring of adverse events (AEs) (including dose-limiting toxicities [DLTs]), clinical laboratory evaluations, ECGs, physical examinations (PEs) and neurological examinations. Assessment of Pharmacokinetics 21 IPTS / 128949854.1 Attorney Docket No. PNP-008WO Blood samples for PK were collected to assess pharmacokinetics. Diagnosis and study population (key eligibility criteria): Inclusion Criteria ^ Healthy participants between 18 and 55 years old (inclusive) at Screening. ^ Medically healthy at Screening with no clinically significant or relevant diseases, abnormalities, or medical conditions as determined by the Investigator based on the participant’s medical history, PE and neurological exam, vital signs, ECG, or laboratory evaluations (hematology, chemistry, and urinalysis). ^ Body weight ≥ 50 kg (110 lbs.) and a body mass index ≥ 18 and ≤ 32 kg / m2. Exclusion Criteria ^ Any clinically significant abnormality on PE at Screening that, in the opinion of the Investigator, would require exclusion from the study. ^ Abnormal resting vital signs prior to dosing. ^ Clinically significant abnormal safety laboratory parameters at Screening (serum chemistry, hematology, or urinalysis) per Investigator and / or Sponsor. ^ A history of cardiac abnormalities, including a family history of long QT syndrome. ^ Abnormal and clinically relevant ECG changes at Screening. In Examples 1A and 1B, two trials in healthy adult volunteers to assess the safety, tolerability and pharmacokinetics of Compound 1 were conducted. The first Phase 1 trial had two parts. Part 1 was a randomized, double-blind and placebo-controlled SAD trial that evaluated doses from 0.25 mg to 3 mg and Part 2 was an open label single cohort evaluation of the effect of a high-fat meal on the pharmacokinetics of a 1 mg single dose of Compound 1. The second Phase 1 trial was a randomized, double-blind and placebo-controlled MAD trial that evaluated once-daily doses ranging from 0.25 mg to 1.25 mg over two or four weeks. Each cohort for the SAD Part 1 and MAD trials consisted of six subjects receiving Compound 1 and two subjects receiving a placebo. In Part 2 of the SAD trial, there were six subjects who all received Compound 1. Part 1 and Part 2 of the SAD trial is unblinded, whereas the MAD trial has completed but currently remains blinded and awaiting database lock. For both Phase 1 trials, no clinically meaningful abnormal changes in laboratory values or ECG were observed, nor were there any relevant vital sign changes. In the SAD Part 1 trial, 22 IPTS / 128949854.1 Attorney Docket No. PNP-008WO all doses were well tolerated with no SAEs, and all drug related treatment emergent adverse events (“TEAEs”) were rated as mild (grade 1) or moderate (grade 2). All moderate drug related TEAEs observed were at the two highest doses (2 mg and 3 mg) and were generally consistent with the effects seen in nonclinical toxicology studies with Compound 1. The pharmacokinetics of Compound 1 in the SAD Part 1 trial were consistent with the observations from the nonclinical studies, characterized by low clearance and a long terminal elimination half-life of approximately 8 to 14 days (Table 5). Table 5. PK Parameters of Compound 1 after Administration of Compound 1 Tablets under Fasted Conditions (Part I) – PK Analysis Population bTwo potential outliers in T1 / 2 estimation were observed for Cohort 3 (Subject 1307, 1140 hours) and Cohort 4 (Subject 1405, 3850 hours). After excluding the 1140 hour T1 / 2 value for Cohort 3, the mean T1 / 2 was 181 hours and CV% was 63.3%. After excluding the 3850 hour T1 / 2 value for Cohort 4, the mean T1 / 2 was 568 hours and CV% was 64.0%. Cohort 1 = 0.25 mg (1 x 0.25 mg Compound 1 tablet); Cohort 2 = 0.5 mg (2 x 0.25 mg Compound 1 tablet); Cohort 3 = 1 mg (1 x 1 mg Compound 1 tablet); Cohort 4 = 2 mg (2 x 1 mg Compound 1 tablet); Cohort 5 = 3 mg (3 x 1 mg Compound 1- tablet) Samples were collected through 144 hours for Cohorts 1 and 2 and through 312 hours for Cohorts 3, 4, and 5. In the SAD Part 2 trial, a modest increase in overall exposure (25 percent increase in area under the curve) and maximum exposure (42 percent increase in Cmax) were observed when Compound 1 was dosed with a high-fat, high-calorie meal (Table 6). Based on the 23 IPTS / 128949854.1 Attorney Docket No. PNP-008WO emerging safety profile and the observed food effect, it is believed that Compound 1 can be dosed without regard to food. Table 6. Statistical Analysis of the Natural Log-Transformed Systemic Exposure of Compound 1 Comparing Administration of Compound 1 (1 mg) Tablet under Fed (Test) and Fasted (Reference) Conditions – PK Analysis Population Dependent GeoMeanaGeoMeanaRatio (%)b90% CIc90% CIcANOVA Variable Fed Fasted (Fed / Fasted) Lower U er CV% a Geometric Mean based on Least Squares Mean b Ratio(%) = Geometric Mean (Test) / Geometric Mean (Ref) c 90% Confidence Interval There were five cohorts in the Phase 1 MAD trial. In the MAD trial, all doses were well tolerated with no SAEs and all drug related TEAEs were rated as mild (grade 1). FIG.1 shows the pharmacokinetic profile of Compound 1 following the two highest single doses from the SAD trial and following the last dose (Day 28) of the two highest dose levels (Cohorts 4 and 5) in the MAD trial. Cohort 4 of the MAD trial was dosed at 0.75 mg per day for 28 days and achieved projected receptor occupancy of 70 percent at day 28 trough. The last cohort of the MAD trial (Cohort 5) was dosed at 0.75 mg per day for 5 days followed by 1.25 mg per day for 23 days. Unaudited blinded data from Cohort 5 indicated maximum exposures (Cmax) up to 3-fold higher than those achieved following the highest single dose (3 mg) in the Phase 1 SAD trial (FIG.1). No drug related TEAEs were observed in any subject in Cohort 5. These observations from the MAD trial, notably the absence of sedation and motoric impairments in Cohort 5, are consistent with the targeted action of Compound 1 to regions of the CNS where TARPγ8 AMPAR is present, in contrast to the effects of other approved anti- seizure medications (ASMs). Example 2. Second Randomized, Double-blind, Placebo-controlled, Multiple Ascending Dose, Safety, Tolerability, and Pharmacokinetic Study of Compound 1 in Healthy Participants This is a second randomized double-blind, placebo-controlled, multiple ascending dose (MAD) study. This study was conducted to evaluate the safety, tolerability, and PK in 24 IPTS / 128949854.1 Attorney Docket No. PNP-008WO dose regimens that employed a faster titration and higher dose than those used in an initial MAD study (Example 1b). The objectives and endpoints of this study are summarized in Table 7. Table 7. Objectives and Endpoints Objectives Endpoints Primary ), as y In Part A, participants received once daily (QD) oral doses of Compound 1 or placebo for 8 days and were followed for 2 weeks after the last dose. Participants were admitted into the clinical research unit (CRU) on Day -1 and were confined to the CRU until Day 11. 25 IPTS / 128949854.1 Attorney Docket No. PNP-008WO Participants were discharged on Day 11 after completion of all assessments and after being deemed medically stable by the Investigator. Participants returned to the CRU for scheduled follow-up visits on Days 15 and 22 (End of Study [EOS]). In Part B, participants received QD oral doses of Compound 1 or placebo for 28 days and were followed for 4 weeks after the last dose. Participants were admitted into the CRU on Day -1 and were confined to the CRU until Day 31. Participants were discharged on Day 31 after completion of all assessments and after being deemed medically stable by the Investigator. Participants returned to the CRU for scheduled follow-up visits on Days 35, 42, and 56 (EOS). The dosing regimens for Cohorts 1 to 3 were as follows: Table 8. Dosing regimens PartaCohort Dose of Compound 1 Compound 1 Formulation Administered (6 active, the the the the the a P Participants were monitored continuously for adverse events (AEs) while on study as well as dose-limiting toxicities (DLTs), defined as any AE or lab abnormality of Common Terminology Criteria for Adverse Events Version 5.0 Grade ≥3 determined to be related to study drug occurring through Day 11 for Part A or through Day 31 for Part B (the DLT evaluation period). For the study’s exploratory objective, cardiodynamic evaluation with serial ECGs extracted from continuous (Holter) recordings paired with PK samples was also performed. Number of Participants (Planned and Analyzed): At least 8 participants were planned to be enrolled and randomized per dose cohort (6 active and 2 placebo). A total of 24 participants were enrolled and randomized: 18 who 26 IPTS / 128949854.1 Attorney Docket No. PNP-008WO received Compound 1 (6 each in Cohorts 1, 2, and 3) and 6 who received placebo (2 each in placebo cohorts matched to Cohorts 1, 2, and 3). Diagnosis and Main Criteria for Inclusion: Inclusion Criteria included the following: ^ Healthy participants between 18 and 55 years old (inclusive) at Screening ^ Medically healthy at Screening with no clinically significant or relevant diseases, abnormalities, or medical conditions as determined by the Investigator based on the participant’s medical history, physical examination, neurological examination, vital signs, ECG, or laboratory evaluations (hematology, chemistry, and urinalysis) ^ Body weight ≥50 kg (110 lb) and a body mass index ≥18 and ≤32 kg / m2at Screening Exclusion Criteria included the following: ^ History of or had any evidence of diabetes mellitus History of renal or liver impairment, autoimmune disease, inflammatory bowel disease, or other disease that could affect the action, absorption, or disposition of the study drug or the clinical or laboratory assessments ^ Documented history or positive serological testing at Screening of HIV, hepatitis B, or hepatitis C, that had not resolved >4 weeks prior to dosing ^ History of malignancy, with exception of nonmelanoma skin cancer or cancer curatively treated ≥5 years before study without evidence of recurrence ^ Underwent a surgical procedure within 3 months before study entry or had any surgical procedure anticipated to be required during the study. If a previous surgical procedure was performed within 3 months and a full recovery was made with no expected impact on study procedures, or safety, then the participant may have been eligible at the discretion of the Investigator and the Medical Monitor ^ Any clinically significant abnormality on physical examination or abnormal safety laboratory parameters at Screening ^ Abnormal resting vital signs prior to dosing (Screening, Day -1): a. Systolic blood pressure <90 or >140 mmHg b. Diastolic blood pressure <50 or >90 mmHg Vital signs may have been repeated once for eligibility purposes if out of range ^ A history of cardiac abnormalities, including a family history of long QT syndrome and / or family history of sudden death in an otherwise healthy individual between the 27 IPTS / 128949854.1 Attorney Docket No. PNP-008WO ages of 1 and 30 years ^ Abnormal and clinically relevant ECG changes at Screening, such as: a. Bradycardia or tachycardia (sinus rate <40 or >90 bpm) b. Complete left bundle branch block c. Right bundle branch block d. Type I or Type II second-degree or third-degree heart block e. Intraventricular conduction delay with QRS duration >120 ms, corrected QT interval using Fridericia’s formula duration >450 ms (males) or >470 ms (females) f. Pathological Q-wave g. Symptomatic or asymptomatic arrhythmias (excluding sinus arrhythmia) h. Evidence of ventricular pre-excitation i. Frequent palpitations or syncopal episodes j. Heart failure ^ Current or recurrent neurological disease (including migraines) or any abnormal finding on neurological examination ^ Current or history of any psychiatric disease Duration of Treatment: Study duration was up to 50 days for Part A (Cohorts 1 and 2), including Screening (Day -28 to Day -2), Inpatient Period (Day -1 to Day 11) with 8 days of dosing, and Follow- up through Day 22. Study duration was up to 84 days for Part B (Cohort 3), including Screening (Day - 28 to Day -2), Inpatient Period (Day -1 to Day 31) with 28 days of dosing, and Follow-up through Day 56. Statistical Methods: Safety Analysis TEAEs were summarized by cohort, treatment, pooled placebo, and pooled active, and system organ class and preferred term, including the number and percentage of participants experiencing events, separately. TEAEs were also summarized by intensity grading and relationship to study drug. Pharmacokinetic Analysis 28 IPTS / 128949854.1 Attorney Docket No. PNP-008WO Plasma concentrations of Compound 1 was summarized by cohort, day, and nominal time point for the PK Analysis Set. The following descriptive statistics was presented for plasma concentrations obtained at each nominal time point: N, n, n(below the level of quantification), arithmetic mean, standard deviation, coefficient of variation (CV%), geometric mean, geometric CV%, median, minimum, and maximum values. PK parameters were summarized by treatment and cohort for the PK Analysis Set. SAFETY RESULTS: Overall, Compound 1 was generally well tolerated at all doses administered. There were no deaths, SAEs, DLTs, or >Grade 2 TEAEs. There were no clinically meaningful changes in laboratory evaluations, vital signs, ECGs, or physical or neurological examinations. Overall, tolerability was consistent with that observed in previous Phase 1 clinical studies with Compound 1 and was acceptable over the dose regimens administered. PHARMACOKINETICS RESULTS: FIG.2 shows the pharmacokinetic profile of Compound 1 following the two highest single doses from the SAD trial (Example 1a), the last dose (Day 28) of the two highest dose levels (Cohorts 4 and 5) in the first MAD trial (Example 1b), and following the last dose (Day 28) of the highest dose level (Cohort 3) in the second MAD trial (Example 2), along with preliminary receptor occupancy based on data from the human PET trial. Cohort 4 of the first MAD trial was dosed at 0.75 mg per day for 28 days and exceeded the preliminary human receptor occupancy level of 70% at day 28 trough. Cohort 5 of the first MAD trial was dosed at 0.75 mg per day for 5 days followed by 1.25 mg per day for 23 days. Data from Cohort 5 showed maximum exposures (Cmax) up to 3-fold higher than those achieved following the highest single dose (3 mg) in the Phase 1 SAD trial and were approximately at the human receptor occupancy level of 85% at day 28 trough. Cohort 3 of the MAD-2 trial was dosed at 0.5 mg per day for 2 days, 1.0 mg per day for 2 days, and 1.75 mg per day for 24 days. Preliminary data from this cohort suggest an approximate 4-fold increase in Cmax compared to the highest single dose (3 mg) in the SAD trial and exceeded the preliminary human receptor occupancy level of 85%. Data from the MAD-2 trial demonstrated that dose titration was feasible after just two days of dosing at the starting dose, and that the higher dose of 1.75 mg once daily was generally well tolerated. Target exposures (those trough concentrations associated with 29 IPTS / 128949854.1 Attorney Docket No. PNP-008WO target projected receptor occupancy in pre-clinical models) were achieved within 5 days of dosing across various dosing regimens. Furthermore, FIG.3 shows that the dosing of Cohort 3 of the second MAD study (MAD-2 study) maintained high level (~80%) of receptor occupancy 28 days after the last dose (1.75 mg). Example 3. A Phase 1, Open-Label Study to Investigate the TARP-γ8 Receptor Occupancy of Compound 1 Using a TARP-γ8 PET Tracer in Healthy Adult Participants This is a Phase 1, open-label, multiple dose study designed to evaluate the safety, tolerability, brain receptor occupancy and pharmacokinetic (PK) profile of Compound 1 in healthy adult participants. A dose-dependent blocking of [18F]JNJ-64511070 uptake in the human brain by Compound 1 was assessed. To evaluate this, a baseline [18F]JNJ-64511070 PET / magnetic resonance (MR) scan and a post Compound 1 scan obtained following repeat dosing (approximately 3 hours post-final dose) were conducted. Number of Participants (Planned): Up to 24 healthy adult participants. Investigational product, dosage, and mode of administration: Compound 1 was formulated as a tablet for oral administration and the strength of tablets was 0.25 mg. PET Tracer and cold ligand: [18F]JNJ-64511070 compound was Good Manufacturing Practice (GMP) manufactured as a sterile solution of [18F]JNJ-64511070 radiotracer substance for intravenous (IV) injection through a venous line by the clinical site. Participants received approximately 185 MBq (5 mCi) (± 10%). 30 IPTS / 128949854.1 Attorney Docket No. PNP-008WO Objectives and endpoints Table 9. Objectives and endpoints Objectives Endpoints Primary e Participants were be admitted to the CCP unit on Day -1 and were confined to the CCP unit until Day 17, except for visits to the imaging facility on Days 1 and 15. Each participant received an IV injection of the PET tracer on two occasions (Day 1 and Day 15) and received QD oral doses of Compound 1 on Days 2 through 15. Participants were discharged from the CCP unit on Day 17 after completion of all assessments and after being deemed medically stable by the Investigator. Participants returnd to the CCP unit for scheduled follow-up visits on Days 21, 28, and 42 (End of Study). A minimum of one and up to four dose levels of Compound 1 was to be evaluated in this study at the discretion of the Sponsor. The highest well tolerated dose level from the 31 IPTS / 128949854.1 Attorney Docket No. PNP-008WO study of Example 1b was 0.75 mg QD for 5 days followed by 1.25 QD for up to 23 days. The proposed first dose level for this study was therefore be 0.75 mg QD for 5 days followed by 1.25 mg QD for 9 days. Additional lower dose levels were to be evaluated following evaluation of available brain RO, PK, and safety and tolerability data from the previous cohort, at the discretion of the Sponsor. Each dose level was planned to enroll 6 participants. Additional participants were to be added to any cohort at the discretion of the Sponsor based on safety findings, PK variability, PET imaging analysis, and / or to ensure the completion of 6 evaluable participants in each cohort. Assessment of Safety Safety was assessed through the monitoring of AEs, vital signs, clinical laboratory evaluations, ECGs, and neurological and physical examinations (PEs). All participants were followed for 4 weeks after the last dose of Compound 1 administration. Assessment of Pharmacokinetics Blood samples for PK were collected at particular timepoints. Assessment of Brain Receptor Occupancy A brain PET / MR-scan was obtained twice, once before the first dose of Compound 1 and once approximately 3 hours after the last dose of Compound 1. To enable the PET scan, an IV injection of approximately 185 MBq (5 mCi) of [18F]JNJ-64511070 was administered. Arterial blood sampling (parent and radiometabolite analysis of [18F]JNJ- 64511070) was performed at specified time points to calculate the input function and allow PET binding quantification. Diagnosis and study population (key eligibility criteria): Inclusion Criteria included the following: ^ Healthy participants between 18 and 55 years old (inclusive) at Screening. ^ Medically healthy at Screening with no clinically significant or relevant diseases, abnormalities, or medical conditions as determined by the Investigator based on the participant’s medical history, physical and neurological exam, vital signs, ECG, or laboratory evaluations (hematology, chemistry, and urinalysis). ^ Body mass index ≥ 18 and ≤ 32 kg / m2. ^ Sufficient arterial access, as determined by Allen’s test. 32 IPTS / 128949854.1 Attorney Docket No. PNP-008WO Exclusion Criteria included the following: ^ History of renal or liver impairment, autoimmune disease, inflammatory bowel disease, or other disease that could affect the action, absorption, or disposition of the investigational product or the clinical or laboratory assessments. ^ A documented history of HIV, hepatitis B (HBV), or hepatitis C (HCV) serology, that has not resolved > 4 weeks prior to dosing. ^ History of any malignancy. ^ Any prior brain surgery. ^ Undergone a surgical procedure within 6 months prior to screening or have any surgical procedure anticipated to be required during the study. If a previous surgical procedure was performed within 6 months and a full recovery was made with no expected impact on study procedures, or safety, then the participant may be eligible at the discretion of the Investigator and the medical monitor. ^ Any clinically significant abnormality on physical examination at Screening that, in the opinion of the Investigator, would require exclusion from the study. ^ Abnormal resting vital signs prior to inclusion (Screening, Day -1, Day 1): a. systolic blood pressure < 90 or > 150 mmHg b. diastolic blood pressure < 50 or > 90 mmHg ^ Clinically significant abnormal safety laboratory parameters at Screening (serum chemistry, hematology, or urinalysis) per the Investigator’s discretion. ^ A history of cardiac abnormalities, including a family history of long QT syndrome and / or family history of sudden death in an otherwise healthy individual between the ages of 1 and 30 years. ^ Abnormal and clinically relevant ECG changes at Screening, such as a. bradycardia or tachycardia (sinus rate < 40 or > 90 bpm) b. complete left bundle branch block c. complete right bundle branch block d. second- or third-degree heart block e. intraventricular conduction delay with QRS duration >120 ms, QTcF duration > 450 ms (males) or > 470 ms (females) f. pathological Q-wave g. symptomatic or asymptomatic arrhythmias (excluding sinus arrhythmia) h. evidence of ventricular pre-excitation 33 IPTS / 128949854.1 Attorney Docket No. PNP-008WO i. frequent palpitations or syncopal episodes j. heart failure ^ Any clinically significant neurological or psychiatric diagnosis, psychological or behavioral problems which, in the opinion of the investigator, would interfere with the participant’s ability to participate in the study. ^ Any suicidal ideation with intent with or without a plan within 2 years before screening or during screening (i.e., answering “Yes” to questions 4 or 5 on the Suicidal Ideation section of the Columbia-Suicide Severity Rating Scale [C-SSRS]). ^ Implanted metal or devices that are not magnetic resonance imaging (MRI) safe. ^ Any anatomical abnormality in the head that would either preclude or tend to confound the analysis of study data, including any clinically significant abnormal findings from MRI of the head. ^ Any medical condition or laboratory abnormality, that in the opinion of the Investigator, would prevent the participant from completing the study, pose a risk to the participant, or confound the ability to interpret study results. ^ Claustrophobia and / or inability to stay still during MRI or PET scans. ^ Participated in a previous research study with exposure to ionizing radiation above 1 mSv in the 12 months prior to inclusion. Statistical Methods: Safety and tolerability Safety data, including vital signs, ECGs, laboratory test results, neurological and physical examinations, and AEs were summarized by dose and assessment timepoints. Change from baseline were included in summary tables for laboratory, ECG, and vital sign parameters. Shifts in grade from baseline to maximum post-baseline grade were summarized for each dose level for applicable laboratory data. Receptor Occupancy (RO) PET images, corrected for motion if necessary, were co-registered rigidly with MRI using current available software by investigator. Head motion was preventively be minimized by appropriate fixing of the head inside the MR head coil at acquisition. Volumetric MRI images were segmented (grey-white matter) and grey matter volume of interest (VOI) 34 IPTS / 128949854.1 Attorney Docket No. PNP-008WO delineations were co-registered to the PET to generate grey-matter time activity curves for the selected brain structures. TARPγ8 occupancy was estimated using baseline and post dose distribution volumes and a Lassen plot, assuming the non-displaceable distribution volume to be constant between baseline and post dose conditions. Distribution volumes was determined by a two-tissue compartment model that was previously validated. Summary The human PET trial was an open label trial in healthy volunteers which utilized a companion PET radiotracer to confirm brain region selectivity and brain target receptor occupancy across a range of dosing and exposure levels, and was designed to confirm neuroanatomical distribution of TARPγ8 and establish the relationship between plasma concentration and brain receptor occupancy after 14 days of dosing with Compound 1 under different dosing regimens. There were three cohorts in the Phase 1 PET trial: Cohort 1 was given the same dosing regimen currently being used in a Phase 2a trial in refractory focal epilepsy (0.75 mg daily for 5 days, followed by 1.25 mg daily for 9 days), and lower doses were used in the other two cohorts to better characterize the plasma concentration versus receptor occupancy relationship. The preliminary PET data demonstrated that Cohort 1 exceeded the projected target receptor occupancy range associated with maximal seizure protection in preclinical models (50%-70%) within five days of dosing while maintaining a tolerability profile generally consistent with prior Phase 1 trial findings. The trial also confirmed that the expression of TARPγ8-containing AMPA receptors is enriched in the hippocampus and cerebral cortex and is minimal in the cerebellum and brain stem (FIG.4). EQUIVALENTS AND SCOPE In the claims articles such as “a,” “an,” and “the” may mean one or more than one unless indicated to the contrary or otherwise evident from the context. 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 35 IPTS / 128949854.1 Attorney Docket No. PNP-008WO includes embodiments in which more than one, or all of the group members are present in, employed in, or otherwise relevant to a given product or process. Furthermore, the disclosure encompasses all variations, combinations, and permutations in which one or more limitations, elements, clauses, and descriptive terms from one or more of the listed claims is introduced into another claim. For example, any claim that is dependent on another claim can be modified to include one or more limitations found in any other claim that is dependent on the same base claim. Where elements are presented as lists, e.g., in Markush group format, each subgroup of the elements is also disclosed, and any element(s) can be removed from the group. It should it be understood that, in general, where the disclosure, or aspects of the disclosure, is / are referred to as comprising particular elements and / or features, certain embodiments of the disclosure or aspects of the disclosure consist, or consist essentially of, such elements and / or features. For purposes of simplicity, those embodiments have not been specifically set forth in haec verba herein. It is also noted that the terms “comprising” and “containing” are intended to be open and permits the inclusion of additional elements or steps. Where ranges are given, endpoints are included. Furthermore, unless otherwise indicated or otherwise evident from the context and understanding of one of ordinary skill in the art, values that are expressed as ranges can assume any specific value or sub–range within the stated ranges in different embodiments of the disclosure, to the tenth of the unit of the lower limit of the range, unless the context clearly dictates otherwise. This application refers to various issued patents, published patent applications, journal articles, and other publications, all of which are incorporated herein by reference. If there is a conflict between any of the incorporated references and the instant specification, the specification shall control. In addition, any particular embodiment of the present disclosure that falls within the prior art may be explicitly excluded from any one or more of the claims. Because such embodiments are deemed to be known to one of ordinary skill in the art, they may be excluded even if the exclusion is not set forth explicitly herein. Any particular embodiment of the disclosure can be excluded from any claim, for any reason, whether or not related to the existence of prior art. Those skilled in the art will recognize or be able to ascertain using no more than routine experimentation many equivalents to the specific embodiments described herein. The scope of the present embodiments described herein is not intended to be limited to the above 36 IPTS / 128949854.1 Attorney Docket No. PNP-008WO Description, but rather is as set forth in the appended claims. Those of ordinary skill in the art will appreciate that various changes and modifications to this description may be made without departing from the spirit or scope of the present disclosure, as defined in the following claims. 37 IPTS / 128949854.1

Claims

Attorney Docket No. PNP-008WO Claims 1. A method of treating a disease, disorder, or condition mediated by AMPA receptor activity in a subject in need thereof, the method comprising orally administering a daily dose of Compound 1 or a pharmaceutically acceptable salt thereof to the subject, wherein the daily dose is from about 0.1 mg to about 5 mg of Compound 1 or a pharmaceutically acceptable salt thereof.

2. The method of claim 1, wherein the daily dose is administered to the subject for at least 2 consecutive days.

3. The method of claim 1, wherein the daily dose is administered to the subject for at least 5 consecutive days.

4. The method of any one of claims 1-3, wherein the daily dose is administered to the subject for chronic administration for at least 5 days out of 7 days of treatment.

5. The method of any one of claims 1-4, wherein the daily dose is administered to the subject for chronic administration for at least 6 days out of 7 days of treatment.

6. The method of any one of claims 1-5, wherein the daily dose is administered to the subject daily.

7. The method of any one of claims 1-6, wherein the disease, disorder, or condition mediated by AMPA receptor activity is selected from the group consisting of epilepsy, seizure, pain, a cognitive disorder, neurodegenerative disorder, and a psychiatric disorder.

8. The method of claim 7, wherein the epilepsy is focal epilepsy.

9. The method of claim 8, wherein the focal epilepsy is drug-resistant focal epilepsy.

10. The method of claim 7, wherein the pain is peripheral neuropathic pain.

11. The method of claim 10, wherein the peripheral neuropathic pain is selected from the group consisting of diabetic neuropathy (e.g., diabetic peripheral neuropathy), postherpetic neuralgia, trigeminal neuralgia, and idiopathic sensory polyneuropathy.

12. The method of claim 7, wherein the pain is arthritis (e.g., osteoarthritis).

13. The method of claim 7, wherein the psychiatric disorder is selected from the group consisting of bipolar disorder, anxiety, schizophrenia, depression, ADHD, PTSD, and MDD.

14. The method of claim 13, wherein the psychiatric disorder is bipolar disorder. 38 IPTS / 128949854.1Attorney Docket No. PNP-008WO 15. The method of claim 14, wherein the bipolar disorder has acute mania.

16. The method of claim 7, wherein the neurodegenerative disorder is Alzheimer's disease.

17. The method of claim 7, wherein the seizure is seizure (e.g., clinical seizure) associated with Alzheimer's disease.

18. The method of any one of claims 1-17, wherein the daily dose is administered to the subject in a single administration.

19. The method of any one of claims 1-18, wherein the daily dose is about 0.125 mg of Compound 1 or a pharmaceutically acceptable salt thereof.

20. The method of any one of claims 1-18, wherein the daily dose is about 0.25 mg of Compound 1 or a pharmaceutically acceptable salt thereof.

21. The method of any one of claims 1-18, wherein the daily dose is about 0.5 mg of Compound 1 or a pharmaceutically acceptable salt thereof.

22. The method of any one of claims 1-18, wherein the daily dose is about 0.75 mg of Compound 1 or a pharmaceutically acceptable salt thereof.

23. The method of any one of claims 1-18, wherein the daily dose is about 1 mg of Compound 1 or a pharmaceutically acceptable salt thereof.

24. The method of any one of claims 1-18, wherein the daily dose is about 1.25 mg of Compound 1 or a pharmaceutically acceptable salt thereof.

25. The method of any one of claims 1-18, wherein the daily dose is about 1.75 mg of Compound 1 or a pharmaceutically acceptable salt thereof.

26. The method of any one of claims 1-18, wherein the daily dose is about 2 mg of Compound 1 or a pharmaceutically acceptable salt thereof.

27. The method of any one of claims 1-18, wherein the daily dose is about 2.25 mg of Compound 1 or a pharmaceutically acceptable salt thereof.

28. The method of any one of claims 1-18, wherein the daily dose is about 2.5 mg of Compound 1 or a pharmaceutically acceptable salt thereof.

29. The method of any one of claims 1-18, wherein the daily dose is about 2.75 mg of Compound 1 or a pharmaceutically acceptable salt thereof. 39 IPTS / 128949854.1Attorney Docket No. PNP-008WO 30. The method of any one of claims 1-18, wherein the daily dose is about 3 mg of Compound 1 or a pharmaceutically acceptable salt thereof.

31. The method of any one of claims 1-18, wherein the daily dose is about 4 mg of Compound 1 or a pharmaceutically acceptable salt thereof.

32. The method of any one of claims 1-31, wherein the daily dose is administered for at least 7 consecutive days, for 14 consecutive days, for 21 consecutive days, or for 28 consecutive days.

33. The method of any one of claims 1-32, wherein the subject is treated for at least 7 days, for at least 14 days, for at least 21 days, or for at least 28 days.

34. The method of any one of claims 1-18, wherein the subject is administered a lower daily dose for a first period of time and then the subject is administered a higher daily dose for a second period of time.

35. The method of claim 34, wherein the lower daily dose is about 0.125 mg, 0.25 mg, 0.5 mg or 0.75 mg of Compound 1 or a pharmaceutically acceptable salt thereof.

36. The method of claim 34 or 35, wherein the higher daily dose is about 0.75 mg, 1.0 mg, 1.25 mg, or 1.75 mg of Compound 1 or a pharmaceutically acceptable salt thereof.

37. The method of any one of claims 34-36, wherein the first period of time is at least 2 days, at least 3 days, or at least 5 days.

38. The method of any one of claims 34-37, wherein the second period of time is at least 20 days, at least 30 days, at least 40 days, at least 50 days, at least 60 days, at least 3 months, at least 4 months, at least 5 months, or at least 6 months.

39. The method of any one of claims 1-18, wherein the subject is administered a first daily dose for a first period of time, then the subject is optionally administered a second daily dose for a second period of time, and then the subject is administered a final daily dose for a third period of time.

40. The method of claim 39, wherein the first daily dose is about 0.125 mg, about 0.25 mg, about 0.50 mg, or about 0.75 mg of Compound 1 or a pharmaceutically acceptable salt thereof. 40 IPTS / 128949854.1Attorney Docket No. PNP-008WO 41. The method of claim 39, wherein the second daily dose is about 0.25 mg, about 0.50 mg, about 0.75 mg, about 1.0 mg, or about 1.25 mg of Compound 1 or a pharmaceutically acceptable salt thereof.

42. The method of claim 39 or 40, wherein the final daily dose is about 0.75 mg, about 1.0 mg, about 1.25 mg, about 1.5 mg, or about 1.75 mg of Compound 1 or a pharmaceutically acceptable salt thereof.

43. The method of any one of claims 39-42, wherein the first period of time is at least 2 days or 3 days.

44. The method of any one of claims 39-43, wherein the second period of time is 1, 2, 3, 4, or 5 days.

45. The method of any one of claims 39-44, wherein the third period of time is at least 20 days, at least 30 days, at least 40 days, at least 50 days, at least 60 days, at least 3 months, at least 4 months, at least 5 months, or at least 6 months.

46. The method of any one of claims 1-45, wherein the method does not result in a serious adverse event (SAE) in the subject.

47. The method of any one of claims 1-46, wherein the method does not result in a clinically meaningful change in laboratory values or electrocardiograms (ECG) or a relevant vital sign change in the subject.

48. The method of any one of claims 1-47, wherein the method does not result in a breakthrough seizure or epilepsy.

49. The method of any one of claims 1-48, wherein the subject is between 18 and 90 years old.

50. An oral formulation comprising: from about 0.1 mg to about 5 mg of Compound 1 or a pharmaceutically acceptable salt thereof; and a pharmaceutically acceptable excipient; wherein the oral formulation is in the form of tablet.

51. The oral formulation of claim 50, wherein the formulation comprises about 0.125 mg of Compound 1 or a pharmaceutically acceptable salt thereof. 41 IPTS / 128949854.1Attorney Docket No. PNP-008WO 52. The oral formulation of claim 50, wherein the formulation comprises about 0.25 mg of Compound 1 or a pharmaceutically acceptable salt thereof.

53. The oral formulation of claim 50, wherein the formulation comprises about 0.75 mg of Compound 1 or a pharmaceutically acceptable salt thereof.

54. The oral formulation of claim 50, wherein the formulation comprises about 1.0 mg of Compound 1 or a pharmaceutically acceptable salt thereof.

55. The oral formulation of claim 50, wherein the formulation comprises about 1.25 mg of Compound 1 or a pharmaceutically acceptable salt thereof.

56. The oral formulation of claim 50, wherein the formulation comprises about 1.75 mg of Compound 1 or a pharmaceutically acceptable salt thereof.

57. The oral formulation of claim 50, wherein the formulation comprises about 2.25 mg of Compound 1 or a pharmaceutically acceptable salt thereof. 42 IPTS / 128949854.1

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