Treatment of early status epilepticus and prolonged seizures with intranasal diazepam

Abstract

The present disclosure provides methods for treating acute repetitive seizures, early status epilepticus, and prolonged seizures in pediatric patients using intranasal diazepam. In some embodiments, the methods comprise intranasally administering a therapeutically effective amount of diazepam nasal spray to a pediatric patient aged 3 months to less than 2 years experiencing acute repetitive seizures or early status epilepticus, or to a pediatric patient aged 3 months to 17 years experiencing a prolonged seizure. The diazepam nasal spray is administered at a weight-based dose of about 0.2 mg / kg to about 0.5 mg / kg depending on the patient's age. The disclosure also provides methods for treating early status epilepticus in pediatric patients aged 2-17 years using intranasal diazepam administered as a single dose of 5 mg, 10 mg, 15 mg, or 20 mg based on the patient's age and weight.

Description

TREATMENT OF EARLY STATUS EPILEPTICUS AND PROLONGED SEIZURES WITH INTRANASAL DIAZEPAM CROSS-REFERENCE TO RELATED APPLICATIONS

[0001] This application claims the benefit of U.S. Provisional Application No. 63 / 771,136, filed on March 13, 2025, and U.S. Provisional Application No. 63 / 775,132, filed on March 20, 2025, the entire disclosures of which are hereby incorporated by reference in their entireties.BACKGROUND

[0002] Status epilepticus is a neurological emergency characterized by prolonged or repetitive seizures without recovery of consciousness between episodes. It can occur in patients with epilepsy as well as those without a prior history of seizures. The condition is associated with significant morbidity and mortality, particularly if not treated promptly.

[0003] Benzodiazepines are commonly used as first-line treatment for status epilepticus due to their rapid onset of action and ability to terminate seizure activity. Traditionally, benzodiazepines have been administered intravenously or intramuscularly in hospital settings. However, these routes of administration require trained medical personnel and are not readily accessible for rapid treatment outside of healthcare facilities.

[0004] There is growing recognition of the potential benefits of treating status epilepticus as early as possible, ideally before patients reach the hospital. This has led to interest in developing formulations of benzodiazepines that can be administered by caregivers or patients themselves soon after seizure onset. Intranasal delivery offers a non-invasive route that may allow for more rapid treatment initiation compared to waiting for emergency medical services.

[0005] Diazepam is a benzodiazepine with a long history of use in treating seizures and status epilepticus. Its lipophilic properties allow it to cross the blood-brain barrier rapidly. However, traditional oral and rectal formulations have limitations in terms of absorption and ease of administration during a seizure. An intranasal formulation of diazepam could potentially address some of these challenges.

[0006] Pediatric patients present unique considerations in the treatment of status epilepticus. Dosing must be carefully adjusted based on age and weight. Additionally, ease of administration is particularly important in young children who may have difficulty’ cooperating with treatment during a seizure episode. Safe and effective options for rapid treatment of status epilepticus in children outside of hospital settings remain an area of ongoing research and development.

[0007] Diazepam nasal spray (VALTOCO®) is approved for acute treatment of seizure clusters in patients with epilepsy aged ≥6 years. A previous pharmacokinetic (PK) study showed diazepam nasal 11629946371.1spray had similar bioavailability, but less interpatient variability compared with diazepam rectal gel in healthy adult volunteers.SUMMARY

[0008] In some embodiments, the method for treating early status epilepticus in a pediatric patient aged 2-17, comprises: intranasally administering to the pediatric subject experiencing early status epilepticus, a solution composition comprising: a therapeutically effective amount of diazepam; an alkyl glycoside; and a carrier system comprising one or more natural or synthetic tocopherols or tocotrienols and one or more alcohols, wherein the early status epilepticus is treated.

[0009] In some embodiments, the therapeutically effective amount of diazepam may be about 2 mg to about 20 mg diazepam in a volume of about 10 μL to 200 μL of the composition. In certain embodiments, the therapeutically effective amount of diazepam may be about 5 mg to about 20 mg in a volume of 100 μL to 200 μL of the composition.

[0010] The composition may be provided in a pre-primed single use dosage device containing about 100 μL of the composition in some implementations. intranasally administration may comprise delivering about 5 mg to about 10 mg of diazepam in a volume of about 100 μL of the composition to a single nostril of the pediatric subject in certain embodiments.

[0011] In some embodiments, intranasally administering may comprise delivering about 7.5 mg diazepam in a volume of 100 μL of the composition to each nostril of the pediatric subject. Alternatively, intranasally administering may comprise delivering about 20 mg diazepam in a volume of 100 μL of the composition to a single nostril of the pediatric subject in some embodiments. In other embodiments, intranasally administering may comprise delivering about 10 mg diazepam in a volume of 100 μL of the composition to each nostril of the pediatric subject.

[0012] The method may include specific dosing regimens based on the patient's age and weight. For example, for a subject aged about 2 to about 5 years weighing about 6 kg to about 11 kg, intranasally administering may comprise delivering about 5 mg of diazepam in a volume of about 100 μL of the composition to a single nostril of the pediatric subject. For a subject aged about 2 to about 5 years weighing about 12 kg to about 22 kg, intranasally administering may comprise delivering about 10 mg of diazepam in a volume of about 100 μL of the composition to a single nostril of the pediatric subject. For a subject aged about 2 to about 5 years weighing about 23 kg to about 33 kg, intranasally administering may comprise delivering about 7.5 mg of diazepam in a volume of about 100 pL of the composition to each nostril of the pediatric subject.

[0013] In some embodiments, for a subject aged about 6 years to about 11 years weighing about 10 kg to about 18 kg, intranasally administering may comprise delivering about 5 mg of diazepam in a volume of about 100 μL of the composition to a single nostril of the pediatric subject. For a subject 21629946371.1aged about 6 years to about 11 years weighing about 19 kg to about 37 kg, intranasally administering may comprise delivering about 10 mg of diazepam in a volume of about 100 μL of the composition to a single nostril of the pediatric subject. For a subject aged about 6 years to about 11 years weighing about 38 kg to about 55 kg, intranasally administering may comprise delivering about 7.5 mg of diazepam in a volume of about 100 μL of the composition to each nostril of the pediatric subject. For a subject aged about 6 years to about 11 years weighing about 56 kg to about 74 kg, intranasally administering may comprise delivering about 10 mg of diazepam in a volume of about 100 μL of the composition to each nostril of the pediatric subject, or about 20 mg of diazepam in a volume of about 100 μL of the composition to a single nostril of the pediatric subject.

[0014] In some embodiments, for a subject aged about 12 years to about 17 years weighing about 14 kg to about 27 kg, intranasally administering may comprise delivering about 5 mg of diazepam in a volume of about 100 pl. of the composition to a single nostril of the pediatric subject. For a subject aged about 12 years to about 17 years weighing about 28 kg to about 50 kg, intranasally administering may comprise delivering about 10 mg of diazepam in a volume of about 100 μL of the composition to a single nostril of tire pediatric subject. For a subject aged about 12 years to about 17 years weighing about 51 kg to about 75 kg, intranasally administering may comprise delivering about 7.5 mg of diazepam in a volume of about 100 pL of the composition to each nostril of the pediatric subject. For a subject aged about 12 years to about 17 years weighing greater than about 76 kg, intranasally administering may comprise delivering about 10 mg of diazepam in a volume of about 100 pL of the composition to each nostril of the pediatric subject, or about 20 mg of diazepam in a volume of about 100 μL of the composition to a single nostril of the pediatric subject.

[0015] In some embodiments, the alkyl glycoside may be an alkyl maltoside. In some embodiments, the alkyl glycoside may be selected from dodecyl maltoside, tetradecyl maltoside, or a combination thereof. The composition may comprise about 0.2% w / v to about 1% w / v of the alkyl glycoside in certain embodiments.

[0016] The one or more alcohols may comprise a mixture of ethanol and benzy l alcohol in some implementations. In certain embodiments, the composition may comprise about 1% w / v to about 25% w / v ethanol and about 10% w / v to about 40% w / v benzyl alcohol.

[0017] In some embodiments, the administering may be performed by a caregiver. The early status epilepticus may be a pre-hospital episode of status epilepticus in certain embodiments.

[0018] The early status epilepticus may be generalized status epilepticus, focal status epilepticus, focal status epilepticus with impaired consciousness, unclassified status epilepticus, tonic-clonic status epilepticus, absence status epilepticus, or a combination thereof in some implementations. In certain embodiments, where the early status epilepticus is generalized status epilepticus, termination of the status epilepticus may occur within 30 minutes of administering the composition.31629946371.1

[0019] In some embodiments, administering the composition may result in rapid termination of early status epilepticus with a median time from administering the composition to status epilepticus cessation of about 5 minutes for generalized status epilepticus, about 12 minutes for focal status epilepticus, or about 8 minutes for unclassified status epilepticus.

[0020] In certain embodiments, no seizure recurrence may occur within about 1 hour, about 12 hours, or about 24 hours of termination of the early status epilepticus.

[0021] In some embodiments, the method for treating acute repetitive seizures in a pediatric patient aged 3 months to less than 2 years, comprises: intranasally administering to the pediatric subject experiencing acute repetitive seizures, a solution composition comprising: a therapeutically effective amount of diazepam; an alkyl glycoside; and a carrier system comprising one or more natural or synthetic tocopherols or tocotrienols and one or more alcohols, wherein the acute repetitive seizures are treated.

[0022] In some embodiments, the therapeutically effective amount of diazepam may be about 0.2 mg / kg to about 0.5 mg / kg of the pediatric subject's body weight. In some embodiments, for a pediatric subject aged about 3 months to less than 6 months, the therapeutically effective amount of diazepam may be about 0.2 mg / kg to about 0.5 mg / kg. In some embodiments, for a pediatric subject aged about 6 months to less than 2 years, the therapeutically effective amount of diazepam may be about 0.5 mg / kg.

[0023] In some embodiments, the method for treating early status epilepticus in a pediatric patient aged 3 months to less than 2 years, comprises: intranasally administering to the pediatric subject experiencing early status epilepticus, a solution composition comprising: a therapeutically effective amount of diazepam; an alkyl glycoside; and a carrier system comprising one or more natural or synthetic tocopherols or tocotrienols and one or more alcohols, wherein the early status epilepticus is treated.

[0024] In some embodiments, the method for treating a prolonged seizure in a pediatric patient aged 3 months to 17 years, comprises: intranasally administering to the pediatric subject experiencing a prolonged seizure, a solution composition comprising: a therapeutically effective amount of diazepam; an alkyl glycoside; and a carrier system comprising one or more natural or synthetic tocopherols or tocotrienols and one or more alcohols, wherein tire prolonged seizure is treated. In some embodiments, the prolonged seizure may be a seizure lasting about 3 to about 5 minutes. In some embodiments, the prolonged seizure may be consistent with impending status epilepticus.

[0025] In some embodiments, for a pediatric subject aged about 3 months to less than 6 months, the therapeutically effective amount of diazepam may be about 0.2 mg / kg to about 0.5 mg / kg. In some embodiments, for a pediatric subject aged about 6 months to less than 2 years, the therapeutically effective amount of diazepam may be about 0.5 mg / kg. In some embodiments, for a pediatric subject aged about 2 years to about 5 years, the therapeutically effective amount of diazepam may be about 0.541629946371.1mg / kg. In some embodiments, for a pediatric subject aged about 6 years to about 11 years, the therapeutically effective amount of diazepam may be about 0.3 mg / kg. In some embodiments, for a pediatric subject aged about 12 years to about 17 years, the therapeutically effective amount of diazepam may be about 0.2 mg / kg.

[0026] In some embodiments, the administering may be performed by a caregiver. In some embodiments, the administering may be performed by trained emergency service personnel or in an emergency department. In some embodiments, the prolonged seizure or early status epilepticus may be a pre-hospital episode.BRIEF DESCRIPTION OF FIGURES

[0027] Non-limiting and non-exhaustive examples are described with reference to the following figures.

[0028] Figure 1 shows early status epilepticus events treated past t1 with diazepam nasal spray in patients aged 3-16 years.

[0029] Figure 2 A and Figure 2B show the proportion of patients with, and proportion of, early status epilepticus events terminated within 20 minutes (Figure 2 A) and within 30 or 60 minutes (Figure 2B) from dose administration by seizure type.

[0030] Figure 3 shows the proportion of early status epilepticus events treated with a second dose.

[0031] Figure 4 shows early status epilepticus events treated past t1 with diazepam nasal spray in pediatric patients.

[0032] Figure 5 A and 5B shows a responder analysis: Proportion of early status epilepticus events terminated in ≤t2 (Figure 5A) and ≤20 minutes (Figure 5B) from dose administration by seizure type.

[0033] Figure 6 shows seizure recurrence within 1, 12, and 24 hours of status epilepticus termination.

[0034] Figure 7 shows the proportion of early status epilepticus events treated with a second dose across age and seizure type subgroups.

[0035] Figure 8 shows prolonged seizures treated 5-15 minutes after onset with diazepam nasal spray in children aged 2-5 years.

[0036] Figure 9 shows generalized status epilepticus treated after t1 with diazepam nasal spray in children aged 2-5 years.51629946371.1

[0037] Figure 10 shows a responder analysis by seizure type showing the proportion of status epilepticus episodes and patients per seizure type treated after t1 that terminated before t2 in children aged 2-5 years.

[0038] Figure 11 shows the proportion of status epilepticus episodes and patients per seizure type that were treated after t1 with seizure recurrence within 1, 12, and 24 hours of status epilepticus termination in children aged 2-5 years.DETAILED DESCRIPTION

[0039] Before the present compositions and methods are described, it is to be understood that various embodiments of intranasal benzodiazepine compositions and methods of their use are disclosed herein. Unless indicated otherwise, all technical and scientific terms used herein have the meaning commonly understood by one of ordinary skill in the art. It is also to be understood that the terminology used in the description is for the purpose of describing the particular embodiments or embodiments only and is not intended to limit the scope. The disclosed intranasal compositions, method of their manufacture, and methods of their use are not strictly limited to the particular compositions, processes, or methods described, as these can vary to an extent one of skill in the art will recognize without diverging from the benefits and advantages imparted by the compositions and methods. Though one of skill in the art will readily recognize obvious variations and substitutions that may be made to accomplish the same result through equivalent means or function, for the purpose of describing the various embodiments and embodiments of intranasal benzodiazepine compositions, methods of their manufacture, and methods of their use, preferred compositions and methods are now described.

[0040] The compositions disclosed herein are suitable for administration to the nasal cavity. As such, the phrases “intranasal solution,” “intranasal composition,” and “intranasal formulation” are used interchangeably to mean a composition suitable for administration to the nasal mucosal membranes which line the nasal cavity,

[0041] As used herein, the term “subject” and “patient” expressly includes humans and nonhuman mammalian subjects. The term “non-human mammal” as used herein extends to, but is not restricted to, household pets and domesticated animals. Non-limiting examples of such animals include primates, cattle, sheep, ferrets, mice, rats, swine, camels, horses, poultry, fish, rabbits, goats, dogs and cats. As used herein, the term “pediatric” refers to a subject of age 2 to 17, inclusive.

[0042] As used herein, “treating” and other grammatical forms thereof (e.g., treat, treatment) may improve symptoms of a seizure disorder or of an acute seizure. Improvement may include reducing the frequency, length, or severity" of the acute seizure or of recurring episodes of seizures.61629946371.1

[0043] As used herein, tlie term “about” when used in connection with a numerical value means within plus or minus 10% of the stated value. For example, “about 10 mg” includes values from 9 mg to 11 mg, and “about 0.5 mg / kg” includes values from 0.45 mg / kg to 0.55 mg / kg.

[0044] As used herein, “acute repetitive seizures” (ARS), also referred to as “seizure clusters,” are defined as intermittent, stereotypic episodes of frequent seizure activity tliat are distinct from a patient’s usual seizure pattern in patients with epilepsy 2 years of age and older.

[0045] As used herein, “prolonged seizure” (PS) is defined as a single seizure event exceeding the typical duration for a patient but remaining below the threshold for status epilepticus (SE), specifically lasting between about 3 and about 5 minutes for generalized tonic-clonic (GTC) seizures or between about 5 and about 10 minutes for focal seizures.

[0046] As used herein, "early status epilepticus" means a prolonged seizure or series of seizures without full recovery' between them, lasting beyond the time point 11 as defined by the International League Against Epilepsy (ILAE), where tl is 5 minutes for generalized convulsive status epilepticus and 10 minutes for focal status epilepticus with impaired consciousness. In some embodiments, early status epilepticus events are defined as those that were ongoing at the time of treatment and met the ILAE criteria for ti (>5 minutes for generalized early status epilepticus and >10 minutes for focal early status epilepticus with impaired consciousness). Unclassified early status epilepticus events may be defined conservatively, using ti for focal seizures with impaired consciousness, as >10 minutes. Time point t2 may be 30 minutes for generalized and 60 minutes for focal and unclassified seizures.

[0047] In any embodiment, the methods and compositions disclosed herein may comprise the recited steps and components. As used here, “comprise” is open language used to recite steps or components that are included in the recited method or composition but to indicate that other elements may also be included, even though said elements are not explicitly recited. In any embodiment, the methods and compositions disclosed herein may consist essentially of the recited steps and components. As used here, “consist essentially of’ is used to recite steps or components that are included in the recited method or composition and to indicate that other elements may also be included but said other elements would not materially affect the properties of the composition or the results of tlie method. In any embodiment, tlie methods and compositions disclosed herein may consist of the recited steps and components. As used here, “consist of’ is closed language used to recite steps or components tliat are included in the recited method or composition and that no other elements are included other than those explicitly recited. Any use of the term comprise, comprises or comprising may be replaced with “consisting essentially of” or “consisting of.”

[0048] Surprisingly, administration of a benzodiazepine to the nasal mucosal membranes of a pediatric subject via the various intranasal compositions, as disclosed herein, induces a therapeutic1629946371.1benefit to the pediatric subject substantially earlier than would be expected based on measured systemic levels of the benzodiazepine. A therapeutic effect is not only experienced by the pediatric subject, but measured via EEG well before (e.g., less than 2 minutes after administration) the systemic concentration of benzodiazepine reaches therapeutically relevant levels. As used herein, the term “pharmacodynamic” or “PD” is used to describe qualitative effects the administered benzodiazepine has on the pediatric subject, such as a change in EEG data, a change in seizure length or severity, a change in symptoms associated therewith, or a change associated with side effects caused by the administered benzodiazepine. The term “pharmacokinetic” or “PK” is used to describe, quantitatively, movement and processing of the benzodiazepine drug by the pediatric subject’s body, such as plasma concentrations of the drug and any metabolites thereof (e.g., Cmax, Tmax), bioavailability, half-life, and the like. While various embodiments of the PK profile of a benzodiazepine administered intranasally via the intranasal compositions as disclosed herein are similar to embodiments of the PK profile of a benzodiazepine administered intravenously (e.g., similar AUC and bioavailability) and orally (e.g., similar Cmax and Tmax), many of the adverse side effects associated with IV, oral, and rectal administration of benzodiazepines, such as somnolence, headaches, and depression / suicidal thoughts and behaviors, are reduced. Therefore, the intranasal compositions and methods of their use as provided herein represent a substantial improvement in tire treatment of seizures and seizure disorders, both in the rapid realization of therapeutic benefit after administration and in improved patient compliance after experiencing reduced unpleasant side effects.

[0049] The present disclosure relates to methods and compositions for treating early status epilepticus in a pediatric subject. Specifically, the disclosure provides approaches for administering intranasal diazepam to pediatric subjects aged 2-17 years experiencing early status epilepticus.

[0050] In some embodiments, the methods for treating early status epilepticus in a pediatric patient aged 2-17, comprise: intranasally administering to the pediatric subject experiencing early status epilepticus, a solution composition comprising: a therapeutically effective amount of diazepam; an alkyl glycoside; and a carrier system comprising one or more natural or synthetic tocopherols or tocotrienols and one or more alcohols, wherein the early status epilepticus is treated.

[0051] " Administering to a nasal mucosal membrane" means delivering the composition as a spray to one or both nostrils of the pediatric subject using a pre-primed single use dosage device. The device may be available in different dose configurations to accommodate various patient weights and ages.

[0052] In some embodiments, the therapeutically effective amount of diazepam means a dose ranging from about 2 mg to about 20 mg, administered in a volume of about 10 pL to 200 pL of the composition, that is sufficient to terminate the early status epilepticus episode. In some embodiments,81629946371.1the therapeutically effective amount may be about 5 mg to about 20 mg in a volume of 100 μL to 200 μL of the composition.

[0053] In some embodiments, the alkyl glycoside may be an alkyl maltoside. In some embodiments, the alkyl glycoside is a non-ionic surfactant comprising a hydrophilic maltose head group and a hydrophobic alkyl tail, selected from dodecyl maltoside, tetradecyl maltoside, or a combination thereof. The composition may comprise about 0.2% w / v to about 1% w / v of the alkyl glycoside.

[0054] In some embodiments, the carrier system means a mixture comprising one or more natural or synthetic tocopherols or tocotrienols and one or more alcohols, wherein the alcohols may include ethanol and benzyl alcohol. In some embodiments, the composition may comprise about 1% w / v to about 25% w / v ethanol and about 10% w / v to about 40% w / v benzyl alcohol.

[0055] In some embodiments, the method includes specific dosing regimens based on the patient's age and weight. In some embodiments, for a subject aged about 2 to about 5 years, tire dose of diazepam to be administered via the methods disclosed herein is as follows: about 6 kg to about 11 kg: about 5 mg to a single nostril; about 12 kg to about 22 kg: about 10 mg dose to a single nostril; about 23 kg to about 33 kg: 7.5 mg to each nostril.

[0056] In some embodiments, for a subject aged about 6 to 11 years, the dose of diazepam to be administered via the methods disclosed herein is as follows: about 10 kg to about 18 kg: 5 mg to a single nostril; about 19 kg to about 37 kg: 10 mg to a single nostril; about 38 to about 55 kg: 7.5 mg to each nostril; about 56 to about 74 kg: 10 mg to each nostril or 20 mg to a single nostril.

[0057] In some embodiments, for a subject aged 12 to 17 years, the dose of diazepam to be administered via the methods disclosed herein is as follows: about 14 to about 27 kg: 5 mg to a single nostril; about 28 kg to about 50 kg: 10 mg to a single nostril; about 51 kg to about 75 kg: 7.5 mg to each nostril; about 76 kg or more: 10 mg to each nostril or 20 mg to a single nostril.

[0058] The method may be used to treat various types of early status epilepticus, including generalized, focal, focal with impaired consciousness, unclassified, tonic-clonic, and absence status epilepticus. For generalized status epilepticus, termination may occur within 30 minutes of administering the composition.

[0059] The method may result in rapid termination of early status epilepticus, with median times to cessation of about 5 minutes for generalized, about 12 minutes for focal, and about 8 minutes for unclassified status epilepticus.

[0060] " Termination of the status epilepticus" means cessation of seizure activity following intranasal administration of the composition, with no recurrence of seizures within a specified time period, such as 24 hours. No seizure recurrence may occur within about 1 hour, 12 hours, or 24 hours of termination of the early status epilepticus.91629946371.1

[0061] The method may be particularly useful for treating "pre-hospital episodes," which means instances of early status epilepticus occurring outside of a hospital setting, where treatment may be administered by a caregiver. This approach may enable rapid intervention and seizure control across various clinical scenarios, potentially reducing the need for emergency department visits or inpatient care.

[0062] In some embodiments, the methods for treating early status epilepticus in a pediatric patient aged 2-17, comprise: intranasally administering to the pediatric subject experiencing early status epilepticus, a solution composition comprising: a therapeutically effective amount of diazepam; an alkyl glycoside; and a carrier system comprising one or more natural or synthetic tocopherols or tocotrienols and one or more alcohols, wherein the early status epilepticus is treated.

[0063] In some embodiments, the therapeutically effective amount of diazepam may be about 2 mg to about 20 mg diazepam in a volume of about 10 μL to 200 μL of the composition. In certain embodiments, the therapeutically effective amount of diazepam may be about 5 mg to about 20 mg in a volume of 100 μL to 200 μL of the composition.

[0064] The composition may be provided in a pre-primed single use dosage device containing about 100 μL of the composition in some implementations. Intranasally administering may comprise delivering about 5 mg to about 10 mg of diazepam in a volume of about 100 μL of the composition to a single nostril of the pediatric subject in certain embodiments.

[0065] In some embodiments, intranasally administering may comprise delivering about 7.5 mg diazepam in a volume of 100 pL of the composition to each nostril of the pediatric subject. Alternatively, intranasally administering may comprise delivering about 20 mg diazepam in a volume of 100 pL of the composition to a single nostril of the pediatric subject in some embodiments. In other embodiments, intranasally administering may comprise delivering about 10 mg diazepam in a volume of 100 pL of the composition to each nostril of tlie pediatric subject.

[0066] The method may include specific dosing regimens based on the patient's age and weight. For example, for a subject aged about 2 to about 5 years weighing about 6 kg to about 11 kg, intranasally administering may comprise delivering about 5 mg of diazepam in a volume of about 100 μL of the composition to a single nostril of the pediatric subject. For a subject aged about 2 to about 5 years weighing about 12 kg to about 22 kg, intranasally administering may comprise delivering about 10 mg of diazepam in a volume of about 100 μL of the composition to a single nostril of the pediatric subject. For a subject aged about 2 to about 5 years weighing about 23 kg to about 33 kg, intranasally administering may comprise delivering about 7.5 mg of diazepam in a volume of about 100 pL of the composition to each nostril of the pediatric subject.

[0067] In some embodiments, for a subject aged about 6 years to about 11 years weighing about 10 kg to about 18 kg, intranasally administering may comprise delivering about 5 mg of diazepam in a 101629946371.1volume of about 100 pL of the composition to a single nostril of the pediatric subject. For a subject aged about 6 years to about 11 years weighing about 19 kg to about 37 kg, intranasally administering may comprise delivering about 10 mg of diazepam in a volume of about 100 μL of the composition to a single nostril of the pediatric subject. For a subject aged about 6 years to about 11 years weighing about 38 kg to about 55 kg, intranasally administering may comprise delivering about 7.5 mg of diazepam in a volume of about 100 pL of the composition to each nostril of the pediatric subject. For a subject aged about 6 years to about 11 years weighing about 56 kg to about 74 kg, intranasally administering may comprise delivering about 10 mg of diazepam in a volume of about 100 pL of the composition to each nostril of the pediatric subject, or about 20 mg of diazepam in a volume of about 100 μL of the composition to a single nostril of the pediatric subject.

[0068] In some embodiments, for a subject aged about 12 years to about 17 years weighing about 14 kg to about 27 kg, intranasally administering may comprise delivering about 5 mg of diazepam in a volume of about 100 μL of the composition to a single nostril of the pediatric subject. For a subject aged about 12 years to about 17 years weighing about 28 kg to about 50 kg, intranasally administering may comprise delivering about 10 mg of diazepam in a volume of about 100 μL of the composition to a single nostril of the pediatric subject. For a subject aged about 12 years to about 17 years weighing about 51 kg to about 75 kg, intranasally administering may comprise delivering about 7.5 mg of diazepam in a volume of about 100 pL of the composition to each nostril of the pediatric subject. For a subject aged about 12 years to about 17 years weighing greater than about 76 kg, intranasally administering may comprise delivering about 10 mg of diazepam in a volume of about 100 pL of the composition to each nostril of the pediatric subject, or about 20 mg of diazepam in a volume of about 100 μL of the composition to a single nostril of the pediatric subject.

[0069] In some embodiments, the alkyl glycoside may be an alkyl maltoside. In some embodiments, the alkyl glycoside may be selected from dodecyl maltoside, tetradecyl maltoside, or a combination thereof. The composition may comprise about 0.2% w / v to about 1% w / v of the alkyl glycoside in certain embodiments.

[0070] The one or more alcohols may comprise a mixture of ethanol and benzy l alcohol in some implementations. In certain embodiments, the composition may comprise about 1% w / v to about 25% w / v ethanol and about 10% w / v to about 40% w / v benzyl alcohol.

[0071] In some embodiments, the administering may be performed by a caregiver. The early status epilepticus may be a pre-hospital episode of status epilepticus in certain embodiments.

[0072] The early status epilepticus may be generalized status epilepticus, focal status epilepticus, focal status epilepticus with impaired consciousness, unclassified status epilepticus, tonic-clonic status epilepticus, absence status epilepticus, or a combination thereof in some implementations. In certain111629946371.1embodiments, where the early status epilepticus is generalized status epilepticus, termination of the status epilepticus may occur within 30 minutes of administering the composition.

[0073] In some embodiments, administering the composition may result in rapid termination of early status epilepticus with a median time from administering the composition to status epilepticus cessation of about 5 minutes for generalized status epilepticus, about 12 minutes for focal status epilepticus, or about 8 minutes for unclassified status epilepticus.

[0074] In some embodiments, administering the composition may result in a decrease in mortality and morbidity from status epilepticus. In some embodiments, the composition may result in a decrease in, or prevention of hospital stays or a combination thereof. In some embodiments, administering the composition may result in a decrease in the side effects associated with status epilepticus including, but not limited to prolonged seizures lasting more than 5 minutes, seizures that occur repeatedly without regaining consciousness between them, confusion or altered mental status, loss of muscle control, abnormal breathing, drooling or foaming at the mouth, muscle spasms, falling, confusion, unusual noises, loss of bowel or bladder control, clenched teeth, irregular breathing, unusual behavior, difficulty speaking, or any combination thereof.

[0075] In certain embodiments, no seizure recurrence may occur within about 1 hour, about 12 hours, or about 24 hours of termination of the early status epilepticus,

[0076] In certain embodiments, the methods disclosed herein further comprise administering a second dose of the composition within about 24 hours of the administering the composition. In certain embodiments, the methods disclosed herein further comprise administering a second dose of the composition after at least 4 hours of the administering the composition. In some embodiments, the second dose is the same dose as the composition initially administered to the subject,

[0077] In some embodiments, the methods for treating status epilepticus in a pediatric patient aged 2-17, comprise: intranasally administering to the pediatric subject experiencing early status epilepticus, a solution composition comprising: a therapeutically effective amount of diazepam; an alkyl glycoside; and a carrier system comprising one or more natural or synthetic tocopherols or tocotrienols and one or more alcohols, wherein the status epilepticus is treated.

[0078] In some embodiments, the therapeutically effective amount of diazepam may be about 2 mg to about 20 mg diazepam in a volume of about 10 pL to 200 pL of the composition. In certain embodiments, the therapeutically effective amount of diazepam may be about 5 mg to about 20 mg in a volume of 100 μL to 200 μL of the composition.

[0079] The composition may be provided in a pre-primed single use dosage device containing about 100 pL of the composition in some implementations. Intranasally administering may comprise121629946371.1delivering about 5 mg to about 10 mg of diazepam in a volume of about 100 μL of the composition to a single nostril of the pediatric subject in certain embodiments.

[0080] In some embodiments, intranasally administering may comprise delivering about 7.5 mg diazepam in a volume of 100 pL of the composition to each nostril of the pediatric subject. Alternatively, intranasally administering may comprise delivering about 20 mg diazepam in a volume of 100 pL of the composition to a single nostril of the pediatric subject in some embodiments. In other embodiments, intranasally administering may comprise delivering about 10 mg diazepam in a volume of 100 μL of the composition to each nostril of the pediatric subject.

[0081] The method may include specific dosing regimens based on the patient's age and weight. For example, for a subject aged about 2 to about 5 years weighing about 6 kg to about 11 kg, intranasally administering may comprise delivering about 5 mg of diazepam in a volume of about 100 μL of the composition to a single nostril of the pediatric subject. For a subject aged about 2 to about 5 years weighing about 12 kg to about 22 kg, intranasally administering may comprise delivering about 10 mg of diazepam in a volume of about 100 μL of the composition to a single nostril of the pediatric subject. For a subject aged about 2 to about 5 years weighing about 23 kg to about 33 kg, intranasally administering may comprise delivering about 7.5 mg of diazepam in a volume of about 100 pL of the composition to each nostril of the pediatric subject.

[0082] In some embodiments, for a subject aged about 6 years to about 11 years weighing about 10 kg to about 18 kg, intranasally administering may comprise delivering about 5 mg of diazepam in a volume of about 100 μL of the composition to a single nostril of the pediatric subject. For a subject aged about 6 years to about 11 years weighing about 19 kg to about 37 kg, intranasally administering may comprise delivering about 10 mg of diazepam in a volume of about 100 μL of the composition to a single nostril of the pediatric subject. For a subject aged about 6 years to about 11 years weighing about 38 kg to about 55 kg, intranasally administering may comprise delivering about 7.5 mg of diazepam in a volume of about 100 pL of the composition to each nostril of the pediatric subject. For a subject aged about 6 years to about 11 years weighing about 56 kg to about 74 kg, intranasally administering may comprise delivering about 10 mg of diazepam in a volume of about 100 pL of the composition to each nostril of the pediatric subject, or about 20 mg of diazepam in a volume of about 100 μL of the composition to a single nostril of the pediatric subject.

[0083] In some embodiments, for a subject aged about 12 years to about 17 years weighing about 14 kg to about 27 kg, intranasally administering may comprise delivering about 5 mg of diazepam in a volume of about 100 μL of the composition to a single nostril of the pediatric subject. For a subject aged about 12 years to about 17 years weighing about 28 kg to about 50 kg, intranasally administering may comprise delivering about 10 mg of diazepam in a volume of about 100 μL of the composition to a single nostril of the pediatric subject. For a subject aged about 12 years to about 17 years weighing 131629946371.1about 51 kg to about 75 kg, intranasally administering may comprise delivering about 7.5 mg of diazepam in a volume of about 100 pL of the composition to each nostril of the pediatric subject. For a subject aged about 12 years to about 17 years weighing greater than about 76 kg, intranasally administering may comprise delivering about 10 mg of diazepam in a volume of about 100 pL of the composition to each nostril of the pediatric subject, or about 20 mg of diazepam in a volume of about 100 μL of the composition to a single nostril of the pediatric subject.

[0084] In some embodiments, the alkyl glycoside may be an alkyd maltoside. In some embodiments, the alkyl glycoside may be selected from dodecyl maltoside, tetradecyl maltoside, or a combination thereof. The composition may comprise about 0.2% w / v to about 1% w / v of the alkyl glycoside in certain embodiments.

[0085] The one or more alcohols may comprise a mixture of ethanol and benzyl alcohol in some implementations. In certain embodiments, the composition may comprise about 1% w, W to about 25% w / v ethanol and about 10% w / v to about 40% w / v benzyl alcohol,

[0086] In some embodiments, the administering may be performed by a caregiver. The status epilepticus may be a pre-hospital episode of status epilepticus in certain embodiments.

[0087] The status epilepticus may be generalized status epilepticus, focal status epilepticus, focal status epilepticus with impaired consciousness, unclassified status epilepticus, tonic-clonic status epilepticus, absence status epilepticus, or a combination thereof in some implementations. In certain embodiments, where the status epilepticus is generalized status epilepticus, termination of the status epilepticus may occur within 30 minutes of administering the composition.

[0088] In some embodiments, administering the composition may result in rapid termination of status epilepticus with a median time from administering the composition to status epilepticus cessation of about 5 minutes for generalized status epilepticus, about 12 minutes for focal status epilepticus, or about 8 minutes for unclassified status epilepticus.

[0089] In certain embodiments, no seizure recurrence may occur within about 1 hour, about 12 hours, or about 24 hours of termination of the status epilepticus.

[0090] The present disclosure also relates to methods and compositions for treating early status epilepticus in a subject. Specifically, the disclosure provides approaches for administering intranasal diazepam to adult subjects aged greater than 17 years experiencing early status epilepticus.

[0091] In some embodiments, the methods for treating early status epilepticus in an adult patient aged greater than 17 years, comprise: intranasally administering to the subject experiencing early status epilepticus, a solution composition comprising: a therapeutically effective amount of diazepam; an alkyl glycoside; and a carrier system comprising one or more natural or synthetic tocopherols or tocotrienols and one or more alcohols, wherein the early status epilepticus is treated.141629946371.1

[0092] In some embodiments, the therapeutically effective amount of diazepam means a dose ranging from about 2 mg to about 20 mg, administered in a volume of about 10 uL to 200 pL of the composition, that is sufficient to terminate the early status epilepticus episode. In some embodiments, the therapeutically effective amount may be about 5 mg to about 20 mg in a volume of 100,uL to 200 pL of the composition.

[0093] In some embodiments, for a subject aged greater than 17 years, the dose of diazepam to be administered via the methods disclosed herein is as follows: about 14 to about 27 kg: 5 mg to a single nostril; about 28 kg to about 50 kg: 10 mg to a single nostril; about 51 kg to about 75 kg: 7.5 mg to each nostril; about 76 kg or more: 10 mg to each nostril or 20 mg to a single nostril.

[0094] In some embodiments, the alkyl glycoside may be an alkyl maltoside. In some embodiments, the alkyl glycoside is a non-ionic surfactant comprising a hydrophilic maltose head group and a hydrophobic alkyl tail, selected from dodecyl maltoside, tetradecyl maltoside, or a combination thereof. The composition may comprise about 0.2% w / v to about 1% w / v of the alkyl glycoside.

[0095] In some embodiments, the carrier system means a mixture comprising one or more natural or synthetic tocopherols or tocotrienols and one or more alcohols, wherein the alcohols may include ethanol and benzyl alcohol. In some embodiments, the composition may comprise about 1% w / v to about 25% w / v ethanol and about 10% w / v to about 40% w / v benzyl alcohol.

[0096] The method may be used to treat various types of early status epilepticus, including generalized, focal, focal with impaired consciousness, unclassified, tonic-clonic, and absence status epilepticus. For generalized status epilepticus, termination may occur within 30 minutes of administering the composition.

[0097] The method may result in rapid termination of early status epilepticus, with median times to cessation of about 5 minutes for generalized, about 12 minutes for focal, and about 8 minutes for unclassified status epilepticus.

[0098] The method may be particularly useful for treating "pre-hospital episodes," which means instances of early status epilepticus occurring outside of a hospital setting, where treatment may be administered by a caregiver. This approach may enable rapid intervention and seizure control across various clinical scenarios, potentially reducing the need for emergency department visits or inpatient care,

[0099] In some embodiments, the methods for treating early status epilepticus in a subject aged greater than 17 years comprise: intranasally administering to the subject experiencing early status epilepticus, a solution composition comprising: a therapeutically effective amount of diazepam; an alkyl glycoside; and a carrier system comprising one or more natural or synthetic tocopherols or tocotrienols and one or more alcohols, wherein the early status epilepticus is treated.151629946371.1

[0100] In some embodiments, the therapeutically effective amount of diazepam may be about 2 mg to about 20 mg diazepam in a volume of about 10 pL to 200 ti L of the composition. In certain embodiments, the therapeutically effective amount of diazepam may be about 5 mg to about 20 mg in a volume of 100 pL to 200 pL of the composition.

[0101] The composition may be provided in a pre-primed single use dosage device containing about 100 pL of the composition in some implementations. Intranasally administering may comprise delivering about 5 mg to about 10 mg of diazepam in a volume of about 100 μL of the composition to a single nostril of the subject in certain embodiments.

[0102] In some embodiments, intranasally administering may comprise delivering about 7.5 mg diazepam in a volume of 100 pL of the composition to each nostril of the subject. Alternatively, intranasally administering may comprise delivering about 20 mg diazepam in a volume of 100 pL of the composition to a single nostril of the subject. In other embodiments, intranasally administering may comprise delivering about 10 mg diazepam in a volume of 100 pL of the composition to each nostril of the subject.

[0103] In some embodiments, the alkyl glycoside may be an alkyd maltoside. In some embodiments, the alkyl glycoside may be selected from dodecyl maltoside, tetradecyl maltoside, or a combination thereof. The composition may comprise about 0.2% w / v to about 1% w / v of the alkyl glycoside in certain embodiments.

[0104] The one or more alcohols may comprise a mixture of ethanol and benzy l alcohol in some implementations. In certain embodiments, the composition may comprise about 1% W / T to about 25% w / v ethanol and about 10% w / v to about 40% w / v benzyl alcohol.

[0105] In some embodiments, the administering may be performed by a caregiver. The early status epilepticus may be a pre-hospital episode of status epilepticus in certain embodiments.

[0106] The early status epilepticus may be generalized status epilepticus, focal status epilepticus, focal status epilepticus with impaired consciousness, unclassified status epilepticus, tonic-clonic status epilepticus, absence status epilepticus, or a combination thereof in some implementations. In certain embodiments, where the early status epilepticus is generalized status epilepticus, termination of the status epilepticus may occur within 30 minutes of administering the composition.

[0107] In some embodiments, administering the composition may result in rapid termination of early status epilepticus with a median time from administering the composition to status epilepticus cessation of about 5 minutes for generalized status epilepticus, about 12 minutes for focal status epilepticus, or about 8 minutes for unclassified status epilepticus.

[0108] In certain embodiments, no seizure recurrence may occur within about 1 hour, about 12 hours, or about 24 hours of termination of the early status epilepticus.161629946371.1

[0109] In certain embodiments, the methods disclosed herein further comprise administering a second dose of the composition within about 24 hours of the administering the composition. In certain embodiments, the methods disclosed herein further comprise administering a second dose of the composition after at least 4 hours of the administering the composition. In some embodiments, the second dose is the same dose as the composition initially administered to the subject.

[0110] In some embodiments, the methods for treating status epilepticus in a subject comprises: intranasally administering to the subject experiencing status epilepticus, a solution composition comprising: a therapeutically effective amount of diazepam; an alkyl glycoside; and a carrier system comprising one or more natural or synthetic tocopherols or tocotrienols and one or more alcohols, wherein the status epilepticus is treated.

[0111] In some embodiments, the therapeutically effective amount of diazepam may be about 2 mg to about 20 mg diazepam in a volume of about 10 pL to 200 pL of the composition. In certain embodiments, the therapeutically effective amount of diazepam may be about 5 mg to about 20 mg in a volume of 100 pL to 200 pL of the composition.

[0112] The composition may be provided in a pre-primed single use dosage device containing about 100 μL of the composition in some implementations. Intranasally administering may comprise delivering about 5 mg to about 10 mg of diazepam in a volume of about 100 μL of the composition to a single nostril of the subject in certain embodiments,

[0113] In some embodiments, intranasally administering may comprise delivering about 7.5 mg diazepam in a volume of 100 pL of the composition to each nostril of the subject. Alternatively, intranasally administering may comprise delivering about 20 mg diazepam in a volume of 100 pL of the composition to a single nostril of the subject in some embodiments. In other embodiments, intranasally administering may comprise delivering about 10 mg diazepam in a volume of 100 pL of the composition to each nostril of the subject.

[0114] In some embodiments, the alkyl glycoside may be an alkyd maltoside. In some embodiments, the alkyl glycoside may be selected from dodecyl maltoside, tetradecyl maltoside, or a combination thereof. The composition may comprise about 0.2% w / v to about 1% w / v of the alkyl glycoside in certain embodiments.

[0115] The one or more alcohols may comprise a mixture of ethanol and benzyl alcohol in some implementations. In certain embodiments, the composition may comprise about 1% w / v to about 25% w / v ethanol and about 10% w / v to about 40% w / v benzyl alcohol.

[0116] In some embodiments, the administering may be performed by a caregiver. The status epilepticus may be a pre-hospital episode of status epilepticus in certain embodiments.171629946371.1

[0117] The status epilepticus may be generalized status epilepticus, focal status epilepticus, focal status epilepticus with impaired consciousness, unclassified status epilepticus, tonic-clonic status epilepticus, absence status epilepticus, or a combination thereof in some implementations. In certain embodiments, where the status epilepticus is generalized status epilepticus, termination of the status epilepticus may occur within 30 minutes of administering the composition.

[0118] In some embodiments, administering the composition may result in rapid termination of status epilepticus with a median time from administering the composition to status epilepticus cessation of about 5 minutes for generalized status epilepticus, about 12 minutes for focal status epilepticus, or about 8 minutes for unclassified status epilepticus.

[0119] In certain embodiments, no seizure recurrence may occur within about 1 hour, about 12 hours, or about 24 hours of termination of the status epilepticus.

[0120] The methods described herein provide a composition suitable for intranasal administration (“intranasal composition”) comprising: a therapeutically effective amount of a benzodiazepine drug; about 0.01% w / v to about 1% w / v of an alkyl glycoside; and a carrier system comprising about 30% w / v to about 90% w / v of a natural or synthetic tocopherol, a natural or synthetic tocotrienol, or a combination thereof and about 10% w / v to about 70% w / v of one or more alcohols.

[0121] Benzodiazepines have the general basic structure of formula I:Formula I

[0122] wherein R1-R5 are substitutable chemical moieties. R1 may be an optionally substituted alkyl or may form a optionally substituted heterocyclic ring with R4 (where the hetero atom is the nitrogen (N) in the diazepine ring); R2 is a halogen (e.g., Cl, Br); R3 may be an optionally substituted ary 1 group (e.g., 2 -chloro or 2-fluorophenyl); R5 is -H or -OH; if R4 is not joined with R1 to form an optionally substituted heterocyclic ring, R4 and R4' may together form a carbonyl moiety (C=O) with the carbon to which they are attached; R3' and R6 may together form a double bond or may be combined to form an optionally substituted heterocyclic ring fused to the diazepine ring at the atoms to which they are attached. Benzodiazepines are basic compounds, and as such, may form acid addition salts with 181629946371.1pharmaceutically acceptable acids, such as pharmaceutically acceptable mineral acids and pharmaceutically acceptable organic acids. Reference to a benzodiazepine herein refers to and includes any pharmaceutically acceptable form, such as the free base form, an acid addition salt, a base addition salt, or a solvated form (such as a hydrate).

[0123] Pharmaceutically acceptable mineral acids include hydrochloric acid, sulfuric acid, sulfurous acid, phosphoric acid, phosphorous acid, and others that will be recognized by those of skill in the art. Pharmaceutically acceptable organic acids include acetic acid, benzoic acid, tartaric acid, citric acid, oxalic acid, maleic acid, malonic acid, 1 -hydroxy -2 -naphthoic acid, 2,2-dichloroacetic acid, 2 -hydroxyethanesulfonic acid, 2-oxoglutaric acid, 4-acetamidobenzoic acid, 4-aminosalicylic acid, acetic acid, adipic acid, ascorbic acid (L), aspartic acid (L), benzenesulfonic acid, benzoic acid, camphoric acid (+), camphorsulfonic acid (+). capric acid (decanoic acid), caproic acid (hexanoic acid), caprylic acid (octanoic acid), carbonic acid, cinnamic acid, citric acid, cyclamic acid, dodecylsulfuric acid, ethane- 1,2-di sulfonic acid, ethanesulfonic acid, formic acid, fumaric acid, galactaric acid, gentisic acid, glucoheptonic acid (D), gluconic acid (D), glucuronic acid (D), glutamic acid, glutaric acid, glycerophosphoric acid, glycolic acid, hippuric acid, hydrobromic acid, hydrochloric acid, isobutyric acid, lactic acid (DL), lactobionic acid, lauric acid, maleic acid, malic acid (-L), malonic acid, mandelic acid (DL), methanesulfonic acid, benzenesulfonic acid (besylic acid), naphthalene-l,5-disulfonic acid, naphthalene-2-sulfonic acid, nicotinic acid, nitric acid, oleic acid, oxalic acid, palmitic acid, pantoic acid, phosphoric acid, propionic acid, pyroglutamic acid (-L), salicylic acid, sebacic acid, stearic acid, succinic acid, sulfuric acid, tartaric acid (+L), thiocyanic acid, toluenesulfonic acid (p), and undecylenic acid. Other pharmaceutically acceptable acids may be pharmaceutically acceptable acidic (anionic) polymers or pharmaceutically acceptable amphoteric polymers. One skilled in the art will recognize that other basic active pharmaceutical ingredients may be combined with the foregoing acids to produce acid addition salts.

[0124] Examples of benzodiazepines that may be delivered intranasally via the intranasal compositions as disclosed herein include, but are not limited to, alprazolam, brotizolam, chlordiazepoxide, clobazam, clonazepam, clorazepam, demoxazepam, diazepam, flumazenil, flurazepam, halazepam, olanzapine, midazolam, nordazepam, medazepam, nitrazepam, oxazepam, lorazepam, prazepam, quazepam, triazolam, temazepam, loprazolam, any pharmaceutically acceptable salt thereof, as well as any combinations thereof. For example, particularly useful compositions may comprise diazepam, midazolam, lorazepam, or a pharmaceutically acceptable salt thereof. Diazepam is chemically known as 7-chloro-l,3-dihydro-l-methyl-5-phenyl-l,4-benzodiazepin-2-one and is shown below in Formula II.191629946371.1Formula II

[0125] Compositions for delivering a benzodiazepine intranasally (“intranasal compositions”) comprise a therapeutically effective amount of a benzodiazepine, for example, about 1 mg to about 20 mg of the benzodiazepine per a volume of about 10 pL to 200 pL. For example, an intranasal composition may comprise about 5 mg / mL (0.5% w / v) to about 0.6 g / mL (60% w / v) or about 10 mg / mL to about 250 mg / mL of a benzodiazepine, which also includes concentrations of about 1% w / v to about 50% w / v, about 5% w / v to about 25% w / v, or about 5% w / v to about 15% w / v of a benzodiazepine. These ranges include any discreet concentrations within the disclosed ranges, such as, about 5% w / v, about 7.5% w / v, about 10% w / v, about 15% w / v, and about 20% w / v of a benzodiazepine.

[0126] The intranasal compositions as disclosed herein comprise a benzodiazepine dissolved in a carrier system comprising a natural or synthetic tocopherol, a natural or synthetic tocotrienol, or a combination thereof and one or more alcohols.

[0127] The intranasal compositions may comprise about 30% w / v to about 90% w / v of a natural or synthetic tocopherol, a natural or synthetic tocotrienol, or a combination thereof, such as about 50% w / v to about 75% w / v, about 50% w / v to about 60% w / v, about 45% w / v to about 65% w / v, about 45% w / v to about 85% w / v, or about 10% w / v to about 25% w / v of a natural or synthetic tocopherol, a natural or synthetic tocotrienol, or a combination thereof.

[0128] Examples of suitable natural or synthetic tocopherols or tocotrienols include, but are not limited to, a-tocopherol, p-tocopherol, y-tocopherol, 8-tocopherol, a-tocotrienol, [5-tocotrienol, y-tocotrienol, 8-tocotrienol, tocophersolan, an isomer of any thereof, an ester of any thereof, an analog or derivative of any thereof, and any combination thereof. A synthetic tocopherol may be covalently bonded to a glycol polymer, such as polyethylene glycol, as in vitamin E TPGS (vitamin E polyethylene glycol succinate). Alternatively, the intranasal compositions as disclosed herein may be free of, or substantially free of, such glycol-bound synthetic tocopherols. Many of the various tocopherol and tocotrienols solvents described above are naturally occurring vitamin E compounds or vitamin E esters. Vitamin E is a class of fat-soluble methylated phenols. As used herein, vitamin E refers to any of the natural or synthetic tocopherols, tocotrienols, isomers thereof, esters thereof, or any analogs or 201629946371.1derivatives thereof, as well as combinations thereof. It has been found that vitamin E is an effective carrier for benzodiazepines and does not irritate sensitive mucosal membranes. Typically, vitamin E is considered hydrophobic and, as such, is used in emulsion-type compositions which tend to be unstable. However, when including a vitamin E carrier with one or more lower alcohols, a composition may be provided having enhanced stability and suitability’ as a carrier for intranasal administration of a benzodiazepine.

[0129] Therefore, the carrier system of the intranasal compositions disclosed herein also comprises about 10% w / v to about 70% w / v of one or more alcohols. As used herein, “alcohol” is used to describe a molecule having at least one hydroxyl functional group (-OH) bound to a saturated carbon atom, which includes monohydric alcohols and polyhydric alcohols, such as glycols. The alcohol may be a lower alcohol, which includes compounds with six or fewer carbon atoms, such as ethanol, propanol, butanol, pentanol, benzyl alcohol, ethylene glycol, propylene glycol, butylene glycol, pentylene glycol, any isomer thereof, or any combination thereof. An intranasal composition may comprise about 10% w / v to about 70% w / v of one or more alcohols such as about 15% w / v to about 55% w / v, or about 25% w / v to about 40% w / v, or about 30% w / v of one or more alcohols. For example, an intranasal composition may comprise 15% w / v to about 55% w / v, or about 25% w / v to about 40% w / v, or about 30% w / v of benzyl alcohol, ethanol, or a mixture thereof. In another example, an intranasal composition may comprise a mixture of ethanol and benzyl alcohol. In any embodiment, an intranasal composition may comprise about 1% w / v to about 25% w / v of ethanol and about 5% w / v to about 40% w / v of benzyl alcohol, about 1 % w / v to about 25% w / v of ethanol and about 5% w / v to about 50% w / v of benzyl alcohol, about 10% w / v to about 25% w / v of ethanol and about 5% w / v to about 15% w / v of benzyl alcohol, or about 15% w / v to about 22.5% w / v ethanol and about 7.5% w / v to about 12.5% w / v benzyl alcohol, or about 10% w / v to about 25% w / v ethanol and about 7.5% w / v to about 12.5% w / v benzyl alcohol, or about 17% w / v to about 20% w / v ethanol and about 10% w / v to about 12% w / v benzyl alcohol. In any embodiment, an intranasal composition may comprise about 5% w / v to about 15% w / v of ethanol and about 10% w / v to about 25% w / v of benzyl alcohol, or about 7.5% w / v to about 12.5% w / v ethanol and about 15% w / v to about 22.5% w / v benzyl alcohol, or about 7.5% w / v to about 12.5%w / v ethanol and about 10% w / v to about 25% w / v benzyl alcohol, or about 10% w / v to about 12% w / v ethanol and about 17% w / v to about 20% w / v benzyl alcohol.

[0130] Optionally and in any embodiment, an intranasal composition, as disclosed herein, may be substantially free or free of polymeric glycols, such as polyethylene glycol, without diminishing the therapeutic benefit of the benzodiazepine administered via the intranasal composition. For example, in any embodiment, an intranasal composition, as disclosed herein, may be substantially free or free of a polymeric glycol having a molecular weight greater than about 200 g / mol. Additionally or alternatively, in any embodiment, an intranasal composition as disclosed herein may comprise very little water, substantially no water, or are completely free of water and are non-aqueous. For example, an intranasal 211629946371.1composition may consist essentially of or consist of 1) a benzodiazepine drug; 2) one or more alkyl glycosides (e.g, DDM and / or TDM), and 3) a carrier system consisting of a) one or more natural or synthetic tocopherols or tocotrienols and b) one or more alcohols and is optionally substantially free of water.

[0131] In addition to the benzodiazepine and the carrier system described above, the intranasal compositions, as disclosed herein, comprise about 0.01% w / v to about 1% w / v of an alkyl glycoside, such as octyl-, nonyl-, decyl-, undecyl-, dodecyl, tridecyl, tetradecyl, pentadecyl, octadecyl a- or p-D-maltoside. In any embodiment, an intranasal composition may comprise one or both of dodecyl maltoside (DDM) and tetradecyl maltoside (TDM). For example, in any embodiment, an intranasal composition may comprise about 0.01% w / v to about 1% w / v of the alkyl glycoside, such as about 0.05% w / v to about 0.5% w / v, or about 0.125% w / v to about 0.5% w / v. In particular examples, an intranasal composition comprises about 0.2% w / v to about 0.5% w / v dodecyl glycoside (DDM), about 0.15% w / v to about 0.3% w / v DDM, 0.18% w / v dodecyl glycoside, or about 0.25% w / v DDM.

[0132] The toxicokinetics and metabolism of alkyl glycosides, such as dodecyl maltoside (also known as Intravail A3), have been studied in detail under Organization for Economic Co-operation and Development (OECD) Guidelines for Testing of Chemicals, Orally and nasally administered alkyl glycosides are hydrolyzed to glucose and the corresponding long chain alcohol. No toxic metabolites are formed at any stage in the metabolic process. Dodecyl maltoside is a component (up to approximately 25%) of a mixture of alkyl glycosides that are the subject of an application for Generally Recognized as Safe (GRAS) status designation by the US FDA Center for Food Safety and Nutrition (CFSAN) and the US Environmental Protection Agency (EP A) based on their use as detergents or surfactants as a component of compounds in food industry and agricultural usages. With their use in these contexts, there is no established limitation on the oral or topical exposure allowed for humans.

[0133] Advantageously, it has been observed that the intranasal compositions, as described herein, do not support the growth of bacteria and therefore may be substantially free or free of any antibacterial agents or other preservatives. However, the use of an antibacterial does not preclude the therapeutic benefits of administering a benzodiazepine via an intranasal composition as described herein. Therefore, in any intranasal composition as disclosed herein, one or more additional preservation, antidegradation, antibacterial, or antifungal agents may be included. An intranasal composition, as disclosed herein, may further optionally comprise one or more agents to enhance appearance, taste, or odor.EXAMPLES

[0134] The following examples are provided to illustrate certain embodiments of the present disclosure. These examples should not be construed as limiting the scope of the disclosure.

[0135] Example 1 - ILAE Operational dimensions of t1 and t2 by status epilepticus (SE) type 221629946371.1

[0136] In 2015, the International League Against Epilepsy proposed a novel definition of status epilepticus that integrates what is known on the pathophysiology of status epilepticus on which historical definitions were based, with the need for urgent clinical treatment decision-making (Trinka el al, 2015). They proposed two operational timepoints — (1) ti, the timepoint at which the mechanisms responsible for seizure termination have failed or the mechanisms that lead to abnormally prolonged seizures have been initiated, and (2) t2, the time point past which if there is ongoing seizure activity there is risk of long-term consequences, including neuronal death, neuronal injury, and alteration of neuronal networks, depending on the type and duration of seizures. Thus, once ti has been reached, the seizure is unlikely to terminate on its own and targeted treatment should be started with the goal of achieving seizure cessation before t2 to prevent long-term consequences. The clinical utility of these operational definitions is now widely accepted in the literature (Glauser et al, 2016; Fetta et al, 2024; Rossetti et al, 2016; Pan Y et al, 2022) and is supported by recent research documenting durations of self-limiting seizures (Meritam Larsen et al. 2023). The time domains were defined for different forms of status epilepticus based on observational human studies and experimental animal studies, as shown in Table 1.

[0137] Table 1 - ILAE Operational dimensions of t1 and t2 by status epilepticus (SE) type

[0138] Example 2 - Pediatric use of intranasal diazepam for the treatment of early status epilepticus

[0139] Patients with epilepsy, especially those with seizure clusters or prolonged seizures, are at significant risk for developing status epilepticus, which is a life-threatening neurological emergency that requires prompt diagnosis and treatment to prevent long-term consequences (e.g., neuronal injury') (Trinka et al, 2015). Studies show that the rate of status epilepticus is higher in children than adults, with the overall incidence of pediatric status epilepticus ranging between 3-42 episodes per 100,000 population per year worldwide based on several population-based studies where status epilepticus was typically defined as a seizure persisting for >30 minutes (Trinka et al, 2015; DeLorenzo et al, 1996; Hesdorffer et al, 1998; Novy et al, 2010; Coeytaux et al, 2000; Wu et al, 2002; Chin et al., 2006).231629946371.1Importantly, incidence based on historical definition may not reflect cases of early status epilepticus that were controlled within 30 minutes. Status epilepticus is associated with significant morbidity, including immediate complications (e.g., tachycardia, hypertension, increased intracranial pressure, cerebral edema), neurologic disabilities (e.g., neurologic deficits, cognitive impairment, seizure recurrence), risk of subsequent unprovoked seizures and recurrent status epilepticus, low developmental scores, psychiatric disorders, and low quality of life. Mortality rates after status epilepticus of 3-11% have been reported in children. Delays in treatment and longer seizure duration are independently associated with worse short-term and long-term outcomes, including a higher mortality rate in patients with status epilepticus lasting > 1 hour compared with <1 hour (Gainza-Lein et al, 2018; Gainza-Lein et al, 2021; Towne et al, 1994). Therefore, prompt recognition and treatment for seizure emergencies is critical to reduce the risk of complications and death associated with status epilepticus, thereby improving outcomes.

[0140] To date, no drug has been approved for the treatment of early status epilepticus in adult and pediatric patients with epilepsy in the US. While intravenous (IV) and intramuscular (IM) formulations of benzodiazepines are most commonly used as initial status epilepticus treatments in hospital and emergency medical services (EMS) settings, these routes of administration require trained health-care professionals for delivery and are not readily accessible to patients / caregivers to promptly administer as rescue therapy. Hence, it has long been recognized that there is a need for an easy-to-use, safe, and effective treatment option with rapid onset of action for the treatment of early status epilepticus at home or in the community (Gettings et al, 2025). In the hospital setting, diazepam is a first-line treatment for status epilepticus, and the American Epilepsy Society's evidence-based treatment guidelines recommend intravenous or rectal diazepam for children and adults at doses up to 0.5 mg / kg of patient body weight (Glauseret al, 2016; Keene et al. 2022). Diazepam rectal gel has been developed and approved more than 2 decades ago for community use as an intermittent treatment to control bouts of increased seizure activity (seizure clusters) in the pre-hospital setting. Some publications incorrectly state that diazepam rectal gel has been approved for the treatment of status epilepticus in children (Barcia Aguilar et al, 2020). Of note, diazepam rectal gel requires multiple steps, including positioning and undressing the patient which may be difficult to do for some patients (e.g., larger patients or those in wheelchairs), as well as undertaking several more steps to complete dose administration, which could delay administration (Diastat PI, 2023; Wheless et al, 2024). On the other hand, pre-packaged diazepam nasal spray may address the need for a ready -to-use treatment option that is simple to use and does not require the presence of trained healthcare professionals (Gettings et al, 2025, Kikuchi et al, 2025; Kientz et al, 2022). Therefore, there is a medical need to expand the indication of VALTOCO to treat pre-hospital episodes of early status epilepticus in patients 2 to 17 years of age.

[0141] Table 2 - Proposed Dosage and Administration241629946371.1Dose Based on Age and Weight Administration2-5 Years 6-11 Years 12-17 Years Dose, Number of Nasal Number of mg(0.5 mg / kg) (0.3 mg / kg) (0.2 mg / kg) Spray Devices Sprays Weight, kg Weight, kg Weight, kg6-11 10-18 14-27 5 One 5 mg device One spray in 1 nostril 12-22 19-37 28-50 10 One 10 mg device One spray in 1 nostril 23-33 38–55 51-75 15 Two 7.5 mg devices One spray each nostril 56-74 >76 20 Two 10 mg devices One spray each nostril

[0142] Placebo-controlled clinical trials to establish the safety and efficacy of a pre-hospital treatment for status epilepticus are challenging and impractical to execute and would be incompatible with clinical equipoise. Withholding proven rescue therapy for the treatment of seizure emergencies and subjecting patients to undue risks and long-term neurological damage presents substantial ethical barriers, leading to difficulties in obtaining institutional review board approvals and patient / parental consent — especially when commercially available treatments and EMS / emergency department services are available. As such, data on the safety and effectiveness of pre-hospital early status epilepticus treatments are most feasibly obtained from open-label clinical studies.

[0143] Applicant has conducted two open-label, long-term safety studies evaluating diazepam nasal spray for the treatment of seizure clusters in patients with epilepsy aged 2-5 and 6-65 years (DIAZ.001-08 and DIAZ.001-05, respectively), during which patients or caregivers reported seizure occurrence(s) and dose administration(s) in seizure diaries. Examination of seizure diary data collected during the course of these 2 clinical studies revealed that there were 53 patients with epilepsy in the age group of 2-17 years who experienced a total of >300 seizures treated with diazepam nasal spray after time point h (see Example 1 for ILAE definition; Trinka et al, 2015). These data support the safety and effectiveness of VALTOCO to treat pre-hospital episodes of early status epilepticus in pediatric patients with epilepsy.

[0144] Applicant has completed a Phase 3 long-term, open-label, repeat-dose safety study of diazepam nasal spray for the treatment of seizure clusters in patients aged 6 to 65 years with diverse epilepsies and focal or generalized seizure types (DIAZ.001-05; NCT02721069; Wheless et al, 2021). There were 163 male and female patients enrolled, of whom 78 patients were 6-17 years of age (Tarquinio et al, 2022). Eligible patients had a diagnosis of focal or generalized epilepsy with motor seizures or seizures with clear alteration of awareness and were expected to need benzodiazepine intervention on average at least six times per year. Doses of 5 to 20 mg were assigned according to 251629946371.1patient age and body weight, with dosing of 0.3 mg / kg for patients 6-11 years and 0.2 mg / kg for patients >12 years. After training, caregivers or patients administered a weight-based dose of diazepam nasal spray to treat seizure clusters as needed during daily activities in their usual setting. Second doses were allowed for 4 to 12 hours after the initial dose. Caregivers and patients recorded timing of treated seizures and diazepam administration using seizure diaries. Seizure type was not captured in the seizure diaries; this was determined post hoc based on available baseline information of each patients’ seizure and medical history (Fountain et al, 2024). Seizures without a clear type based on available baseline data were categorized as unclassified. After the initial treatment period of 12 months, patients could elect to remain in the study and continue therapy.

[0145] Applicant is currently completing a Phase 1 / 2a, open-label, single-dose, pharmacokinetic (PK) study of diazepam nasal spray with an open-label, repeat-dose safety period and optional extension period in pediatric patients with epilepsy aged 2-5 years (DIAZ.001-08; NCT05076838), The PK and open-label safety periods of the study have been completed. The optional extension period is ongoing. A. total of 36 patients were enrolled, of whom 31 completed the PK and safety periods. Eligible patients had a clinical diagnosis of either partial or generalized epilepsy with motor seizures or seizures with clear alteration of awareness for which rescue medications had been used at least once in the last 3 months or, in the opinion of the investigator, may have needed a benzodiazepine intervention for seizure control 1-2 times every’ 3 months on average. Doses of 5 to 15 mg were assigned according to tire patient’s age and body weight, with dosing of 0.5 mg / kg based on the FDA approved recommended dosing guidelines for diazepam rectal gel. During the 180-day open-label safety’ period, caregivers were supplied with diazepam nasal spray for use as needed for treating acute repetitive seizures or frequent breakthrough seizures in their usual setting. A second dose could be administered as needed 4-12 hours after the initial dose. Dose administrations and seizure data (treated and untreated) were collected in the patient daily electronic diary during the open-label safety and optional extension periods. Data for seizures in the diary included the type of seizure treated, the date of use, time of seizure onset, time of dosing, and time of seizure resolution. Patients may have been counted in more than 1 seizure / epilepsy type group if they had multiple seizure types. Seizures with insufficient description provided to determine a clear type were categorized as unclassified. After the initial treatment period of 6 months, caregivers could elect to remain in the study and continue therapy in the optional open-label extension period. Data from the completed 180-day safety period and the ongoing optional extension period up to a data cutoff date of 20 April 2024 were included in this analysis.

[0146] From the above-mentioned studies, seizures in patients 2-17 years of age meeting ILAE criteria for early status epilepticus (event lasting >t1 by seizure type) treated with diazepam nasal spray were identified and pooled for statistical analysis with the objective of evaluating the effectiveness of VALTOCO as a treatment for early status epilepticus in the pre-hospital setting.261629946371.1

[0147] Of 114 pediatric patients treated with diazepam nasal spray in the 2 studies, 53 patients with epilepsy aged 3-16 years old had >1 treated early status epilepticus events and a total of 310 events. The median and mean ages were 10 years (range 3-16 years) and 9.8 years, respectively (Table 3). There was a nearly equal mix of males (n=27, 50.9%) and females (n=26, 49.1%).

[0148] Table 3 - Baseline Demographics for Pooled Pediatric PopulationEarly status epilepticus TypeCharacteristic TotalGeneralized Focal Unclassified (N=53a)(n=39) (n=ll) (n=6) Median age, years 10 10 11 4.4(range) (3-16) (3.5-15) (3.5-16) (3-15)Sex, n (%)Female 26 (49.1) 19 (48.7) 6 (54.5) 3 (50.0) Male 27 (50.9) 20 (51.3) 5 (45.5) 3 (50.0) Race, n (%)White 41 (77.4) 33 (84.6) 6 (54.5) 5 (83.3) African American 7 (13.2) 4 (10.3) 2 (18.2) 1 (16.7) Asian 2 (3.8) 1 (2.6) 1 (9.1) 0Multiple 1 (1.9) 0 1 (9.1) 0Oilier 2 (3.8) 1 (2.6) 1 (9.1) 0Dose, n (%)5 mg 0 0 0 010 mg 40 (75.5) 32 (82.1) 7 (63.6) 3 (50.0)15 mg 11 (20.8) 6 (15.4) 4 (36.4) 2 (33.3)20 mg 2 (3.8) 1 (2.6) 0 1 (16.7)1629946371.1a' Patients may have been counted in more than 1 seizure-type subgroup if they had multiple seizure types recorded by caregivers.

[0149] Applicant studied the full pediatric age range of 2 to 17 years (age at enrollment) in this analysis.

[0150] Study Endpoints

[0151] Time from seizure onset to dose administration, time from dose to seizure termination, and total seizure duration for early status epilepticus episodes.

[0152] Proportion of patients and events with status epilepticus termination <20 minutes (all status epilepticus types), and <30 (generalized status epilepticus) or <60 (for focal and unclassified status epilepticus) minutes after dose administration.

[0153] Proportion of patients and proportion of events with any seizure recurrence in 1, 12, or 24 hours after status epilepticus termination.

[0154] Proportion of early status epilepticus events for which a second dose was administered for ongoing status epilepticus as a proxy for effectiveness.

[0155] Proportion of treated early status epilepticus episodes that required hospitalization for serious TEAE of status epilepticus.

[0156] For both studies, data were collected from the patient seizure diaries, regarding time of seizure onset, dose administration, and seizure termination, as well as the type of seizure, when available. Patients with developmental and epileptic encephalopathies were included in the generalized status epilepticus category'. Early status epilepticus events were defined as those that were ongoing at the time of treatment and met the ILAE criteria for ti (>5 minutes for generalized early status epilepticus (as a working approximation of tonic-clonic status epilepticus) and >10 minutes for focal early status epilepticus with impaired consciousness). Unclassified early status epilepticus events were defined conservatively, using ti for focal seizures with impaired consciousness, as >10 minutes. Time point t2 was 30 minutes for generalized and 60 minutes for focal and unclassified seizures. Treated status epilepticus events were analyzed by seizure type for time from seizure start to dose, time from dose to seizure termination, and total seizure duration. Events with incorrect / incomplete data (e.g., invalid or missing dates, stop before start, duration >24 hours, dose after stop or before start) were excluded, as were duplicate records and second doses.

[0157] Data for status epilepticus termination <20 minutes after dose administration, and <30 (for generalized status epilepticus) and <60 (for focal or unclassified status epilepticus) minutes after dose administration were analyzed in a responder analysis that included the number of seizure events and patients corresponding with the seizure type and relevant timing. Data for any seizure recurrence in 1,281629946371.112, or 24 hours after status epilepticus termination were analyzed in a recurrence analysis that included the number of recurrent seizures and patients corresponding with the seizure type. The recurrence analysis included any seizure that occurred after status epilepticus termination (including untreated seizures in the pediatric study of patients aged 2 to 5 years). The proportion of early status epilepticus events for which a second dose was administered for individual ongoing status epilepticus events was analyzed as a proxy for effectiveness by seizure type and age group. Early status epilepticus episodes requiring retreatment were identified from single seizures treated past ti with >1 dose administered. The proportion of treated early status epilepticus episodes (i.e., >ti) that required hospitalization as serious TEAEs of status epilepticus was determined by correlating the dates of treated early status epilepticus episodes with dates of onset of status epilepticus recorded as serious TEAEs,

[0158] Of the 53 pediatric patients with early status epilepticus events, 39 patients (73.6%) had at least 1 generalized seizure treated past t1 (Table 3) with a total of 253 generalized status epilepticus events; 11 patients (20.8%) had at least 1 focal seizure treated past t1 with a total of 26 focal status epilepticus events; and 6 patients had at least 1 unclassified seizure treated past t1 (11.3%) with a total of 31 unclassified status epilepticus events. The majority of seizures (81.6%) treated past ti in this pediatric population was generalized,

[0159] Administration of the composition disclosed herein was associated with rapid termination of early status epilepticus with median time from seizure onset to status epilepticus cessation attained by / before t2. For generalized status epilepticus, the median time from seizure start to dose administration was 11 minutes, median time from dose to status epilepticus termination was 5 minutes, and median overall duration was 20 minutes (notably before t2 of 30 minutes for generalized status epilepticus) (Figure I). For focal status epilepticus, the median times from start to dose was 29,5 minutes, from dose to end was 12 minutes, and overall duration was 60.5 minutes (by t2 of 60 minutes for focal status epilepticus). For unclassified status epilepticus, the median times from start to dose was 16 minutes, dose to end was 8 minutes, and overall duration was 35 minutes (before t2 of 60 minutes for unclassified status epilepticus).

[0160] There was an overall high proportion of patients with status epilepticus termination <20 minutes from dose administration, but a lower proportion of events showed this response for focal and unclassified status epilepticus compared with generalized status epilepticus (Figure 2A and Figure 2B).94.9% (37 / 39) of patients with generalized early status epilepticus and 87.0% (220 / 253) of total generalized events had resolution within 20 minutes from dose. In comparison, 72.7% (8 / 11) of patients with focal status epilepticus and 69.2% (18 / 26) of total focal events, and 83.3% (5 / 6) of patients with unclassified status epilepticus and 77.4% (24 / 31) of unclassified events had cessation in <20 minutes 291629946371.1from dose. Notably, responder analysis for termination within 30 or 60 minutes (dependent on seizure type) from dose administration showed higher proportions of patients and events for all status epilepticus types achieving this outcome, with nearly all patients with generalized status epilepticus events and vast majority of generalized events treated with diazepam nasal spray demonstrating status epilepticus cessation prior to the time point of long-term consequence accrual. 97.4% (38 / 39), 72.7% (8 / 11), and 83.3% (5 / 6) of patients showed termination of status epilepticus events <t2 for generalized, focal, and unclassified events, respectively; 92.1% (233 / 253), 76.9% (20 / 26), and 90.3% (28 / 31) of generalized, focal, and unclassified status epilepticus events, respectively, terminated prior to or by t2.

[0161] An important metric to determine the effectiveness of a treatment for status epilepticus is a recurrence analysis examining the likelihood of a patient experiencing another episode of seizure or status epilepticus (treated or untreated; for the subset of patients aged 6-17 years, only treated episodes were recorded) after the initial event. Across all status epilepticus types, there was a low proportion of patients and events with seizure recurrence in <1. 12, or 24 hours from status epilepticus termination after treatment with diazepam nasal spray (Table 4). There were no episodes of recurrence within 1 hour following cessation of a generalized or focal early status epilepticus event. The proportion of patients with generalized or focal status epilepticus with recurrence <12 or 24 hours from tire end of the initial event were comparable at 7.7% and 9.1%, respectively, for <12h, and 15.4% and 18.2%, respectively, for <24h. Greater than 90% of generalized or focal status epilepticus events terminated with diazepam nasal spray treatment and greater than 80% of patients with generalized or focal events had no recurrence within 24 hours after status epilepticus cessation. The proportion of patients and events with recurrence in the unclassified group were moderately higher than in the generalized or focal groups; however, >85% of patients with unclassified status epilepticus events achieved the outcome of no recurrence within 24 hours. Of note, when a recurrent seizure did occur, nearly all (40 / 41; 97.6%) were recurrent status epilepticus events with duration >ti.

[0162] Table 4 - Recurrence analysis: proportion of patients and early status epilepticus events with seizure recurrenceEarly Status Epilepticus TypeVariable TotalGeneralized Focal Unclassified (N=53a)(n=39) (n=11) (n=6) Recurrence (patients), n (%)<1 hour 1 (1,9) 0 0 1 (16.7)301629946371.1<12 hours 6 (11.3) 3 (7.7) 1 (9.1) 2 (33.3)<24 hours 10 (18.9) 6 (15.4) 2 (18.2) 2 (33.3) Recurrence (events), n (%)<1 hour 1 (3.2) 0 0 1 (3.2)<12 hours 12 (3.9) 8 (3.2) 1 (3.8) 3 (9.7)<24 hours 21 (8.3) 15 (5.9) 2 (7.7) 4 (12.9) Percent patientsachieving no recurrence 81.1% (43) 84.6% (33) 81.8% (9) 66.7% (4) <24hPercent eventsachieving no recurrence 93.2% (289) 94.1% (238) 92.3% (24) 87.1% (27) <24h

[0163] Further supporting the effectiveness of diazepam nasal spray in the treatment of early status epilepticus out-of-the-hospital is the low usage of second doses to treat ongoing status epilepticus episodes (Figure 3 ). 8.7% of generalized status epilepticus events were treated with a second dose while 19.4% of unclassified events were retreated. No focal episodes of early status epilepticus were treated with > 1 dose across both studies. Therefore, 91.3% of generalized, 100% of focal, and 80.6% of unclassified status epilepticus events were treated with a single dose, suggesting high first dose effectiveness of diazepam nasal spray in patients experiencing early status epilepticus past t₁.

[0164] Established status epilepticus occurs when an episode of early status epilepticus does not respond to treatment with first-line benzodiazepines. In these cases, treatment with a second-line non¬ benzodiazepine antiseizure medication is warranted, which typically occurs in hospital settings (Gettings et al, 2025). Thus, in situations where the initial benzodiazepine treatment occurs at home or in the community without effect, emergency medical care is needed. In this pooled pediatric patient population, there was a very low rate of treated early status epilepticus events associated with a hospitalization for ongoing status epilepticus. Of the 114 patients aged 2-17 years in the two studies, there were 11 patients who had at least one serious TEAE of status epilepticus with a total of 17 hospitalizations due to status epilepticus. Only 4 of these patients with serious adverse events of status epilepticus had an episode of seizure lasting longer than and treated past t₁ on the same date, i.e. only 4 patients had a pre-hospitalization treatment of early status epilepticus associated with an SAE of status epilepticus on the same date. There was a total of 7 hospitalizations for status epilepticus associated.311629946371.1with pre-hospitalization early status epilepticus treatment. All treated early status epilepticus events associated with hospitalizations for ongoing status epilepticus were generalized in type. Therefore, the majority of treated early status epilepticus episodes, including all focal or unclassified events, were not associated with hospitalizations for SAE of status epilepticus, suggesting that treatment with diazepam nasal spray may have prevented the need for hospitalization.

[0165] In summary, the data from this pooled cohort analysis demonstrates that treatment with diazepam nasal spray provides consistent control of early status epilepticus episodes treated in the prehospital setting in patients with epilepsy 3-16 years of age. The majority of the patients had status epilepticus termination prior to or by t₂, and >90% of generalized and focal status epilepticus episodes did not have recurrence within 24 hours. Administration of a second dose for an ongoing episode of status epilepticus occurred for only 8.7% of generalized events and 0% of focal episodes, supporting high first-dose effectiveness of >90% of diazepam nasal spray for this indication. The vast majority of treated early status epilepticus episodes (97.7%) were not associated with hospitalizations for established status epilepticus. These findings provide evidence of the safety and effectiveness of immediate treatment with diazepam nasal spray for the neurological emergency of early status epilepticus in the pediatric population.

[0166] These examples demonstrate various embodiments of intranasal diazepam use in pediatric patients with status epilepticus, including efficacy across different age groups and seizure types, pharmacokinetic considerations, long-term safety, and caregiver perspectives.

[0167] Example 3 - treatment of status epilepticus at and after T1 with diazepam nasal spray: a combined cohort analysis

[0168] Background: Status epilepticus (SE) may be characterized as a period of continuous seizure activity or 2 or more seizures without recovery of consciousness; thus, seizure clusters, prolongedseizures, and status epilepticus are not necessarily distinct types of clinical events and may overlap. There is no single agreed upon definition for seizure clusters. The natural evolution of some epileptic syndromes, especially those that are drug resistant, have been known to be characterized by status epilepticus or seizure clustering. These events may put the patient at high risk of morbidity and mortality. The International League Against Epilepsy (1LAE) defines status epilepticus as abnormally prolonged seizures without recovery of consciousness that have timing dimensions. Time point tl (5 minutes for tonic-clonic status epilepticus and 10 minutes for focal status epilepticus with impaired awareness) at which seizures are likely to be prolonged. Time point t2 (30 minutes for tonic-clonic status epilepticus and 60 minutes for focal status epilepticus with impaired awareness) at which point long-term consequences such as neuronalinjury may occur. Seizures lasting beyond 11 are unlikely to stop on their own, and prompt and effective 321629946371.1treatment should be initiated to resolve seizures prior to t2. The early time window for treatment frequently occurs in out-of-hospital / prehospital settings, underscoring the need for rapid, effective, safe treatment options for early status epilepticus at home or in the community. Moreover, rapid treatment of seizure events is associated with higher likelihood of better outcomes, seizure termination and responsiveness to benzodiazepines. Prognosis deteriorates with increasing duration of SE. Immediate-use seizure medication (ISM), including those with nasal routes of administration, is appropriate across this spectrum of epilepsy events. Benzodiazepines are recommended as first-line therapy for status epilepticus in the community. Treatment of seizure clusters with diazepam nasal spray >5 minutes after onset and prolonged seizures within seizure clusters 5-15 minutes after onset has been shown to be effective for seizure termination. Diazepam nasal spray is approved by the US Food and Drug Administration for acute treatment of intermittent, stereotypic episodes of frequent seizure activity (i.e., seizure clusters, acute repetitive seizures) that are distinct from a patient’s usual seizure pattern in patients with epilepsy aged ≥6 years.

[0169] Objective: To describe and assess timing, dosing, and effectiveness of diazepam nasal spray in the subset of seizures meeting ILAE criteria for early status epilepticus (event lasting >tl by seizure type) and examination of resolution by / before t2 in a large pooled dataset of treated seizure events.

[0170] Methods - Study Designs: Data were pooled from 2 studies evaluating diazepam nasal spray as an ISM in patients with epilepsy as of April 20, 2024. A Phase 1 / 2 single-dose pharmacokinetics (PK) and safety study with a 180-day open-label safety period and optional open¬ label extension period evaluated diazepam nasal spray in patients aged 2-5 years. A Phase 3 long-term open-label, repeat-dose safety study with a 12-month treatment period evaluated diazepam nasal spray in patients aged 6-65 years.

[0171] Patients: For inclusion in either study, patients were required to have a clinical diagnosis of either focal or generalized epilepsy with motor seizures or seizures with clear alteration of awareness. In the opinion of the investigator, patients potentially required benzodiazepine treatment for seizure control on average 1-2 times every 3 months or >6 times per year. In the PK and safety study, patients had used rescue medications at least once in the past 3 months prior to enrollment or, in the opinion of the investigator, may have needed a benzodiazepine intervention for seizure control 1-3 times every 3months on average. The long-term safety study included patients who, in the opinion of the investigator, might have needed benzodiazepine intervention for seizure control once every other month (i.e., 6 times per year).

[0172] Data collection of dose administration and seizures: For the PK and safety study of patients aged 2-5 years, an electronic diary was provided for recording usage of diazepam nasal spray, including 331629946371.1date of use, time of seizure onset, time of dosing, and time of seizure resolution, as well as the type of seizure (e.g., focal, generalized). Patients may have been counted in more than 1 seizure / epilepsy type group if they had multiple seizure types, as caregivers reported a seizure description for every treated event. For the long-term safety study in patients aged 6-65 years, a patient diary was used to record drug administration and timing of treated seizures13; seizure type was not captured in the diaries. Seizure type was determined post hoc based on available baseline information of seizure and medical history. Patients with developmental and epileptic encephalopathies were included in the generalized-seizures category. For both studies, seizures without a clear type based on available baseline data were categorized as unclassified.

[0173] Timing analyses: Early status epilepticus events were defined based on the ILAE criteria for tl (>5 minutes for generalized [as a working approximation of tonic-clonic] early status epilepticus and >10 minutes for focal seizures [with alteration of awareness] early status epilepticus). Unclassified early status epilepticus events also were defined with a t1 of >10 minutes. Time point t2 was 30 minutes for generalized and 60 minutes for focal and unclassified seizures. Treated status epilepticus events were analyzed by seizure type, time from seizure start to dose, time from dose to seizure termination, and total seizure duration. Events with incorrect / incomplete data (e.g., invalid or missing dates, seizure stop before start, duration >24 hours, dose after stop or before start) were excluded, as were duplicate records and second doses. A responder analysis assessed proportions of patients and events with status epilepticus termination in <t2 (<30 or <60 minutes) per seizure type. An additional responder analysis taking into consideration the variability in time from status epilepticus onset to time of treatment assessed proportions of patients and events with status epilepticus termination <20 minutes after dose administration across all seizure types. The 20-minute time point reflects the timeline for escalating from first-line (benzodiazepine) to second-line treatment for status epilepticus. A recurrence analysis assessed proportions of patients and events with any seizure recurrence in 1, 12, or 24 hours after status epilepticus termination. The recurrence analysis included any seizure that occurred after status epilepticus termination, (including untreated seizures in the PK and safety study). In a subgroups analysis, patients aged 2-5 years, 6-11 years, and 12-17 years and, in a separate analysis, 18-65 years were evaluated by age group and seizure type for time from treatment to seizure episode termination; unclassified seizures were excluded in these analyses.

[0174] Proxy for effectiveness: Proportion of early status epilepticus events for which a second dose was administered for individual ongoing status epilepticus events was analyzed as a proxy for effectiveness by seizure type and age group. Early status epilepticus episodes requiring retreatment were identified from single seizures treated past tl with >1 dose administered.

[0175] Safety: Treatment-emergent adverse events (TEAEs) and serious TEAEs were reported andsummarized for all pooled patients with early status epilepticus. Proportion of treated early status 341629946371.1epilepticus episodes (i.e., >t1) that required hospitalization as serious TEAEs of status epilepticus was determined by correlating the dates of treated early status epilepticus episodes with dates of onset of status epilepticus recorded as serious TEAEs.

[0176] Results: Of 199 patients treated with 4690 doses of diazepam nasal spray in the 2 studies, 97patients in the 2-65 age group (range 3-59 years) recorded >1 early status epilepticus event for a total of 671 events, which were pooled from the 2 studies: Generalized status epilepticus: n=52 patients, 316 events; Focal status epilepticus: n=31 patients, 245 events: Unclassified status epilepticus: n=17 patients, 110 events; 2 patients in the PK and safety study had >1 early status epilepticus event seizure type: 1 patient with generalized, focal, and unclassified events, and 1 patient with focal and unclassified events. The median age was 15 years (range: 3-59 years); 55.7% were female; most (43.3%) received the 10 mg dose (Table 5).

[0177] Table 5 - Baseline demographics for pooled population with early seEwh hE Tvm1lAelMsiftyd | ( JMedian agty. yem | 15 t 2.3 (3 Mb) C angel |hex. aEmaie ] 54 $ $5,71 j 2815,3,8? R (fel..31 V (52.9) j _ 4.%44..ty 24 U6.2? 12 (38.71. 8 (4",h Dsssty n 04$ _5?ng H i O) f 1 ~~~~~10 mg! 42143.3) 1 32 thl,5?. 7 <22.h$ 5 129.4) 1 _ L, 2? i27.8j 12 t3B,7) 4 (23.4) 120 w £. 8 (47.1 ) J ®i she P an safety slneh nwy have been a>ume4 m nans than I seix^reMypsif they had twlttpk ses / use s>pea see<» kx« by egi >

[0178] Timing Analysis: Median time from dose administration to seizure termination and total duration showed rapid termination and duration by / before t2 (Figure 4). Generalized status epilepticus: median time from seizure start to dose administration, 11 minutes; median time from dose to seizure termination, 5 minutes; median overall duration, 20 minutes (t2=30 minutes). Focal status epilepticus: median time from seizure start to dose administration, 30 minutes; median time from dose to seizure termination, 16 minutes; median duration, 60minutes (12=60 minutes). Unclassified status epilepticus: median time from seizure start to dose administration, 20 minutes; median time from dose to termination, 10 minutes; median duration, 40minutes (12=60 minutes). Median time to seizure termination and total duration were generally similar between pediatric patients and adults, with the exception of moderately longer times with 351629946371.1generalized status epilepticus in adults. The majority of seizures treated past tl were generalized in pediatric patients (81.6%) and focal in adults (60.7%).

[0179] Responder analysis: Median time to seizure termination and total duration were generally similar between pediatric patients and adults, with the exception of moderately longer times with generalized status epilepticus in adults. The majority of seizures treated past tl were generalized in pediatric patients (81.6%) and focal in adults (60.7%). 77.4% (24 / 31) of patients responded. 68.2% (75 / 110) of unclassified status epilepticus events (t2=60 minutes). 76.5% (13 / 17) of patients responded A high proportion of status epilepticus events terminated <20 minutes after dose administration (Figure 5B). 82% (259 / 316) of generalized status epilepticus events. 96.2% (50 / 52) of patients responded.56.3% (138 / 245) of focal status epilepticus events. 90.3% (28 / 31) of patients responded. 68.2% (75 / 110) of unclassified status epilepticus events. 94.1% (16 / 17) of patients responded.

[0180] Recurrence analysis: There was a low proportion of patients and status epilepticus events with seizure recurrence in < 1, 12, or 24 hours of status epilepticus termination (Figure 6). 97.6% (40 / 41) of recurrent seizures in 24 hours were themselves status epilepticus events (i.e., with duration >tl).

[0181] Subgroups timing analysis: A high proportion of seizure episodes were treated after tl in all age groups, and median times to termination of early status epilepticus events were generally rapid Table 6.

[0182] Table 6 - Age subgroups analysis (generalized and focal status epilepticus)Age Cmeg Sehmre Type Treated Mediae Time te (NOh Sctaw After« LW. Miwte2~5y ( n-9 i)~ _! Generalized SE rww[ 6-1 (o -652} >5 mmWs 107(16.4) 3 (0-480?[ 12G7y(^667) | 11] (16.2) 6 (0% 62 ) >1 Sy frt- 300; | 63 (21.0) 15 (0-247)| Focal SO MO H H2.01 2 (6-434)| <3- 11 y (rt“47) [ 3 (6.4} 1.10(0-1150) | 1247y(rtM30) | 12 (10.0) 14.5 (0-65)(>13y (n-S50). [. 219 (25 A] 17 (0-360} SE, status eplfepi ma

[0183] Effectiveness: Second dose usage 1 for treatment of early status epilepticus events was low across subgroups (Figure 7). Second dose use in the overall population: Generalized status epilepticus, 7.3% of events; focal status epilepticus, 4.1%; unclassified status epilepticus, 11.8%. Thus, 92.7% of generalized, 95.9% of focal, and 88.2% of unclassified status epilepticus eventswere treated with a single dose.1629946371.1

[0184] Safety: In the overall early status epilepticus population (n=97 patients), 86 patients (88.7%) had >1 TEAE(Table 7).

[0185] Table 7 - Safety Summary (n=97)PM ferity, » (%)| >1 TEAE 86 (88.7%)Serious TEAE 9625 (25.8%)TEAE, imtmeni-mergent adverse event

[0186] In the overall pooled population (N=199 patients), there was a low rate of early status epilepticus events occurring on the same dates as serious TEAEs of status epilepticus requiring hospitalization. Of 199 pooled patients in this analysis, 12 (6.0%) reported at least 1 serious TEAE of status epilepticus. A total of 18 hospitalizations for TEAE of status epilepticus occurred in these 12 patients. Four patients (all pediatric, aged 2-17 years) with at least 1 pre-hospitalization treatment of seizure >tl associated with serious TEAE of status epilepticus. Seven events (all pediatric) of prehospitalization treatment of seizure >t1 associated with serious TEAE of status epilepticus. This is 2.2% (7 / 316) of the generalized early status epilepticus events. No focal or unclassified status epilepticus events were associated with TEAE of status epilepticus requiring hospitalization. In the age subgroups analysis, 8 status epilepticus episodes were reported as not treatment-related serious TEAEs requiring hospitalization / prolongation by 5 patients aged 2-5y (n=36; 13.9%); 7 episodes in 5 patients 6-1 ly (n=45; 11.1%); 2 episodes in 1 patient 12-17y (n=33; 3.0%), and 1 episode in 1 patient >18y (n=85; 1.2%).

[0187] Conclusions: Diazepam nasal spray provided timely control of early status epilepticus events treated at home in patients with epilepsy 3-59 years of age, with median termination prior to t2. For the majority of seizure events, termination occurred before t2 and also <20 minutes after dose administration. There was low seizure recurrence or second dose usage for ongoing status epilepticus events, suggesting high first-dose effectiveness. The majority of early status epilepticus events (treatment past tl) were not associated with hospitalizations for SAE of status epilepticus, suggesting that treatment may have prevented the need for hospitalization. Consistent with findings that appropriate community treatment can improve status-epilepticus outcomes. Overall, safety was generally consistent with the established profile of diazepam nasal spray. These findings strengthen the evidence of the benefits of immediate treatment with diazepam nasal spray for a range of seizure emergencies, including early status epilepticus.

[0188] The present disclosure also relates to methods and compositions for treating acute repetitive seizures in pediatric patients aged 3 months to less than 2 years. Specifically, the disclosure371629946371.1provides approaches for administering intranasal diazepam to pediatric subjects aged 3 months to less than 2 years experiencing acute repetitive seizures.

[0189] In some embodiments, the methods for treating acute repetitive seizures in a pediatric patient aged 3 months to less than 2 years, comprise: intranasally administering to the pediatric subject experiencing acute repetitive seizures, a solution composition comprising: a therapeutically effective amount of diazepam; an alkyl glycoside; and a carrier system comprising one or more natural or synthetic tocopherols or tocotrienols and one or more alcohols, wherein the acute repetitive seizures are treated.

[0190] In some embodiments, the therapeutically effective amount of diazepam for pediatric patients aged 3 months to less than 2 years may be weight-based. For a pediatric subject aged about 3 months to less than 6 months, the therapeutically effective amount of diazepam may be about 0.2 mg / kg to about 0.5 mg / kg of the pediatric subject's body weight. For a pediatric subject aged about 6 months to less than 2 years, the therapeutically effective amount of diazepam may be about 0.5 mg / kg of the pediatric subject's body weight.

[0191] In some embodiments, the composition may be administered intranasally using a preprimed single use dosage device. The first doses may be administered at a study site by a qualified medical professional and / or by the caregiver with medical supervision and respiratory support available. Subsequent doses may be administered by caregivers on an as-needed basis for treating acute repetitive seizures in their usual setting. A second dose may be administered as needed 4-12 hours after the initial dose.

[0192] In some embodiments, the methods may include monitoring for metabolic acidosis and multisystem organ failure in all pediatric patients with exposure to benzyl alcohol. Subjects with a history of gasping syndrome or apnea may be excluded.

[0193] The present disclosure also relates to methods and compositions for treating early status epilepticus in pediatric patients aged 3 months to less than 2 years.

[0194] In some embodiments, the methods for treating early status epilepticus in a pediatric patient aged 3 months to less than 2 years, comprise: intranasally administering to the pediatric subject experiencing early status epilepticus, a solution composition comprising: a therapeutically effective amount of diazepam; an alkyl glycoside; and a carrier system comprising one or more natural or synthetic tocopherols or tocotrienols and one or more alcohols, wherein the early status epilepticus is treated.

[0195] In some embodiments, the therapeutically effective amount of diazepam for pediatric patients aged 3 months to less than 2 years experiencing early status epilepticus may be weight-based. For a pediatric subject aged about 3 months to less than 6 months, the dose may be about 0.2 mg / kg to 381629946371.1about 0.5 mg / kg. For a pediatric subject aged about 6 months to less than 2 years, the dose may be about 0.5 mg / kg.

[0196] In some embodiments, the initial dose may be administered by trained emergency service personnel or in an emergency department. In some embodiments, the initial dose may be administered by a caregiver prior to the arrival of medical personnel. After each at-home administration, emergency medical services may be called immediately, such that the management by medical personnel of persistent seizure and of the associated increased risk of respiratory compromise may be provided.

[0197] The present disclosure also relates to methods and compositions for treating prolonged seizures in pediatric patients aged 3 months to 17 years. A prolonged seizure may be defined as a seizure lasting about 3 to about 5 minutes, consistent with impending status epilepticus.

[0198] In some embodiments, the methods for treating a prolonged seizure in a pediatric patient aged 3 months to 17 years, comprise: intranasally administering to the pediatric subject experiencing a prolonged seizure, a solution composition comprising: a therapeutically effective amount of diazepam: an alkyl glycoside; and a carrier system comprising one or more natural or synthetic tocopherols or tocotrienols and one or more alcohols, wherein the prolonged seizure is treated.

[0199] In some embodiments, the therapeutically effective amount of diazepam for treating prolonged seizures may be weight-based. For a pediatric subject aged about 3 months to less than 6 months, the dose may be about 0.2 mg / kg to about 0.5 mg / kg. For a pediatric subject aged about 6 months to less than 2 years, the dose may be about 0.5 mg / kg. For a pediatric subject aged about 2 years to about 5 years, the dose may be about 0.5 mg / kg. For a pediatric subject aged about 6 years to about 11 years, the dose may be about 0.3 mg / kg. For a pediatric subject aged about 12 years to about 17 years, the dose may be about 0.2 mg / kg.

[0200] In some embodiments, the prolonged seizure may be a generalized seizure, a focal seizure, a focal seizure with impaired consciousness, or an indeterminable seizure type. In some embodiments, the prolonged seizure may occur as part of a seizure cluster. Seizure clusters, prolonged seizures, and status epilepticus are not necessarily distinct types of seizure episodes and may overlap,

[0201] In some embodiments, the composition may be administered intranasally by a caregiver prior to the arrival of medical personnel. After each at-home administration, emergency medical services may be called immediately.

[0202] In some embodiments, the method may result in termination of the prolonged seizure within about 1 to about 5 minutes of administering the composition. In some embodiments, no seizure recurrence may occur within about 1 hour, about 12 hours, or about 24 hours of termination of the prolonged seizure.391629946371.1

[0203] In some embodiments, the dosing for pediatric subjects aged 2 to 17 years experiencing prolonged seizures may follow the same weight-based dosing regimen as for acute repetitive seizures. For a subject aged about 2 to about 5 years, the dose of diazepam may be as follows: about 6 kg to about 11 kg: about 5 mg to a single nostril; about 12 kg to about 22 kg: about 10 mg to a single nostril; about 23 kg to about 33 kg: 7.5 mg to each nostril. For a subject aged about 6 to 11 years: about 10 kg to about 18 kg: 5 mg to a single nostril; about 19 kg to about 37 kg: 10 mg to a single nostril; about 38 to about 55 kg: 7,5 mg to each nostril; about 56 to about 74 kg: 10 mg to each nostril or 20 mg to a single nostril. For a subject aged 12 to 17 years: about 14 to about 27 kg: 5 mg to a single nostril; about 28 kg to about 50 kg: 10 mg to a single nostril; about 51 kg to about 75 kg: 7.5 mg to each nostril; about 76 kg or more: 10 mg to each nostril or 20 mg to a single nostril.

[0204] Example 4 - Treatment of prolonged seizures and status epilepticus in children aged 2-5 years

[0205] In a post hoc analysis, diazepam nasal spray was assessed as treatment of prolonged seizures and early status epilepticus (i.e., a seizure episode lasting >ti) in children with epilepsy aged 2-5 years.

[0206] Patients with epilepsy aged 2-5 years were enrolled in a phase l / 2a open-label pharmacokinetics (PK) and safety study of diazepam nasal spray that included a single -dose PK period, a 180-day safety period, and an optional extension period. Doses of 5, 10, or 15 mg (0.5 mg / kg) were administered based on patient age and weight. In the safety' and optional extension periods, diazepam nasal spray was administered by caregivers on an as-needed basis. Second doses could be administered if needed. Investigators could adjust the dosage for effectiveness or safety reasons. Data on the timing of administration of diazepam nasal spray, seizure onset, and resolution were collected in electronic diaries.

[0207] Seizures were categorized by time from onset to administration of diazepam nasal spray. Prolonged seizures were defined as seizures treated 5-15 minutes after seizure onset. Status epilepticus after ti was defined as seizures where the time from seizure onset to dosing was >ti (i.e., >5 minutes for generalized seizures and >10 minutes for focal or indeterminable seizures).

[0208] Of 36 enrolled patients, 35 entered and 31 completed the 180-day open-label safety period. Enrolled patients had a mean (±SD) age of 3.9 (±1.0) years and body weight of 17.5 (±4.9) kg. As of April 20, 2024, 332 treated seizure episodes with complete seizure and dose timing data had been recorded, including 91 generalized seizures in 3 patients. 92 focal seizures in 5 patients, and 149 indeterminable seizures in 4 patients.

[0209] Of 172 prolonged seizures, the median time from administration to seizure termination was 3 minutes for all patients (range, 0-118 min; Figure 8).401629946371.1

[0210] A total of 67 status epilepticus episodes (n=9 patients) were treated afterti: 35 generalized (n=3), 11 focal (a 5 >. and 21 indeterminable (n=4). Median (range) time from administration to seizure termination was 1 minute (0-120 minutes) for generalized seizures (Figure 9), 2 minutes (0-454 minutes) for focal seizures, and 3 minutes (0-70 minutes) for indeterminable seizures.

[0211] No second doses were administered during any episode; thus, all status epilepticus episodes that were treated after t: were treated with a single dose. Most seizures ended before ty (62.7%; Figure 10). Rates of seizure recurrence were low within 24 hours (14.9%; Figure 11).

[0212] In the full study population, 7 patients (19.4%) reported a total of 11 TEAEs that were considered at least possibly related to treatment with diazepam nasal spray. All were mild, except 1 moderate case of aspiration pneumonia. Fourteen patients (38.8%) had >1 serious TEAE. Of 36 total events, 8 were cases of status epilepticus in 5 patients. No serious TEAEs were considered related to treatment.

[0213] Seizure clusters, prolonged seizures, and status epilepticus are not necessarily distinct types of seizure episodes and may overlap. Definitions of prolonged seizures and status epilepticus may have substantial overlap and may occur as part of a seizure cluster. In children aged 2-5 years with epilepsy, diazepam nasal spray provided prompt, reliable control of both prolonged seizures and status epilepticus episodes treated after ti. These findings support the effectiveness of diazepam nasal spray as a practical treatment for status epilepticus and prolonged seizures within seizure clusters in children aged 2-5 years.

[0214] Example 5 - Treatment of acute repetitive seizures in pediatric patients aged 3 months to less than 2 years

[0215] The methods disclosed herein are used for treating acute repetitive seizures in pediatric patients aged 3 months to less than 2 years. A Phase 1 / 2, open-label pharmacokinetic (PK) and safety study is conducted to evaluate diazepam nasal spray in patients with epilepsy aged 3 months to less than 2 years for the acute treatment of intermittent, stereotypic episodes of frequent seizure activity (i.e., seizure clusters, acute repetitive seizures) that are distinct from a patient's usual seizure pattern.

[0216] The study includes a single-dose PK period and an open-label safety’ period. The study enrolls approximately 24 subjects to achieve approximately 18 evaluable subjects. Eligible patients may have a clinical diagnosis of either focal or generalized epilepsy with motor seizures or seizures with clear alteration of awareness.

[0217] The therapeutically effective amount of diazepam for pediatric patients aged 3 months to less than 2 years may be weight-based. For example, for a pediatric subject aged about 3 months to less than 6 months, the dose is about 0.2 mg / kg to about 0.5 mg / kg. For a pediatric subject aged about 6411629946371.1months to less than 2 years, the dose is about 0.5 mg / kg. The composition is administered intranasally using a pre-primed single use dosage device.

[0218] The first doses are administered at the study site by a qualified medical professional and / or by the caregiver with medical supervision and respiratory support available. Subsequent doses are administered by caregivers on an as-needed basis for treating acute repetitive seizures in their usual setting. A second dose is administered as needed 4-12 hours after the initial dose.

[0219] The study includes monitoring for metabolic acidosis and multisystem organ failure in all pediatric patients with exposure to benzyl alcohol. Subjects w ith a history of gasping syndrome or apnea are typically excluded. Medications that have significant respiratory depression effects are typically prohibited. Enrollment is staggered, and the first doses are administered at the study site under medical supervision with respiratory’ and cardiovascular monitoring.

[0220] Efficacy is supported by comparing data collected in the study to the efficacy data from the open-label study conducted in pediatric patients 2 to 5 years of age. Matching of diazepam exposures in the study to documented diazepam exposures obtained in prior studies of children with seizures aged 3 months to less than 2 years support efficacy and safety.

[0221] Example 6 - Treatment of early status epilepticus in pediatric patients aged 3 months to less than 2 years

[0222] The methods disclosed herein are used for treating early status epilepticus in pediatric patients aged 3 months to less than 2 years. A Phase 3, open-label efficacy and safety study is conducted to evaluate diazepam nasal spray in patients with epilepsy aged 3 months to 17 years for the treatment of early status epilepticus.

[0223] The study enrolls approximately 40 subjects to achieve approximately 30 evaluable subjects. Eligible patients may have a clinical diagnosis of either focal or generalized epilepsy w ith motor seizures or seizures with clear alteration of awareness.

[0224] In some embodiments, the therapeutically effective amount of diazepam for pediatric patients aged 3 months to less than 2 years experiencing early status epilepticus may be weight-based. For example, for a pediatric subject aged about 3 months to less than 6 months, the dose is about 0.2 mg / kg to about 0.5 mg / kg. For a pediatric subject aged about 6 months to less than 2 years, the dose is about 0.5 mg / kg. For a pediatric subject aged about 2 years to about 5 years, the dose is about 0.5 mg / kg. For a pediatric subject aged about 6 years to about 11 years, the dose is about 0.3 mg / kg. For a pediatric subject aged about 12 years to about 17 years, the dose is about 0.2 mg / kg.

[0225] The initial dose is administered by trained emergency sendee personnel or in an emergency department. The initial dose is administered by a caregiver prior to the arrival of medical personnel. After each at-home administration, emergency medical services may be called immediately.421629946371.1

[0226] The primary efficacy endpoint includes the proportion of patients with seizure termination within a specified time period after dose administration. Key secondary endpoints include time from dose adminis tration to seizure termination, proportion of patients with seizure recurrence within 1, 12, or 24 hours, and proportion of events requiring a second dose.

[0227] Example 7 - Treatment of prolonged seizures in pediatric patients aged 3 months to 17 years

[0228] The methods disclosed herein are used for treating prolonged seizures consistent with impending status epilepticus in pediatric patients aged 3 months to 17 years. A prolonged seizure is defined as a seizure lasting about 3 to about 5 minutes.

[0229] The therapeutically effective amount of diazepam for treating prolonged seizures may be weight-based. For example, for a pediatric subject aged about 3 months to less than 6 months, the dose is about 0.2 mg / kg to about 0.5 mg / kg. For a pediatric subject aged about 6 months to less than 2 years, the dose is about 0.5 mg / kg. For a pediatric subject aged about 2 years to about 5 years, the dose is about 0.5 mg / kg. For a pediatric subject aged about 6 years to about 11 years, the dose is about 0.3 mg / kg. For a pediatric subject aged about 12 years to about 17 years, the dose is about 0.2 mg / kg.

[0230] The composition is administered intranasally by a caregiver prior to the arrival of medical personnel. After each at-home administration, emergency medical services may be called immediately, such that the management by medical personnel of persistent seizure and of the associated increased risk of respiratory compromise may be provided.

[0231] The prolonged seizure is a generalized seizure, a focal seizure, a focal seizure w ith impaired consciousness, or an indeterminable seizure type. The prolonged seizure occurs as part of a seizure cluster.

[0232] The method of tire study is expected to result in termination of the prolonged seizure within about 1 to about 5 minutes of administering the composition. No seizure recurrence occurs within about 1 hour, about 12 hours, or about 24 hours of termination of the prolonged seizure.

[0233] The dosing for pediatric subjects aged 2 to 17 years experiencing prolonged seizures follows the same weight-based dosing regimen as for acute repetitive seizures, such as shown in the tables above.

[0234] A number of implementations have been described. Nevertheless, it will be understood that various modifications may be made without departing from the spirit and scope of the disclosure. Accordingly, other implementations are within the scope of the following claims.431629946371.1

Claims

CLAIMS1. A method for treating acute repetitive seizures in a pediatric patient aged 3 months to less than 2 years, comprising:intranasally administering to the pediatric subject experiencing acute repetitive seizures, a composition comprising:a therapeutically effective amount of diazepam;an alkyl glycoside; anda carrier system comprising one or more natural or synthetic tocopherols or tocotrienols and one or more alcohols,wherein the acute repetitive seizures are treated.

2. The method of claim 1, wherein the pediatric subject is aged about 3 months to less than 6 months, and wherein the therapeutically effective amount of diazepam is about 0.2 mg / kg to about 0.5 mg / kg of the pediatric subject's body weight.

3. The method of claim 1, wherein the pediatric subject is aged about 6 months to less than 2 years, and wherein the therapeutically effective amount of diazepam is about 0.5 mg / kg of the pediatric subject's body weight.

4. The method of claim 1, wherein the composition is provided in a pre-primed single use dosage device.

5. The method of claim 1, wherein the alkyl glycoside is selected from dodecyl maltoside, tetradecyl maltoside, or a combination thereof.

6. The method of claim 1, wherein tire one or more alcohols comprises a mixture of ethanol and benzyl alcohol.

7. The method of claim 1, wherein tire intranasally administering is performed by a caregiver.

8. A method for treating early status epilepticus in a pediatric patient aged 3 months to less than 2 years, comprising:intranasally administering to the pediatric subject experiencing early status epilepticus, a composition comprising:a therapeutically effective amount of diazepam;an alkyl glycoside; anda carrier system comprising one or more natural or synthetic tocopherols or tocotrienols and one or more alcohols,wherein the early status epilepticus is treated.441629946371.

19. The method of claim 8, wherein the pediatric subject is aged about 3 months to less than 6 months, and wherein the therapeutically effective amount of diazepam is about 0.2 mg / kg to about 0.5 mg / kg of the pediatric subject's body weight.

10. The method of claim 8, wherein the pediatric subject is aged about 6 months to less than 2 years, and wherein the therapeutically effective amount of diazepam is about 0.5 mg / kg of the pediatric subject's body weight.

11. The method of claim 8, wherein the early status epilepticus is generalized status epilepticus, focal status epilepticus, focal status epilepticus with impaired consciousness, unclassified status epilepticus, tonic-clonic status epilepticus, absence status epilepticus, or a combination thereof.

12. The method of claim 8, wherein the intranasally administering is performed by trained emergency service personnel or in an emergency department.

13. The method of claim 8, wherein the intranasally administering is performed by a caregiver prior to the arrival of medical personnel.

14. A method for treating a prolonged seizure in a pediatric patient aged 3 months to 17 years, comprising:intranasally administering to the pediatric subject experiencing a prolonged seizure, a composition comprising:a therapeutically effective amount of diazepam;an alkyl glycoside; anda carrier system comprising one or more natural or synthetic tocopherols or tocotrienols and one or more alcohols,wherein the prolonged seizure is treated.

15. The method of claim 14, wherein the prolonged seizure is a seizure lasting about 3 to about 5 minutes.

16. The method of claim 14, wherein the prolonged seizure is consistent with impending status epilepticus.

17. The method of claim 14, wherein the pediatric subject is aged about 3 months to less than 6 months, and wherein the therapeutically effective amount of diazepam is about 0.2 mg / kg to about 0.5 mg / kg of the pediatric subject's body weight,18. The method of claim 14, wherein the pediatric subject is aged about 6 months to less than 2 years, and wherein the therapeutically effective amount of diazepam is about 0.5 mg / kg of the pediatric subject's body weight.451629946371.

119. The method of claim 14, wherein the pediatric subject is aged about 2 years to about 5 years, and wherein the therapeutically effective amount of diazepam is about 0.5 mg / kg of the pediatric subject's body weight.

20. The method of claim 14, wherein the pediatric subject is aged about 6 years to about 11 years, and wherein the therapeutically effective amount of diazepam is about 0.3 mg / kg of the pediatric subject's body weight.

21. The method of claim 14, wherein the pediatric subject is aged about 12 years to about 17 years, and wherein the therapeutically effective amount of diazepam is about 0.2 mg / kg of the pediatric subject's body weight,22. The method of claim 14, wherein the intranasally administering is performed by a caregiver.

23. The method of claim 14, wherein the prolonged seizure occurs as part of a seizure cluster.

24. The method of claim 14, wherein intranasally administering the composition results in termination of the prolonged seizure within about 1 to about 5 minutes.

25. The method of claim 14, wherein no seizure recurrence occurs within about 24 hours of termination of the prolonged seizure.461629946371.1

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