Method for improving cognitive function with fenfluramine

Abstract

To provide a formulation for use in improving neurologic function, the formulation comprising fenfluramine or a pharmaceutically acceptable salt thereof.SOLUTION: The present specification discloses a method of improving cognitive function in a patient, as measured by improvement in scores on a validated scale measuring cognitive function, such as the Behavioral Rating Inventory of Executive Function (BRIEF). The method comprises the steps of: administering a test to the patient to obtain a pre-procedure test score; treating the patient with fenfluramine or a pharmaceutically acceptable salt thereof; and re-administering the cognitive function test to the patient after the treatment to obtain a post-treatment score to enable observation of improvement in test scores. In some embodiments, the patient is also being treated for symptoms of epilepsy.SELECTED DRAWING: Figure 7

Description

Technical Field

[0001] Field of the Invention The present invention generally relates to the field of improving cognitive function. Cognitive function includes processes such as thinking and language development and use, visuospatial cognition, and memory ability, as well as prediction, planning, judgment, self-awareness, executive function, and decision-making. Specifically, provided is a method for improving cognitive function by treating a patient with fenfluramine or a pharmaceutically acceptable salt, acid, base, or amine thereof. Improvement in cognitive function may be indicated by measuring a change in any one of various metrics, such as by obtaining a baseline measurement of the function. Cognitive function may be measured using the Behavior Rating Inventory of Executive Function (BRIEF), the Wechsler Memory Test, the Montreal Cognitive Assessment (MOCA) scale, the Executive Function: Means and Instrument for Neurobehavioral Assessment and Research (EXAMINER), and the function of the patient's central nervous system (CNS) may be measured using the Clinical Global Impression (CGI) scale as a pre-treatment examination score or other valid scale for measuring cognition and other neurological functions. After treatment with fenfluramine, the examination can be re-administered to obtain a post-treatment cognitive examination score or evaluation. Thus, improvement in other aspects of cognition and CNS function, as measured by improvement in, for example, BRIEF score or CGI score, can be observed and quantified. In some embodiments, the patient is also being treated for seizure symptoms.

Background Art

[0002] Background Fenfluramine, that is, 3-trifluoromethyl-N-ethylamphetamine, is an amphetamine derivative having the following structure: TIFF2025113312000002.tif34128.

[0003] Fenfluramine was first marketed in the United States in 1973 for the treatment of obesity. However, in 1997, fenfluramine was withdrawn from the US and world markets because its use was associated with the development of valvular heart disease and pulmonary hypertension. Subsequently, the drug was withdrawn from sale worldwide and is no longer indicated for use in any therapeutic area.

[0004] Without being bound by theory, the adverse effects associated with the use of fenfluramine as an appetite suppressant are thought to be due to the interaction of norfenfluramine, the major metabolite of fenfluramine, with the 5-HT2B receptor, which has been reported to be associated with valvular heart disease. Fenfluramine is metabolized in vivo to norfenfluramine by cytochrome P450 enzymes in the liver. Cytochrome P450 enzymes such as CYP2D6, CYP2B6, and CYP1A2 are mainly responsible for the production of norfenfluramine from fenfluramine in humans. The enzymes CYP2C9, CYP2C19, and CYP3A4 are also involved. Such metabolism involves the cleavage of the N-ethyl group to produce norfenfluramine as shown below. TIFF2025113312000003.tif23128

[0005] Fenfluramine acts primarily as a serotonin releasing agent. Serotonin (also known as "5-hydroxytryptamine" or "5-HT") is a neurotransmitter thought to regulate numerous sensory, motor, and behavioral processes in the mammalian nervous system. These diverse responses are induced through the activation of a large family of receptor subtypes.

[0006] Phentermine and its major metabolite, norphentermine, have been reported to be potent substrates of the norepinephrine transporter (Rothman, et al., J. Pharmacol. Exp. Ther. 305(3):1191-9 (Non-Patent Document 1)). Phentermine disrupts the vesicular storage of neurotransmitters and causes the release of serotonin by restoring serotonin transporter function. Phentermine also functions as a norepinephrine-releasing agent to a relatively low extent, particularly via its active metabolite, norphentermine. In addition to monoamine release, phentermine binds very weakly to the serotonin 5-HT2 receptor, and norphentermine binds to and activates the serotonin 5-HT2B and 5-HT2C receptors with high affinity and the serotonin 5-HT2A receptor with moderate affinity. The consequences of increased serotonergic and noradrenergic neurotransmission are satiety and decreased appetite. Thus, weight loss, decreased appetite, and / or emaciation may be observed in subjects treated with phentermine.

[0007] Despite past concerns about the cardiovascular safety that occurred when high doses of phentermine were used for the treatment of adult obesity, attempts have been made to identify further therapeutic uses of the product while comparing the known cardiovascular risks of phentermine with its potential therapeutic effects. One disorder for which new treatment options are highly needed is epilepsy, particularly in epileptic syndromes that are resistant to known treatments. Epilepsy is a dysfunction of the central nervous system (CNS) characterized by abnormal discharges and susceptibility to recurrent seizures. There are numerous causes of epilepsy, including, but not limited to, birth trauma, perinatal infections, anoxia, infectious diseases, toxin ingestion, brain tumors, genetic or degenerative diseases, head injury or trauma, metabolic abnormalities, cerebrovascular attacks, and alcohol withdrawal.

[0008] A number of compounds may be used to treat various types of epilepsy, and different epilepsy subtypes may respond differently to different anti-seizure drugs. For example, cannabidiol has been studied for the treatment of drug-resistant seizures in Dravet syndrome and has been reported to reduce the frequency of seizure episodes (Devinsky, et al., 2017, New Engl. J. Med. 376(21):2011-2020 (Non-Patent Document 2)).

[0009] Dravet syndrome (DS) is an infantile-onset severe genetic epileptic encephalopathy, often caused by mutations or deletions in the voltage-gated sodium channel (SCN1A). Initially, by 1 year of age, patients with DS experience prolonged seizures, and by 2 years, additional types of seizures begin to occur, typically accompanied by developmental delay, probably due to recurrent seizures that cause brain damage such as cerebral hypoxia. Ultimately, this form of childhood epilepsy results in poor and / or delayed language development, disruption of autonomic function, as well as motor and cognitive / intellectual and behavioral dysfunction. Children with Dravet syndrome may experience multiple seizures per day and have a high risk of sudden unexplained death during episodes of status epilepticus and uncontrolled epilepsy. Seizure management includes treatment with benzodiazepines, valproates, and / or stiripentol. Some reduction in seizure activity has been reported with the use of bromide and topiramate, or the ketogenic diet. Despite these options, available anti-epileptic drugs (AEDs) do not achieve adequate seizure control in most DS patients.

[0010] A particular drug may be effective for one form of epilepsy, but completely ineffective for other forms, and may even be contraindicated due to exacerbation of symptoms such as increased frequency and severity of seizures. As a result, the effectiveness of a particular drug for a particular type of epilepsy is completely unpredictable, and the discovery that a particular drug is effective in treating a type of epilepsy that was not previously known to be effective for that drug is often surprising, even when it is known that the drug is effective for other types of epilepsy. Furthermore, the treatment of epilepsy with fenfluramine may be contraindicated for co-administration with other therapeutic agents and / or treatment with other therapeutic agents.

[0011] Children and adults with epileptic encephalopathies such as Dravet syndrome and Lennox-Gastaut syndrome often experience the complication of cognitive dysfunction, including abilities such as self-regulation, impulse suppression and / or attention control, emotion control, problem-solving, tolerance of change and / or attention switching, idea initiation / generation, working memory, planning, and integration. Cognitive function is often evaluated using laboratory-based ability measures or tests such as the Behavior Rating Inventory of Executive Function (BRIEF), the Wechsler Memory Scale, the Montreal Cognitive Assessment (MOCA) scale, the Executive Function: Means and Instrument for Neurobehavioral Assessment and Research (EXAMINER), or other valid scales that measure cognitive function.

[0012] A more general assessment scale for psychological and mental states is the Clinical Global Impression (CGI), developed for use in clinical trials supported by the NIMH, which provides a simple, independent assessment from the perspective of a clinician of the patient's overall function before and after starting a study drug. The CGI provides a global aggregate scale determined by the clinician that takes into account all available information, including the patient's medical history, psychosocial situation, symptoms, behavior, and knowledge of the impact of symptoms on the patient's functional abilities.

[0013] CGI actually includes two companion one-item measures for assessing the following: (a) the severity of symptoms on a scale of 1 to 7 to establish a baseline for comparison, and (b) the change from the start of treatment on a similar 7-point scale. After a clinical evaluation, the CGI form can be completed in less than 1 minute by an experienced evaluator. In fact, CGI represents a clinical impression that encompasses more than just a symptom checklist. It is easily understandable and can be used relatively easily by clinicians other than researchers. Moreover, CGI can track clinical progress over time and has been shown to correlate with more time-consuming assessment measures across a wide range of mental and central nervous system dysfunctions.

[0014] In clinical practice, CGI is administered by experienced clinicians who are familiar with the possible course of the disease and treatment being tested. Thus, CGI evaluators can make expert clinical global judgments about the severity of the disease over various time points within the context of their clinical experience. Clinicians make judgments about the overall picture of the patient at each visit: the level of the patient in terms of disease severity, distress, and other aspects of impairment, as well as the impact of the disease on function. CGI is evaluated regardless of the clinician's opinion as to whether any clinical change is due to drug therapy or not and without considering the etiology of the symptoms.

[0015] CGI-I evaluations may also be performed by parents or caregivers or anyone who frequently observes and interacts with the patient. Evaluations by patients / caregivers are not based on clinical experience with other patients with the disease but are conducted through more frequent observation of the subject and may identify fluctuations in the psychological and mental functioning of the individual patient.

[0016] There has long been a need to provide methods and compositions for improving a patient's cognitive function, particularly in children and young adults. In some embodiments, the patient is also being treated for an epileptic disorder or condition, such as Dravet syndrome and / or Lennox-Gastaut syndrome. In some embodiments of the method, fenfluramine is the only pharmaceutically active ingredient administered to the patient. In some embodiments of the method, fenfluramine is used as adjuvant therapy in the patient. The present disclosure relates to such a surprising and unexpected finding that administration of fenfluramine over a period of time is associated with an improvement in at least one measure of cognitive function, such as the BRIEF score, thus helping to meet such a need. As described herein, administration of fenfluramine can be beneficial in treating diseases and conditions that affect cognitive function.

PRIOR ART DOCUMENTS

NON-PATENT DOCUMENTS

[0017]

Non-Patent Document 1

Non-Patent Document 2

SUMMARY OF THE INVENTION

[0018] According to a first aspect of the present invention, provided herein is a method for improving cognitive function in a patient (e.g., measured by tests such as the Behavior Rating Inventory of Executive Function (BRIEF), the Wechsler Memory Scale, the Montreal Cognitive Assessment (MOCA) scale, the Executive Function: Means and Instrument for Neurobehavioral Evaluation and Research (EXAMINER), or other valid scales for measuring cognitive function) comprising the step of administering fenfluramine or a pharmaceutically acceptable salt thereof. In some embodiments, the patient is also being treated for epilepsy or epileptic encephalopathy, such as Dravet syndrome and / or Lennox-Gastaut syndrome. In some embodiments, the BRIEF test is administered to the patient before and after treatment with fenfluramine to evaluate cognitive function and measure / quantify improvement. In some embodiments, fenfluramine is administered over a period of months or years (e.g., 1, 2, 3, 6, 9, 12, 15, 18, 21 months, etc., e.g., up to 3 years, including 3 years) before measuring / observing changes in cognitive function.

[0019] According to a further aspect of the invention, there is provided herein a method of improving psychological and mental functions, including but not limited to cognitive functions in a patient, as measured by a global clinical impression scale, such as the Clinical Global Impression of Improvement (CGI-I), the method comprising administering fenfluramine or a pharmaceutically acceptable salt thereof to improve the functional aspects of the patient's condition. In some embodiments, the patient is also being treated for epilepsy or epileptic encephalopathy, such as Dravet syndrome and / or Lennox-Gastaut syndrome. In some embodiments, the CGI-I is evaluated by a clinician who conducts the treatment before and after treatment with fenfluramine to assess overall psychological and mental functions and to measure / quantify improvement. In another embodiment, the evaluation is performed by a parent or caregiver. In some embodiments, fenfluramine is administered over a period of weeks, months or years (e.g., 1, 2, 3, 6, 9, 12, 15, 18, 21 months, etc., e.g., up to 3 years, including 3 years) before measuring / observing changes in function. In some embodiments, the improvement in the patient's CGI-I assessment continues to improve over a period of months or years.

[0020] According to a further aspect of the invention, the patient may be diagnosed with, or may have been diagnosed with, a disease or condition selected from epilepsy or epileptic encephalopathy (such as Dravet syndrome, Doose syndrome, infantile spasms, Lennox-Gastaut syndrome, etc.); attention disorders (such as attention deficit disorder (ADD) or attention deficit hyperactivity disorder (ADHD)); developmental disorders such as autism spectrum disorder (ASD) including autism, Asperger's syndrome, pervasive developmental disorder (PDD), and pervasive developmental disorder not otherwise specified (PDD-NOS); oppositional defiant disorder (ODD); learning disorders (such as dyslexia, dyscalculia); Tourette syndrome; traumatic brain injury; lead exposure; anxiety and / or depressive states; and low birth weight, or any combination thereof.

[0021] According to a further aspect of the present invention, a patient may be treated for epilepsy, may have been treated for epilepsy, or may be being treated for epilepsy. According to a further aspect of the present invention, a patient diagnosed with epilepsy is under 18 years of age. According to a further aspect of the present invention, a patient diagnosed with epilepsy is an adult over 18 years of age.

[0022] According to a further aspect of the present invention, a patient may be diagnosed with, or may have been diagnosed with, Dravet syndrome and / or epileptic encephalopathy.

[0023] According to a further aspect of the present invention, the symptoms of epileptic encephalopathy are seizures, fenfluramine is formulated with a pharmaceutically acceptable carrier, and the effective dose is less than 10.0 mg / kg / day, or less than 1.0 mg / kg / day, or approximately 0.8 mg / kg / day, or approximately 0.5 mg / kg / day, or approximately 0.2 mg / kg / day, or approximately 0.01 mg / kg / day.

[0024] According to a further aspect of the present invention, fenfluramine may be administered in an administration form selected from the group consisting of oral, injectable, transdermal, inhaled, nasal, buccal, rectal, intravaginal, and parenteral delivery.

[0025] According to a further aspect of the present invention, the administration form is an oral composition in an amount selected from the group consisting of 30 mg / day or less, 20 mg / day or less, 10 mg / day or less, and 5 mg / day or less.

[0026] According to a further aspect of the invention, at least one co-therapeutic agent may also be co-administered to the patient / subject, where the agent is selected from the group consisting of brivaracetam, bromides (e.g., potassium bromide, sodium bromide), cannabidiol, carbamazepine, clonidine, Ergenyl Chrono, ethosuximide, felbamate, fosphenytoin, lacosamide, lamotrigine, levetiracetam, levocarnitine, mesuximide, nitrazepam, oxcarbazepine, perampanel, phenobarbital, pregabalin, progabide, pyridoxine, rufinamide, stiripentol, sulthiame, tizanidine, topiramate, valproic acid semisodium, valproic acid sodium, valproic acid, verapamil, zonisamide, and benzodiazepines, such as clobazam, clonazepam, diazepam, ethyl loflazepate, lorazepam, and midazolam, and pharmaceutically acceptable salts or bases of any of these.

[0027] According to a further aspect, the subject / patient may have been previously treated with an agent prior to treatment with fenfluramine, where the agent is selected from the group consisting of acetazolamide, brivaracetam, carbamazepine, clobazam, clonazepam, diazepam, Ergenyl Chrono, ethosuximide, felbamate, gabapentin, lacosamide, lamotrigine, levetiracetam, lorazepam, mesuximide, oxcarbazepine, perampanel, phenobarbital, phenytoin, phenytoin sodium, pregabalin, rufinamide, stiripentol, sulthiame, topiramate, valproic acid semisodium, valproic acid sodium, valproic acid, vigabatrin, zonisamide, and pharmaceutically acceptable salts or bases of any of these.

[0028] According to a further aspect of the invention, the fenfluramine treatment is continued for a period of time and in an effective amount effective to improve cognitive function, which can be evaluated by improvement in effective scales, including but not limited to Behavioral Rating Inventory of Executive Function (BRIEF), Wechsler Memory Scale, Montreal Cognitive Assessment (MOCA) scale, Executive Function: Means and Instrument for Neurobehavioral Evaluation and Research (EXAMINER), or other effective clinical and / or indicator scales for measuring cognitive function.

[0029] Within the BRIEF test, there are multiple scales that can be used to measure specific aspects of cognitive function. The BRIEF has two main indices: the Behavioral Regulation Index (BRI) (including scales for inhibition, shifting, and emotional control) and the Metacognition Index (MI) (including scales for initiation, working memory, planning / organization, materials organization, and monitoring).

[0030] According to an aspect of the invention, there is provided a kit comprising a fenfluramine formulation, packaging, and an accompanying document including instructions for use in improving cognitive function in a patient.

[0031] According to an aspect of the invention, there is provided a kit comprising a container having multiple doses of a formulation comprising a pharmaceutically acceptable carrier and an active ingredient comprising fenfluramine; and instructions for treating a patient with the formulation and evaluating the patient's cognitive function before and after treatment with the formulation.

[0032] According to a further aspect of the invention, there is provided a method for treating, preventing and / or remitting seizures in a patient diagnosed with epilepsy, the method comprising administering to the patient an effective dose of fenfluramine alone or in combination with one or more drugs described herein, wherein the epilepsy is Dravet syndrome or Lennox-Gastaut syndrome.

[0033] According to a further aspect of the present invention, provided herein is a method of treating a patient who exhibits a mutation in one or more of the genes selected from the group consisting of SCN1A, SCN1B, SCN2A, SCN3A, SCN9A, GABRG2, GABRD, and PCDH19 by administering to the patient an effective dose of fenfluramine.

[0034] An even further aspect of the present invention contemplates a method for stimulating one or more 5-HT receptors in a patient's brain by administering to the patient an effective amount of fenfluramine or a pharmaceutically acceptable salt thereof. Exemplary one or more 5-HT receptors are selected from the group consisting of 5-HT1, 5-HT 1A , 5-HT 1B , 5-HT 1C , 5-HT 1D , 5-HT 1E , 5-HT 1F , 5-HT2, 5-HT 2A , 5-HT 2B , 5-HT 2C , 5-HT3, 5-HT4, 5-HT5, 5-HT 5A , 5-HT 5B , 5-HT6, and 5-HT7. In addition, non-5-HT binding may be present in the brain, including sigma1, M1 muscarinic, and B-adrenergic.

[0035] In some embodiments of this method, fenfluramine is the only pharmaceutically active ingredient administered to the patient.

[0036] In some embodiments of this method, fenfluramine is used as adjuvant therapy in the patient. In some embodiments of this method, fenfluramine is used as adjuvant therapy in a patient having epilepsy or epileptic encephalopathy. In some embodiments of this method, fenfluramine is used as adjuvant therapy in a patient having Dravet syndrome or Lennox-Gastaut syndrome (LGS).

[0037] Yet another aspect of the invention contemplates co - administration of fenfluramine with one or more co - therapeutic agents in effective amounts, where the co - therapeutic agent is selected from the group consisting of brivaracetam, bromides (e.g., potassium bromide, sodium bromide), cannabidiol, carbamazepine, clonidine, ergoline chrono, ethosuximide, felbamate, fosphenytoin, lacosamide, lamotrigine, levetiracetam, levocarnitine, mesuximide, nitrazepam, oxcarbazepine, perampanel, phenobarbital, pregabalin, progabide, pyridoxine, rufinamide, stiripentol, sulthiame, tizanidine, topiramate, valproic acid semisodium, valproic acid sodium, valproic acid, verapamil, zonisamide, and benzodiazepines such as clobazam, clonazepam, diazepam, ethyl loflazepate, lorazepam, and midazolam. The use of pharmaceutically acceptable salts or bases of the co - therapeutic agent is also contemplated.

[0038] In another aspect, the subject / patient may have been previously treated with an agent prior to treatment with fenfluramine, where the agent is selected from acetazolamide, brivaracetam, carbamazepine, clobazam, clonazepam, diazepam, ergoline chrono, ethosuximide, felbamate, gabapentin, lacosamide, lamotrigine, levetiracetam, lorazepam, mesuximide, oxcarbazepine, perampanel, phenobarbital, phenytoin, phenytoin sodium, pregabalin, rufinamide, stiripentol, sulthiame, topiramate, valproic acid semisodium, valproic acid sodium, valproic acid, vigabatrin, zonisamide, and pharmaceutically acceptable salts or bases of any of these.

[0039] As described herein, the discovery that fenfluramine can be used in the treatment of diseases or disorders that affect cognitive function is explained. Thus, in some aspects, the present disclosure contemplates co - administration of fenfluramine with one or more co - therapeutic agents in effective amounts.

[0040] Aspects of the invention include methods of treating or preventing seizure symptoms in a patient diagnosed with epilepsy, comprising administering to the patient an effective amount of fenfluramine or a pharmaceutically acceptable salt, wherein the amount is administered in an amount in the range of from about 10.0 mg / kg / day, 1.0 mg / kg / day, 0.8 mg / kg / day, 0.5 mg / kg / day, 0.2 mg / kg / day to about 0.01 mg / kg / day, or in an amount of about 30 mg / day or less, 20 mg / day or less, 10 mg / day or less, and 5 mg / day or less, and may be administered in the absence of administration of any other pharmaceutically active compound.

[0041] In another aspect, methods of treating or preventing seizure symptoms involve the initiation of fenfluramine treatment in a patient. In some embodiments, the starting dose of fenfluramine provided is about 0.2 mg / kg / day over a period of 4 - 7 days, and thereafter the dose is increased by about 0.2 mg / kg / day every 4 - 7 days up to a maximum dose of about 0.8 mg / kg / day or a recommended maximum dose of 30 mg / day. In another aspect, the patient has already received drug therapy for treating or preventing seizures that may interact with fenfluramine, and the initiation of fenfluramine treatment is provided at about 0.2 mg / kg / day over a period of 4 - 7 days, and thereafter the dose is increased by about 0.2 mg / kg / day every 4 - 7 days up to a maximum dose of about 0.5 mg / kg / day or a recommended maximum dose of 20 mg / day.

[0042] In another aspect of the invention, a method is implemented in which an effective dose is administered in a form selected from the group consisting of oral, injectable, transdermal, buccal, inhaled, nasal, buccal, rectal, intravaginal, or parenteral, and the formulation is for oral use, the formulation may be a liquid which may be a solution or a suspension, and may be present in a container sealed with a cap connected to a graduated syringe for determining the volume withdrawn from the container, the volume withdrawn being related to the amount of fenfluramine in a given liquid volume of the formulation, for example, 1 milliliter of the formulation contains 2.5 mg of fenfluramine. In another aspect of the invention, the method is administered with a solid oral formulation in the form of tablets, capsules, lozenges, or sachets.

[0043] The method may be implemented as co-treatment with different pharmaceutically active compounds. The method may be implemented in the process in which a patient first then undergoes a series of tests to confirm the diagnosis of epilepsy.

[0044] [Invention 1001] A formulation for use in improving neurological function, evaluated by observing at least one rank level of statistically significant improvement in a patient using the BRIEF test, the formulation comprising fenfluramine or a pharmaceutically acceptable salt thereof and wherein the use is for the repeated administration over several days until the patient shows an improvement in the BRIEF score as compared to the previous BRIEF score obtained prior to the repeated administration. The formulation for said use. [Invention 1002] A formulation for use of the present invention 1001, wherein the patient is diagnosed with a disease or condition selected from epilepsy or epileptic encephalopathy (e.g., Dravet syndrome, Doose syndrome, infantile spasms, Lennox-Gastaut syndrome); attention disorders (e.g., attention deficit disorder (ADD) or attention deficit hyperactivity disorder (ADHD)); developmental disorders such as autism spectrum disorder (ASD) including autism, Asperger syndrome, pervasive developmental disorder (PDD), and pervasive developmental disorder not otherwise specified (PDD-NOS); oppositional defiant disorder (ODD); learning disorders (e.g., dyslexia, dyscalculia); Tourette syndrome; traumatic brain injury; lead exposure; anxiety and / or depressive states; and low birth weight, or any combination thereof. [The present invention 1003] A formulation for use of the present invention 1001, wherein the patient is diagnosed with either Dravet syndrome or Lennox-Gastaut syndrome. [The present invention 1004] A formulation for use of any one of the present inventions 1001 to 1003, further comprising a co-therapeutic agent. [The present invention 1005] A formulation for use of any one of the present inventions 1001 to 1004, wherein phentermine is formulated with a pharmaceutically acceptable carrier and administered at an effective dose selected from less than about 10.0 mg / kg / day, less than 1.0 mg / kg / day, about 0.8 mg / kg / day, about 0.5 mg / kg / day, about 0.2 mg / kg / day, and about 0.01 mg / kg / day. [The present invention 1006] A formulation for use of any one of the present inventions 1001 to 1005, wherein phentermine is administered in a dosage form selected from the group consisting of oral, injectable, transdermal, inhaled, nasal, buccal, rectal, intravaginal, and parenteral delivery. [The present invention 1007] A formulation for use of any one of the present inventions 1001 to 1006, wherein the dosage form is an oral composition administered in an amount selected from the group consisting of 30 mg / day or less, 20 mg / day or less, 10 mg / day or less, and 5 mg / day or less. [The present invention 1008] At least one co-therapeutic agent is administered, and the agent is selected from the group consisting of brivaracetam, bromides (e.g., potassium bromide, sodium bromide), cannabidiol, carbamazepine, clonidine, ergineurone chrono, ethosuximide, felbamate, fosphenytoin, lacosamide, lamotrigine, levetiracetam, levocarnitine, mesuximide, nitrazepam, oxcarbazepine, perampanel, phenobarbital, pregabalin, progabide, pyridoxine, rufinamide, sultiam, tizanidine, topiramate, stiripentol, sodium valproate seminate, sodium valproate, valproic acid, verapamil, zonisamide, and benzodiazepines, e.g., clobazam, clonazepam, diazepam, ethyl loflazepate, lorazepam, and midazolam, and pharmaceutically acceptable salts or bases thereof, for use in any of the uses of the present invention from 1001 to 1007. [The present invention 1009] Administration continues for a period such as to improve cognitive function as indicated by improvement in at least one BRIEF score, and the period is selected from the group consisting of 1 month, 2 months, 3 months, 6 months, 9 months, 12 months, 15 months, 18 months, 21 months, 2 years, and 3 years. Improvement of the cognitive function is evaluated by observing a statistically significant improvement in at least one BRIEF score at an improvement rate selected from the group consisting of 5% or more, 10% or more, 15% or more, 25% or more, 50% or more, or 75% or more, for use in any of the uses of the present invention from 1001 to 1008. [The present invention 1010] Phentermine formulation; Packaging; and An attachment including instructions for use in improving cognitive function as evaluated by improvement in at least one BRIEF score in a patient A kit comprising. [The present invention 1011] A container containing a plurality of doses of a formulation comprising a pharmaceutically acceptable carrier and an active ingredient comprising phentermine; and Instructions for treating a patient with the formulation and for evaluating the patient's BRIEF score before and after treatment with the formulation A kit comprising [Invention 1012] A formulation for use in improving the Behavior Rating Inventory of Executive Function (BRIEF) score in a patient, the formulation comprising Phentermine or a pharmaceutically acceptable salt thereof and the use being for repeated administration once or twice daily over a period of time the period being selected from the group consisting of 1 month, 2 months, 3 months, 6 months, 9 months, 12 months, 15 months, 18 months, 21 months, 2 years, and 3 years The formulation for said use, wherein the improvement in the BRIEF score is obtained as compared to the patient's previous BRIEF score obtained prior to at least some of the repeated administrations [Invention 1013] A formulation for use in treating a patient, the formulation comprising a therapeutically effective amount of phentermine or a pharmaceutically acceptable salt, base, or acid thereof and the use being for repeated administration over several days until the patient shows an improvement in the Clinical Global Impression (CGI) rank as compared to the previous CGI obtained prior to the repeated administration of the formulation The formulation for said use [Invention 1014] A formulation for use in treating a patient diagnosed with Tourette syndrome, the formulation comprising a therapeutically effective amount of phentermine or a pharmaceutically acceptable salt, base, or acid thereof in an amount of 0.2 mg / kg / day or more and up to 30 mg / day a co-therapeutic agent and the co-therapeutic agent and phentermine A liquid formulation for use in repeated administration over several weeks until the patient shows improvement in the Clinical Global Impression (CGI) rank as compared to the previous CGI obtained before repeated daily administration of the formulation. The formulation for said use. [Invention 1015] The formulation for use according to Invention 1014, wherein the co-therapeutic agent is selected from the group consisting of carbamazepine, ethosuximide, phenytoin, lamotrigine, levetiracetam, phenobarbital, topiramate, valproic acid, valproate, verapamil, and benzodiazepines such as clobazam, clonazepam, diazepam, lorazepam, and midazolam, and pharmaceutically acceptable salts or bases thereof. These and other objects, advantages, and features of the invention will become apparent to those skilled in the art by reading the details of the method for treating seizure symptoms described below.

Brief Description of the Drawings

[0045]

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Mode for Carrying Out the Invention

[0046] Detailed Description of the Invention Before describing the method, kit, and formulation, it should be understood that the present invention is not limited to the specific embodiments described, and such an invention may of course be changed. Since the scope of the present invention is limited only by the appended claims, it should also be understood that the terms used herein are for the purpose of describing specific embodiments only and are not intended to be limiting.

[0047] When a range of values is provided, each intervening value between the upper and lower limits of that range is also specifically disclosed as being included, up to one tenth of the unit of the lower limit, unless a clear indication to the contrary is given by the context. Each of the smaller ranges between any described value or intervening value within the described range and any other described value or intervening value within the described range is included within the present invention. Any specifically excluded limit values within the described range are separate, but the upper and lower limits of these smaller ranges may independently be included in or excluded from the range, and each range that includes any one of the limit values, neither of the limit values, or both of the limit values within the smaller range is also included within the present invention. When the described range includes one or both of the limit values, ranges that exclude any one or both of such included limit values are also included in the present invention.

[0048] Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. Although any methods and materials similar or equivalent to those described herein can be used in the practice or testing of the present invention, some possible and preferred methods and materials will now be described. All publications mentioned herein are hereby incorporated by reference herein for the purpose of disclosing and describing the methods and / or materials associated with the publications cited thereby. It is understood that the present disclosure supersedes any disclosure of the incorporated publications to the extent of any conflict.

[0049] It should be noted that, as used herein and in the appended claims, the singular forms "a", "an", and "the" include plural references unless the context clearly dictates otherwise. Thus, for example, reference to "a seizure" includes a plurality of such seizures, reference to "the formulation" includes one or more formulations known to those of ordinary skill in the art, and their equivalents, and the like.

[0050] The publications discussed herein are provided solely for their disclosure prior to the filing date of the present application. Nothing herein is to be construed as an admission that the present invention is not entitled to antedate such publication by virtue of prior invention. Further, the dates of the publications provided may be different from the actual publication dates and may need to be independently confirmed.

[0051] Similar to the subject matter of multiple related patent applications (US 2017-0056344-A1; US 2017-0071949-A1; US 2018-0055789-A1; and US 2018-0092864-A1) and issued patents (9,549,909; 9,610,260; 9,603,814; and 9,603,815), fenfluramine has been found to be effective in treating, alleviating, or minimizing the symptoms of epilepsy, for example, reducing the number, intensity, and / or length of seizures. Fenfluramine is particularly useful in the treatment of epilepsy, especially epileptic encephalopathies such as Dravet syndrome and Lennox-Gastaut syndrome.

[0052] Cognitive function can be impaired in patients suffering from the symptoms of epilepsy. For example, executive function (also sometimes referred to as "higher-order" cognitive function) can be evaluated using laboratory-based measures of ability or by using the Behavior Rating Inventory of Executive Function (BRIEF).

[0053] There are multiple valid tests used to measure cognitive function, including, but not limited to, the Behavior Rating Inventory of Executive Function (BRIEF), the Wechsler Memory Test, the Montreal Cognitive Assessment (MOCA) scale, the Executive Function: Means and Instrument for Neurobehavioral Evaluation and Research (EXAMINER), and other clinical and / or metric scales.

[0054] As described below in this specification, it has been discovered that administration of fenfluramine may be beneficial in treating diseases and disorders that affect cognitive function. In some embodiments, a subject / patient may be administered fenfluramine to improve and treat a cognitive function disease or disorder. In some embodiments, the patient is also being treated for seizure symptoms. As used herein, the Behavior Rating Inventory of Executive Function (BRIEF) is administered to the patient to obtain a pre-treatment (i.e., baseline) BRIEF score, then the patient is treated with fenfluramine or a pharmaceutically acceptable salt thereof, and then, after a period of time following treatment, the BRIEF is re-administered to the patient to obtain a post-treatment score, a method for improving and measuring cognitive function, such as by a scale (including but not limited to) the BRIEF score, and a method for determining whether there is a significant improvement in the BRIEF score are provided.

[0055] Behavior Rating Inventory of Executive Function (BRIEF) The Behavior Rating Inventory of Executive Function (BRIEF) test was first developed by Gerard Gioia, Ph.D., Peter Isquith, Ph.D., Steven Guy, Ph.D., and Lauren Kenworthy, Ph.D. (Gioia, et al., (2000). Child Neuropsychology. 6(3):235-238). The BRIEF questionnaire is a standardized and valid assessment scale for measuring executive function in children aged 2-18 years in home and school environments. They are designed to provide a standardized method of questioning multiple raters about executive function in daily life in a form that is not specific to any particular disorder and are applicable to a wide range of children.

[0056] Regarding the BRIEF, the term executive function is used as an inclusive construct that includes a set of related cognitive functions responsible for goal-directed actions, actions aimed at goals, and problem-solving actions. Specific subdomains that make up this set of regulatory or management functions include the ability to initiate actions, the ability to inhibit competing actions or stimuli, the ability to select relevant task goals, the ability to plan and organize means to solve complex problems, the ability to flexibly shift problem-solving strategies when needed, and the ability to monitor and evaluate actions.

[0057] The BRIEF-P is for preschool children aged 2 - 5; the BRIEF is for those aged 6 - 18; the BRIEF-SR is for adolescents aged 11 - 18 for self-report only; and the BRIEF-A is for adults aged 18 - 90 for self / informant report.

[0058] Since it is not disorder-specific, the BRIEF can be used to assess executive function behaviors in children and adolescents who experience a wide range of difficulties, such as those related to learning disabilities and attention disorders, traumatic brain injury, lead exposure, pervasive developmental disorders, depressive states, and other developmental, neurological, psychiatric, and medical conditions.

[0059] Test format In the BRIEF test, parents / caregivers and / or patients (e.g., self-report for children or adolescents) answer a series of statements or questions in questionnaire form, where the responses of "N" = not a problem, "S" = sometimes a problem, and "O" = often a problem are used to indicate that the behaviors being described or evaluated have occurred in the past six months.

[0060] The questionnaires of the BRIEF Parent and Teacher Rating Forms each contain 86 items within 8 non-overlapping clinical scales and 2 validity scales. Based on theoretical and empirical analyses (see Chapter 5 of Gioia), the clinical scales, taken together, form two indices: (a) Behavioral Regulation (3 scales), and (b) Metacognition (5 scales), as well as the Global Executive Composite (GEC), an aggregate score that takes into account all 8 clinical scales of the BRIEF and represents the child's overall executive functioning. There are also 2 validity scales for measuring the negativity and inconsistency of responses. The score for the negativity scale measures the extent to which respondents answered items negatively rather than normally, while the score for the inconsistency scale indicates the degree to which respondents answered similar items inconsistently.

[0061] The Behavioral Regulation Index (BRI) represents the child's ability to transform cognitive set through appropriate inhibitory control and regulate emotions and behavior. It is composed of scales for Inhibition, Shift, and Emotional Control. Appropriate behavioral regulation may be a precursor to appropriate metacognitive problem-solving. Behavioral regulation enables metacognitive processes that lead to successful, proactive, and systematic problem-solving and, more generally, support appropriate self-regulation.

[0062] The Metacognition Index (MI) represents the child's ability to initiate, plan, integrate, and sustain future-oriented problem-solving in working memory. This index is interpreted as the ability to reflect the child's ability to cognitively self-manage tasks and monitor his or her performance of abilities. The MI is directly related to the child's ability to actively solve problems in various situations. It is composed of scales for Initiation, Working Memory, Planning / Organization, Materials Organization, and Monitoring. Behavioral Regulation Scale · Inhibition: Measures the ability to control impulsivity (inhibitory control) and the ability to stop activity in behavior. · Shift: The ability to move freely from one activity / situation to another; transition; the ability to allow change; the ability to switch or alternate attention; measures problem-solving flexibility. · Emotional control: Measures the ability to appropriately regulate emotional reactions. Meta-cognition scale · Initiation: Measures the ability to initiate activities and the ability to independently generate ideas or problem-solving strategies. · Working memory: Measures the ability to hold information in mind for the purpose of completing tasks when encoding information or when successively creating goals / plans. · Planning / Organization: Measures the ability to predict future events; the ability to set goals; the ability to develop processes; the ability to grasp main ideas; the ability to organize and understand main points in written or oral presentations. · Tool organization: Measures the ability to bring order to work areas, play areas, and storage areas (e.g., desks, lockers, backpacks, and bedrooms). · Monitor: Measures the ability to check work and evaluate one's own performance; the ability to follow the course of the effects of one's own actions on other people.

[0063] Implementation The BRIEF is very easy to administer and requires only a copy of the form and a pencil. The parent form is completed by the parent (preferably both parents). One preferred criterion is that they should have had recent contact with the child over the past six months. Similarly, the teacher form can be completed by any adult (teacher or aide) who has had extended contact with the child at school during this one month. Multiple evaluations across classrooms are strongly recommended as they are useful for comparison purposes.

[0064] Reliability and validity The questions selected for inclusion in the BRIEF were determined based on inter-rater reliability correlations and item-total correlations that were most likely to be of informational value to clinicians. The BRIEF has demonstrated excellent reliability, with high retest reliability (rs ≈.88 (teachers),.82 (parents)), internal consistency (Cronbach's alpha coefficients ≈.80 to.98), and moderate correlations between parent and teacher ratings (rs ≈.32 to.34). Evidence for the convergent and discriminant aspects of the BRIEF's validity is provided through its correlations with other measures of emotional and behavioral functioning. The BRIEF has also shown utility in distinguishing between inpatient and outpatient children and adolescents with attention deficit / hyperactivity disorder (ADHD).

[0065] Scoring and Interpretation The raw scores for all scales of the BRIEF questionnaire can be computer-analyzed by the Software Portfolio (BRIEF-SP), which provides separate norm tables, numerical T scores, percentiles, and 90% confidence intervals for four developmental age groups (ages 5 to 18 years) for both the parent and teacher forms. The T scores provide information about a child's individual score compared to the scores of other respondents in the standardized sample. The percentiles represent the percentage of children in the standardized sample who fall below a given raw score.

[0066] Clinical information collected from the BRIEF questionnaire is best understood within the context of a complete evaluation that includes an account of the child's and family's medical history and observations of the child's behavior. Thus, high scores obtained on the BRIEF suggest higher-order dysfunction in specific domains of executive function. Particular attention should also be paid to the Inconsistency scale, considering that scores of 7 or above on the rater responses imply a high degree of inconsistency.

[0067] Use The BRIEF is useful for evaluating children with various disabilities and impairments. In particular, the BRIEF is often used to evaluate executive function in children with developmental and / or acquired neurological conditions, including learning disabilities, Tourette syndrome, traumatic brain injury, pervasive developmental disorders, high-functioning autism, and low birth weight. The BRIEF is most often used to evaluate attention deficit / hyperactivity disorder.

[0068] Attention Deficit / Hyperactivity Disorder Because the BRIEF utilizes specific behaviors typically associated with this disorder (e.g., working memory, metacognitive skills), the BRIEF is often used to evaluate ADHD in children and has been shown to be superior to other assessment systems, such as the Behavior Assessment System for Children (BASC).

[0069] McCandless & O'Laughlin (2007) found that the BRIEF's Metacognition and Behavioral Regulation scales are clinically useful for identifying children with and without ADHD. In particular, the Metacognition scale (Working Memory subscale) is useful for identifying the presence of ADHD, while the Behavioral Regulation scale (Inhibition subscale) demonstrated clinical superiority in differentiating the inattentive subtype and the combined subtype (i.e., inattentive and hyperactive) of this disorder (McCandless & O'Laughlin (2007) Journal of Attention Disorders. 10(4):381-389).

[0070] The BRIEF was also useful for highlighting differences between ADHD and other diagnoses. For example, parents completed the BRIEF on children (ages 6 - 11) with diagnoses of ADHD, ADHD and reading disorder (RD), RD only, or no diagnosis. Children with ADHD showed higher scores on all BRIEF scales compared to children whose formal diagnosis was not investigated; children with reading disorder showed significant difficulty on the Working Memory and Plan / Organize subscales of the Metacognition scale.

[0071] According to aspects of the present disclosure, the fenfluramine treatment continues for an effective period and in an effective amount over an effective period for improving cognitive function, which can be evaluated by improvement in one of a plurality of valid scales, such as, but not limited to, the Behavior Rating Inventory of Executive Function (BRIEF), the Wechsler Memory Test, the Montreal Cognitive Assessment (MOCA) scale, the Executive Function: Means and Instrument for Neurobehavioral Evaluation and Research (EXAMINER), or other valid clinical and / or metric scales that measure cognitive function.

[0072] When the BRIEF test is administered to parents / caregivers and / or patients (e.g., pediatric or adolescent self-report), the responses indicate whether certain cognitive functions measured within two main indices (the Behavior Regulation Index (BRI) and the Metacognition Index (MI)) have occurred in the past six months. The BRI includes three scales (Inhibition, Shift, and Emotional Control), and the MI includes five scales (Initiation, Working Memory, Planning / Organization, Materials Organization, and Monitoring scales).

[0073] The Clinical Global Impression, CGI, assessment was developed for use in clinical trials sponsored by the NIMH and provides a simple independent assessment from the perspective of the clinician of the patient's overall function before and after initiating the investigational drug. The CGI provides a global aggregate scale determined by the clinician that takes into account all available information, including the patient's medical history, psychosocial situation, symptoms, behavior, and knowledge of the impact of the symptoms on the patient's functional ability.

[0074] CGI actually includes a two-item, one-scale measure that assesses the following: (a) the severity of psychopathology on a scale of 1 to 7, and (b) change from initiation of treatment on a similar 7-point scale. After a clinical evaluation, the CGI form can be completed by an experienced rater in less than 1 minute. In practice, CGI represents a clinical impression that encompasses more than just a symptom checklist. It is easily understandable and can be used relatively easily by clinicians other than researchers. Moreover, CGI can track clinical progress over time and has been shown to correlate with more time-consuming assessment measures across a wide range of psychiatric diagnoses.

[0075] In clinical practice, the CGI is administered by experienced clinicians who are knowledgeable about the possible course of the disease and treatment under study. Thus, CGI raters can make expert clinical judgments about the severity of the disease over various time points within the context of their clinical experience. Clinicians make judgments about the overall picture of the patient at each visit: the level of the patient's disease severity, distress, and other aspects of impairment, as well as the impact of the disease on functioning. The CGI is evaluated regardless of the clinician's opinion as to whether any clinical change is due to drug therapy or not, and without considering the etiology of the symptoms.

[0076] CGI-I evaluations may also be done by parents or caregivers or anyone who observes and interacts frequently with the patient. Such evaluations are not based on experience with other patients with the disorder, but are made in response to observed changes and fluctuations in the psychological and mental functioning of the individual patient, which are observed more frequently than those made by the investigator or treating physician.

[0077] In patients treated with fenfluramine, a significant and unexpected improvement in scores on cognitive tests was observed. For example, when taking the BRIEF test, patients taking fenfluramine tended to show improvement in cognitive function, improving scores on multiple scales within the BRI scale and / or the MI scale, which was the opposite of the tendency for cognitive function decline observed on these scales in epileptic patients treated with placebo.

[0078] In patients treated with fenfluramine, a significant and unexpected improvement in the clinically global impression score, which is statistically valid, was shown in patients during the clinical trials described herein, including an increase in the assessment of moderate and marked improvement continuing over several months and years of treatment. The improvement in CGI as a treatment effect is shown by the percentage of patients showing improvement.

[0079] As described herein, the description "improvement in cognitive function" means that after fenfluramine treatment, the patient's score on a valid measure of cognitive function, such as the BRIEF, Wechsler Memory Test, MOCA, and / or EXAMINER scale, improves compared to the baseline score. In some embodiments, the improvement in cognitive function is measured as percent improvement and is statistically significant. In some embodiments, at least one score is improved by 5% or more, 10% or more, 15% or more, 25% or more, 50% or more, or 75% or more.

[0080] As described herein, the description "improvement in clinically global impression" means that after fenfluramine treatment, the patient's score on a valid measure of nervous system function, such as CGI-I, improves compared to the CGI-S baseline score. In some embodiments, the improvement in function is measured by assigning an evaluation score at baseline and re-evaluating the patient with a new evaluation score. Improvement is shown by achieving an improvement in rank of at least one level above the previous rank. Nervous system function improvement may include an assessment of symptoms related to behavior, cognition, motor ability (ataxia, tremor, abnormal gait), conversation, agility, or frequency or severity of seizures, depending on the patient being treated or the disease state.

[0081] To avoid ambiguity, the term "prevention" of seizures means complete or partial prevention (suppression) of seizures. Ideally, the method of the present invention results in complete prevention of seizures. However, the present invention also encompasses methods in which the incidence of seizures is reduced by at least 40%, at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, or at least 90%. In addition, the present invention also encompasses methods in which the severity period of seizures is reduced by at least 40%, at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, or at least 90%.

[0082] Serotonin (5-HT) is a monoamine neurotransmitter that is thought to regulate numerous sensory, motor, and behavioral processes in the mammalian nervous system. These diverse responses are elicited through the activation of a large family of receptor subtypes. The complexity of this signaling system and the lack of selective drugs make it difficult to clarify the specific roles of 5-HT receptor subtypes or to determine how serotonergic drugs regulate mood and behavior. Among the many subtypes of serotonin receptors, the 1B and 2C subtypes are most strongly associated with the regulation of feeding and body weight, and these receptors are expressed in hypothalamic regions thought to be involved in the regulation of food intake. Both 1B and 2C receptor agonists have been shown to suppress feeding in rodents, and 2C receptor knockout mice exhibit chronic hyperphagia and obesity. Furthermore, knockout mice lacking functional 5-HT2C receptors (formerly called 5-HT1C) have been shown to have hyperphagia that leads to obesity, partial leptin resistance, increased fat deposition, insulin resistance, and glucose intolerance. Thus, the 5-HT2C receptor has been reported to be involved in the serotonergic control of food intake and body weight. Knockout mice also have a tendency to die naturally from seizures, suggesting that the 5-HT2C receptor also mediates the tonic inhibition of neural network excitability (Tecott LH, et al. Eating disorder and epilepsy in mice lacking 5-HT2C serotonin receptors. Nature. 1995, 374(6522):542-6).

[0083] Phentermine, that is, 3-trifluoromethyl-N-ethylamphetamine, has the following structure: is an amphetamine derivative having TIFF2025113312000004.tif38128.

[0084] Phentermine is a racemic mixture of two enantiomers, dexfenfluramine and levo-phentermine, and has been reported to increase the circulating levels of serotonin, a neurotransmitter that regulates mood, appetite, and other functions.

[0085] Phentermine was first marketed in the United States in 1973 for the treatment of obesity. However, in 1997, phentermine was withdrawn from the US and world markets because its use was associated with the development of valvular heart disease and pulmonary hypertension. Subsequently, the drug was withdrawn from sale worldwide and is no longer indicated for use in any therapeutic area. Without being bound by theory, the adverse effects associated with the use of phentermine as an appetite suppressant are thought to be due to the interaction of nor-phentermine, the major metabolite of phentermine, with 5-HT2B, which is associated with valvular heart disease.

[0086] Phentermine and its major metabolite, nor-phentermine, have been reported to be potent substrates of the norepinephrine transporter. (Rothman, et al., J. Pharmacol. Exp. Ther. 305(3):1191-9). Phentermine also functions as a norepinephrine-releasing agent to a relatively low extent, particularly via its active metabolite, nor-phentermine. Phentermine causes the release of serotonin by disrupting the vesicular storage of neurotransmitters and restoring serotonin transporter function. At high concentrations, nor-phentermine also functions as a dopamine-releasing agent, and phentermine can do the same at very high doses. In addition to monoamine release, phentermine binds very weakly to the serotonin 5-HT2 receptor, and nor-phentermine binds to and activates the serotonin 5-HT2B and 5-HT2C receptors with high affinity and the serotonin 5-HT2A receptor with moderate affinity. The result of increased serotonergic and noradrenergic neurotransmission is a decrease in satiety and appetite.

[0087] Despite past concerns about the cardiovascular safety that occurred when high-dose fenfluramine was used in the treatment of adult obesity, attempts are being made to identify additional therapeutic uses for the product while comparing and examining the known cardiovascular risks of fenfluramine against its potential therapeutic effects. One disorder for which new treatment options are highly needed is epilepsy, particularly in epileptic syndromes that are treatment-resistant to known treatments. Epilepsy is a dysfunction of the central nervous system (CNS) characterized by abnormal discharges and susceptibility to recurrent seizures. There are numerous causes of epilepsy, including but not limited to birth trauma, perinatal infections, anoxia, infectious diseases, toxin ingestion, brain tumors, genetic or degenerative diseases, head injury or trauma, metabolic abnormalities, cerebrovascular attacks, and alcohol withdrawal.

[0088] Although several anti-epileptic drugs have been developed, approximately one-third of patients with epilepsy are treatment-resistant to the treatment. Therefore, the search for new mechanisms and drug therapies that can regulate cellular excitability continues. Three drugs that are particularly effective for partial-onset seizures are vigabatrin, a selective and irreversible GABA transaminase inhibitor that significantly increases the total brain levels of GABA; tiagabine, a potent inhibitor of GABA uptake into neurons and glial cells; and topiramate, which is thought to produce its anti-epileptic effects through multiple mechanisms, including modification of Na + dependency and / or Ca 2+ dependency action potentials, enhancement of GABA-mediated Cl - influx into neurons, and suppression of kainate-mediated conductance at AMPA / kainate-type glutamate receptors (Angehagen, et al., 2003, Neurochemical Research, 28(2):333-340).

[0089] Historically, the investigation of the effectiveness of fenfluramine in epileptic patients has led to a common paradigm, namely, "the main action of fenfluramine is on behaviors that trigger or induce seizures, and it does not treat or prevent seizures themselves."

[0090] For example, Aicardi and Gastaut (New England Journal of Medicine (1985), 313:1419 and Archives of Neurology (1988) 45:923-925) reported that four cases of self-induced photosensitive seizures, that is, seizures caused by patients that deliberately start in bright light or sunlight, were found to respond to treatment with fenfluramine.

[0091] Clemens, in Epilepsy Research (1988) 2:340-343, reported a case of treating a juvenile with pattern sensitivity-induced seizures that were resistant to antiepileptic treatment with fenfluramine and suppressing the behaviors that induced the patient's forced seizures. According to the report, fenfluramine successfully terminated these self-induced seizures. Clemens concluded that this was because fenfluramine blocked the photosensitive stimulation mechanism and secondarily reduced the pathological driving force towards seizure-stimulating behaviors / forcing, that is, it was not due to treating the seizures themselves.

[0092] In Neuropaediatrics, (1996); 27(4):171-173, Boel and Casaer reported on a study of the effects of fenfluramine in children with treatment-resistant epilepsy, all of whom showed compulsive seizure-inducing behavior. They observed that when fenfluramine was administered at a dose of 0.5 - 1 mg / kg / day, this resulted in a decrease in the number of seizures experienced by the patients, and concluded that "this drug may have superior antiepileptic activity in a selected group of young patients with idiopathic or symptomatic generalized epilepsy, i.e., children with self-induced seizures." The authors stated that "fenfluramine does not have direct antiepileptic activity, but it is quite possible that it acts through its effect on the compulsive impulses that trigger seizures." Thus, the authors suggested that fenfluramine affects behavior and not the seizures themselves.

[0093] In a short report on epilepsy published in that journal (Epilepsia, 43(2):205-206, 2002), Boel and Casaer commented that "fenfluramine seems to have a therapeutic effect in patients with refractory epilepsy and self-induced seizures." However, the authors did not think that the effect of fenfluramine was due to general antiseizure activity.

[0094] Multiple subtypes of epilepsy are characterized, each with its own distinct clinical symptoms, signs, and phenotypes, pathophysiological basis, and different responses to various treatments. This disclosure is applicable to a range of different types of epilepsy and epilepsy subtypes, including Dravet syndrome, Doose syndrome, infantile spasms, and Lennox-Gastaut syndrome. There are a number of characterized epilepsy subtypes. For example, the most recent classification system, and one widely recognized in the art, is that adopted by the Classification and Terminology Commission of the International League Against Epilepsy (the “ILAE”). [See, e.g., Berg et al., “Revised terminology and concepts for organization of seizures,” Epilepsia, 51(4):676-685 (2010)]: I. Electroencephalogram-clinical syndromes organized by age of onset: A. Neonatal period (1. Benign familial neonatal epilepsy (BFNE), 2. Early myoclonic encephalopathy (EME), 3. Ohtahara syndrome); B. Infantile period (1. Infantile epilepsy with migrating focal seizures, 2. West syndrome, 3. Myoclonic epilepsy in infancy (MEI), 4. Benign infantile epilepsy, 5. Benign familial infantile epilepsy, 6. Dravet syndrome, 7. Myoclonic encephalopathy in non-progressive disorders); C. Childhood (1. Febrile seizures plus (FS+) (which may start in infancy), 2. Panayiotopoulos type syndrome, 3. Epilepsy with myoclonic atonia (old term: drop attacks), 4. Benign epilepsy with centrotemporal spikes (BECTS), 5. Autosomal dominant nocturnal frontal lobe epilepsy (ADNFLE), 6. Late-onset childhood occipital epilepsy (Gastaut type), 7. Myoclonic absence epilepsy, 8. Lennox-Gastaut syndrome, 9. Epileptic encephalopathy with continuous spike-wave during sleep (CSWS), 10. Landau-Kleffner syndrome (LKS), 11. Childhood absence epilepsy (CAE); D. Adolescence - Adulthood (1. Juvenile absence epilepsy (JAE), 2. Juvenile myoclonic epilepsy (JME), 3. Epilepsy presenting only with generalized tonic - clonic seizures, 4. Progressive myoclonic epilepsy (PME), 5. Autosomal - dominant epilepsy with auditory features (ADEAF), 6. Other familial temporal lobe epilepsy); E. Those with low age - relatedness (1. Familial focal epilepsy with variable foci (from childhood to adulthood), 2. Reflex epilepsy). II. Specific symptom groups with clear definition: A. Mesial temporal lobe epilepsy with hippocampal sclerosis (MTLE with HS); B. Rasmussen syndrome; C. Gelastic seizures due to hypothalamic hamartoma; D. Unilateral seizure - hemiplegia - epilepsy; E. 1. Other epilepsies identified based on presumed cause (presence or absence of known structural or metabolic diseases), and then 2. Main seizure expression pattern (generalized or focal). III. Epilepsies attributed to structural / metabolic causes and classified by cause: A. Cortical malformations (such as hemimegalencephaly, heterotopic gray matter, etc.); B. Neurocutaneous syndromes (such as tuberous sclerosis complex, Sturge - Weber syndrome, etc.); C. Tumors; D. Infections; E. Trauma. IV. Vascular malformations: A. Perinatal brain injury, B. Stroke, C. Other causes. V. Epilepsies of unknown cause. VI. Diseases associated with epileptic seizures but not diagnosed as epilepsy types in the conventional classification: A. Benign neonatal seizures (BNS); and B. Febrile seizures (FS).

[0095] See Berg et. al, “Revised terminology and concepts for organization of seizures,” Epilepsia, 51(4):676 - 685 (2010)).

[0096] Part V of the ILAE classification system emphasizes the fact that there are still subtypes of epilepsy where the list is far from complete, not fully characterized, or not yet recognized as distinct syndromes.

[0097] Those skilled in the art recognize that different subtypes of epilepsy have various causes, being induced by different stimuli, regulated by different biological pathways, and regardless of whether they are caused by genetic, environmental, and / or brain diseases or injuries. In other words, those skilled in the art recognize that the relationships associated with one epileptic subtype are not necessarily applicable to other subtypes. The fact that there are numerous compounds used to treat different types of epilepsy and that different epileptic subtypes react differently to different antiepileptic drugs is particularly important. That is, a particular drug may be effective against one form of epilepsy but completely ineffective against another, or may even be contraindicated due to exacerbation of symptoms, such as an increase in the frequency and severity of seizures. As a result, the effectiveness of a particular drug for a particular type of epilepsy is completely unpredictable, and the discovery that a particular drug is effective in treating a type of epilepsy that was not previously known to be effective for that drug is often surprising even when the effectiveness of the drug for other epileptic types is known. Furthermore, as will be described in detail below, effective treatment of certain forms of epilepsy with fenfluramine is contraindicated for co - administration with and / or treatment with certain other therapeutic agents.

[0098] One form of epilepsy that can be treated with fenfluramine is known as Dravet syndrome. Dravet syndrome is a rare and catastrophic form of intractable epilepsy that begins in infancy. According to DravetFoundation.org, children with Dravet syndrome do not outgrow the condition as they get older, and Dravet syndrome affects every aspect of their daily lives. Children with seizure disorders also face delays in behavior and development; problems with movement and balance; bone problems; problems with speech and language delays; problems with growth and nutrition; sleep disorders; chronic infections; and autonomic dysfunction, such as problems regulating body temperature, among others, although the onset of these symptoms is not uniform and some patients may be affected by some symptoms and not others to varying degrees. People with this disorder also have a higher risk of death during seizures.

[0099] First, by one year of age, patients with Dravet syndrome experience prolonged seizures. By two years of age, additional types of seizures begin to occur, which typically coincide with developmental delays due to recurrent seizures that likely cause brain damage, such as hypoxic brain injury.

[0100] Cognitive impairment and problem behaviors are common features in patients with Dravet syndrome. The impairments are relatively uniform in quality but vary in degree. Developmental delays become gradually apparent from the second year. Generally, children start walking at a normal age, but unsteady gait occurs over a very long period. Speech also starts at a normal age, but progress is extremely slow, and many patients do not reach the stage of forming simple sentences. The fine motor functions of the patients do not fully develop. They are hindered by segmental myoclonus and poor hand-eye coordination. Sleep disorders are often present. Even patients with milder cognitive impairment may not be able to draw patterns and may only be able to write letters in block letters. Lack of concentration is one of the major factors contributing to learning disabilities and hyperactive and defiant behaviors. Affected children are restless, do not listen to what adults say, and show no interest in playing with educational toys or participating in the daily activities of their age group. Conversely, affected children can often solve puzzles or repeatedly watch cartoons. Not all of these characteristics are present in all patients, and the characteristics tend to be less severe in patients diagnosed more recently (Dravet, C. Epilepsia, 52(Suppl. 2):3-9, 2011). Parental observations and neuropsychological examinations in the months following the onset of seizures confirm a deceleration of development and, in some cases, a decline in cognitive scales and / or significant fluctuations in cognitive measurements (Ragona, F., Epilepsia, 52(Suppl. 2):39-43, 2011).

[0101] Children with Dravet syndrome are prone to experiencing multiple seizures per day. Epileptic seizures are highly likely to cause death in patients with Dravet syndrome; approximately 10-15% of patients diagnosed with Dravet syndrome die in childhood, and in some cases, it is between the ages of 2 and 4. The mean age at death of the patients is reported to be 8.7±9.8 years (SD), 73% of the deaths occur before the age of 10, and 93% occur before the age of 20. In addition, the patients are at risk of many related conditions, including orthopedic developmental problems, growth disorders, and chronic infections.

[0102] Children with Doose syndrome are of particular concern for having a tendency to have episodes of status epilepticus, which are epileptic seizures lasting for more than five minutes. This severe and intractable condition is typically classified as a medical emergency requiring immediate medical intervention, which typically involves hospitalization for intravenous anti-seizure drug therapy and / or artificial coma due to medical procedures. Status epilepticus can be life-threatening. It may also be accompanied by severe cerebral hypoxia, which may possibly lead to damage to brain tissue. Frequent hospitalizations of children with Doose syndrome clearly afflict not only the patients but also their families and caregivers.

[0103] The treatment costs for patients with Doose syndrome are also high because the affected children always require management and many of them need to be institutionalized when they reach their teens.

[0104] Seizures in Doose syndrome can be difficult to manage but can be reduced by anti-seizure drug therapies such as clobazam, stiripentol, topiramate, and valproate. Since the course of the disorder varies among individuals, treatment protocols may differ. A high-fat, low-carbohydrate diet known as the ketogenic diet is also beneficial. Dietary regulation can be helpful but does not eliminate the symptoms. Until a better form of treatment or therapy is discovered, patients with this disease will have myoclonic epilepsy for the rest of their lives.

[0105] Currently, although several anti-seizure therapies can be used to reduce the incidence of seizures in patients with Doose syndrome, the results obtained by such therapies are typically inadequate, and at best, such therapies only result in a partial cessation of seizures. Seizures associated with Doose syndrome are typically treatment-resistant to conventional treatments. Furthermore, many anti-seizure drugs such as clobazam and clonazepam have undesirable side effects, which are particularly acute and prominent in pediatric patients.

[0106] The brain that is not epileptic has a natural balance of excitation (able to induce seizures) and inhibition (able to reduce seizures). Sodium channel blockers mainly affect sodium channels at specific stages of their resting, activation, and inactivation cycles, mostly by delaying the recovery from the inactivated state, thereby causing a cumulative decrease in Na+. Sodium channel blockers are widely used to treat epilepsy caused by excessive excitatory neurotransmission (except for SCN1A mutation-related epilepsy). In some epilepsies, sodium channel blockers may function to correct imbalances in excitatory and / or inhibitory neurotransmitters and make seizures less likely to occur. However, although sodium channel blockers are beneficial in the treatment of some epilepsies, this class of drugs is contraindicated in Dravet syndrome because it has been recognized that sodium channel blockers lead to a higher incidence of seizures in almost all patients with Dravet syndrome.

[0107] Although not bound by theory, approximately 70 - 90% of patients with Dravet syndrome have a nonsense mutation in the SCN1A gene that encodes the α1 subunit of the sodium ion channel (Nav1.1), which contains 2,009 amino acids and is mainly expressed in inhibitory neurons. At least 70 - 80% of patients with Dravet syndrome have SCN1A mutations in the exons of the gene that cause loss of sodium channel function. Dravet has suggested that 85% of patients have SNC1A mutations (Dravet C., The core Dravet syndrome phenotype. Epilepsia 2011; 52 (Suppl 2): 3 - 9). Some researchers predict that, since only the coding region of the SCN1A gene has been sequenced, many of the remaining patients may carry mutations in the regulatory regions (outside the coding sequence) of the gene that impair or prevent the expression of this channel. Mice with loss - of - function mutations in the NaV1.1 channel have severe impairments in sodium current and action potential firing in hippocampal GABAergic inhibitory neurons without a detectable effect on excitatory pyramidal neurons, which causes hyperexcitability and contributes to the seizures observed in Dravet syndrome. Complete loss - of - function mutations in NaV1 encoded by SCNA1 cause Dravet syndrome, accompanied by severe refractory epilepsy, as well as the co - morbidities of ataxia, abnormal gait, speech and conversation problems, sleep disorders, and cognitive dysfunction.

[0108] In Nav1.1 channels with impaired function, sodium currents and action potential firing are also impaired in the cerebellum, which can contribute to ataxia, as well as in the thalamic reticular nucleus and the suprachiasmatic nucleus of the hippocampus, which can contribute to circadian rhythm disorders and sleep disorders, and in GABAergic Purkinje neurons (Noebels et. al., Jasper's Basic Mechanisms of the Epilepsies, 4th edition, Bethesda (Md.): National Center for Biotechnology Information (US); 2012).

[0109] Since mild loss-of-function mutations in NaV1.1 channels are present in a mild epilepsy phenotype called familial febrile seizures, an integrated loss-of-function hypothesis has been proposed for the spectrum of epilepsy syndromes caused by genetic changes in NaV1.1 channels: mild dysfunction predisposes to febrile seizures, moderate dysfunction leads to GEFS+ epilepsy, and severe loss of function causes co-morbidities of intractable epilepsy and Dravet syndrome. (Catterall WA, et al., NaV1.1 channels and epilepsy. J. Physiol. 2010; 588: 1849-59).

[0110] Experts in this field were surprised that haploinsufficiency (where only one of the functional copies of the gene is defective, as opposed to the usual two) was not sufficient to maintain the healthy neural network function of NaV channels and caused epilepsy, as a decrease in sodium current should lead to a decrease in excitability rather than hyperexcitability. The mechanistic basis of hyperexcitability and comorbidities in Dravet syndrome has been tested using animal models created by targeted deletion or mutation of the SCN1A gene in mice. Homozygous null NaV1.1 (- / -) mice developed ataxia and died on postnatal (P) day 15 (Ogiwara, et al., 2007, J. Neurosci. 27:5903-5914., Yu, et al. 2006, Nat. Neurosci. 9:1142-1149). Heterozygous NaV1.1 (+ / -) mice showed spontaneous seizures and sporadic death starting after P21, highly dependent on the genetic background.

[0111] Loss of NaV1.1 did not change the voltage-dependent activation or inactivation of sodium channels in hippocampal neurons. However, the sodium current density was substantially reduced in inhibitory interneurons of NaV1.1 (+ / -) and NaV1.1 (- / -) mice, but not in excitatory pyramidal neurons. This decrease in sodium current caused a loss of sustained high-frequency firing of action potentials in hippocampal and cortical interneurons, thereby impairing their in vivo inhibitory function that depends on the generation of high-frequency bursts of action potentials.

[0112] Considering that sodium channel blockers have been reported to prevent seizure activity in some epilepsy, treating Dravet patients lacking SCN1A function with sodium channel blockers may be expected to prevent seizures in patients with Dravet syndrome. Instead, treating patients with Dravet syndrome with sodium channel blockers leads to an increase in seizure activity. One explanation is that in Dravet syndrome patients, the problem may be too little inhibition rather than excessive excitation. Thus, giving sodium channel blockers to Dravet syndrome patients reduces the amount of inhibitory neurotransmitter in the brain and shifts the balance towards more seizure activity. Thus, certain anti-seizure drugs classified as sodium channel blockers are currently known to exacerbate seizures in many Dravet patients. Thus, according to the present disclosure, sodium channel blocker drugs may be contraindicated in the context of the present invention and may include the following: phenytoin, carbamazepine, gabapentin, lamotrigine, oxcarbazepine, rufinamide, lacosamide, eslicarbazepine acetate, and fos-phenytoin. Similarly, selective GABA uptake inhibitors / GABA transaminase inhibitors including tiagabine and vigabatrin should also be avoided in Dravet syndrome. A double-blind placebo trial was conducted using stiripentol, a positive allosteric modulator of the GABAA receptor, as a GABAergic agent. This drug was added to clobazam and valproate and was found to improve focal treatment-resistant epilepsy as well as Dravet syndrome and showed efficacy in the trial.

[0113] Stiripentol has been found to reduce the rate of tonic-clonic seizures by up to 70% and is approved for the treatment of Dravet syndrome in Europe, Canada, Japan, and Australia, but not in the United States. Stiripentol has some antiseizure activity on its own but functions primarily by suppressing the metabolism of other antiseizure drugs and thereby extending their activity. Stiripentol is labeled for use in combination with clobazam and valproate. However, concerns remain regarding the use of stiripentol due to its inhibitory effects on the liver's cytochrome P450 enzymes. Additionally, the interactions of stiripentol with numerous drugs mean that combination therapy (typically required in patients with Dravet syndrome) can be problematic. In addition, the effectiveness of stiripentol is limited, and patients rarely become seizure-free.

[0114] Side effects or adverse events resulting from multiple drug therapies are additive, and the use of polytherapy, the use of more than two antiepileptic drugs for the treatment of Dravet syndrome, can impose a significant burden on patients because the effectiveness of the therapy is limited due to intolerance. In other words, the small benefit of drug therapy may not outweigh the risks or negative effects that the drugs have on patients.

[0115] In cases of more drug-resistant seizures, treatment with benzodiazepines, valproate, and / or stiripentol, or treatment with bromide and topiramate, as well as non-pharmacological interventions such as the ketogenic diet and vagus nerve stimulation, are used as alternative treatments. Treatment also includes cognitive rehabilitation with psychomotor therapy and talk therapy. In addition, valproate is often administered to prevent recurrence of febrile seizures, and benzodiazepines are used for long-term seizures, but these treatments are usually insufficient.

[0116] Various compounds have been tested for treating various types of epilepsy, and various epilepsy subtypes react differently to different anti-seizure drugs. For example, cannabidiol (CBD) has received orphan drug designation in the United States for the treatment of Dravet syndrome, and cannabidiol has been tested for the treatment of drug-resistant seizures in Dravet syndrome and has been reported to reduce the frequency of seizure attacks (Devinsky, et al., 2017, NEJM 376(21):2011-2020).

[0117] Another exemplary form of epilepsy that can be treated by fenfluramine is Lennox-Gastaut syndrome (LGS). LGS was first described in 1960 and is named after neurologists William G. Lennox (Boston, USA) and Henri Gastaut (Marseille, France). LGS is a refractory form of childhood-onset epilepsy that most often appears between the ages of 2 and 6, but can also occur at a younger or older age. LGS is characterized by frequent seizures and various seizure types, which typically involve developmental delays as well as mental and behavioral problems. In children, common causes of LGS include perinatal brain injury, brain malformations such as tuberous sclerosis or cortical dysplasia, CNS infections, and degenerative or metabolic abnormalities of the nervous system.

[0118] Multiple daily seizures of various types are typical in LGS. It is also typical to have seizures that spread widely. The most common seizure types are axial tonic seizures, atonic seizures, and yawn seizures, although myoclonic seizures, generalized tonic-clonic seizures, and focal seizures can also occur in any LGS patient. Atonic seizures, atypical yawn seizures, tonic seizures, focal seizures, and tonic-clonic seizures are also common. In addition, many LGS patients have a seizure condition, often non-convulsive, characterized by dizziness, apathy, and unresponsiveness. Furthermore, most patients have atonic seizures, also called drop attacks, which weaken the muscles and cause the patient to suddenly and unpredictably fall to the ground, often resulting in serious injury, which is why patients often wear helmets to prevent head injury.

[0119] In addition to multiple daily seizures of various types, children with LGS often have a cessation / delay of psychomotor development and behavioral disorders.

[0120] This syndrome is also characterized by specific findings on electroencephalogram (EEG), specifically, slow spike-wave complexes during the interictal period (i.e., between seizures) and fast rhythms during sleep.

[0121] Diagnosis LGS is a syndrome, and thus its diagnosis is based on specific clinical symptoms, the presence of signs, and clinical tests. LGS is typically identified by three features, including multiple types of seizures, mental retardation or regression, and an abnormal EEG with generalized slow spike-wave discharges. Physicians use EEG to assist in the diagnosis of LGS. Since the three features associated with LGS, such as tonic seizures, may not be well established, the diagnosis can be difficult at the onset of initial symptoms and a sleep EEG may be required to confirm the condition. Therefore, even though there may be overlap with other epilepsies in the clinical picture, LGS is agreed to be a clearly defined diagnosis by both the International League Against Epilepsy (ILAE), considered to be the world's leading medical society of epilepsy experts, and the FDA.

[0122] When a patient suffers from high-frequency, diverse seizures with a typical pattern of electroencephalogram (EEG), i.e., a slow spike-wave pattern of tardive dyskinesia, or multifocal and generalized sharp-wave discharges at 1.5 - 2.5 Hz, the diagnosis of LGS is clearer. During sleep, a rigid pattern (tachykinetic) is often observed.

[0123] General medical examinations usually reveal developmental delays and cognitive impairments in children with LGS. These may precede the occurrence of seizures or may take up to two years after the onset of seizures to become apparent.

[0124] There may be multiple etiologies for LGS, including genetic, structural, metabolic, or idiopathic ones. Approximately one quarter have no history of epilepsy, neurological abnormalities, or developmental delays prior to the onset of LGS symptoms. The underlying pathologies that can cause LGS may include encephalitis and / or meningitis, cerebral malformations (e.g., cortical malformations), birth injuries, hypoxic-ischemic injuries, frontal lobe lesions, and trauma.

[0125] An important differential diagnosis is the "pseudo-Lennox syndrome", also known as atypical benign partial epilepsy in childhood, which differs from LGS in that there are no tonic seizures, and sleep EEG provides the best basis for differentiating between the two. In addition, the "pseudo-Lennox syndrome" has etiologies and prognoses completely different from those of LGS.

[0126] Treatment The optimal treatment for Lennox-Gastaut syndrome has not yet been established. Many different medications and therapies have been tried in the past, and some are still currently being used in the treatment of this disorder, with varying degrees of success. For example: lamotrigine, felbamate, rufinamide, clobazam, clonazepam, topiramate are approved in the US and EU. Nitrazepam and valproate are approved in the EU (and used in the US), and zonisamide and benzodiazepines are used in the US and EU (although not currently approved). Mpm pharmacological therapies used in the US and EU include vagus nerve stimulation, ketogenic diet, and surgery.

[0127] A variety of treatment approaches, including conventional antiepileptic drug therapy, dietary therapy, and surgery, are currently being used in LGS, but the evidence supporting these therapies is not robust, and treatment is often ineffective. The use of multiple common first-choice treatments is based on clinical experience or conventional knowledge. Examples include a broad spectrum of antiseizure drug therapies, such as valproic acid, and benzodiazepines, most commonly clonazepam and clobazam. A few drugs have been proven effective in some patients with certain seizure types by double-blind placebo-controlled trials. Examples include clobazam, lamotrigine, topiramate, felbamate, and rufinamide, but most patients continue to have severe seizures even while taking these medications. Currently used second-choice drugs, such as zonisamide, are prescribed based on the results of some open-label general trials. Ketogenic diet may be useful in some patients with LGS who are treatment-resistant to drug treatment. Surgical options in LGS include corpus callosotomy (for drop seizures), vagus nerve stimulation, and focal cortical resection (in the presence of a resectable single lesion). However, it should be noted that significant improvement from any of these treatments, alone or in combination, is rare.

[0128] Despite the severity of the symptoms of LGS and the frequency with which it occurs (accounting for up to 10% of all childhood epilepsy), there is currently no standard evidence-based treatment for the disease. According to a comprehensive review of the literature [see Hancock EC & Cross JH, Treatment of Lennox-Gastaut syndrome (review), published in The Cochrane Library 2013, Issue 2], only nine randomized controlled trials evaluating drug treatment for this syndrome were found. The authors concluded that the research was insufficient and that "… there is no monotherapy that has been shown to be highly effective in this syndrome to date" (page 12 of the same reference). The authors further concluded that "the optimal treatment for LGS remains uncertain and, to date, no study has shown any one drug to be highly effective" (page 12 of the same reference).

[0129] Although not bound by theory, fenfluramine was known to induce the release of serotonin (5-HT) in the brain by disrupting its vesicular storage and to inhibit serotonin reuptake. The mechanism of action of fenfluramine made it suitable for the treatment of epilepsy. In fact, there are no scientific publications indicating that abnormalities in 5-HT are a candidate for the pathophysiological cause underlying LGS or that they are causally related to the seizures associated with this specific epileptic condition, nor are there even publications assuming so. Furthermore, since there was no scientific hypothesis related to serotonin abnormalities in LGS, there are no studies, not even individual case reports, in the medical literature explaining attempts to treat LGS using drug therapies that interact with serotonin. The fact that there is not even data or speculation in the literature regarding the general use of fenfluramine or serotoninergic substances for the treatment of LGS strongly supports the unexpected nature of the present invention: that LGS is a devastating treatment-resistant epileptic condition and that, considering the number of people affected, treating physicians are strongly motivated to conduct research on any treatment for which there is some perceived possibility of effectiveness.

[0130] Accordingly, according to the present disclosure, provided herein is a method for treating epilepsy by administering an effective dose of fenfluramine to a patient to stimulate one or more 5-HT receptors in the patient's brain, wherein the one or more 5-HT receptors are 5-HT1, 5-HT 1A ,, 5-HT 1B ,, 5-HT 1C ,, 5-HT 1D ,, 5-HT 1E ,, 5-HT 1F ,, 5-HT2, 5-HT 2A ,, 5-HT 2B ,, 5-HT 2C ,, 5-HT3, 5-HT4, 5-HT5, 5-HT 5A ,, 5-HT 5B selected from one or more of 5-HT6, and 5-HT7, etc. In certain embodiments of this aspect of the invention, the patient is diagnosed with epilepsy.

[0131] In some embodiments, fenfluramine may be used in the treatment of patients with epilepsy, particularly those with Dravet syndrome, Lennox-Gastaut syndrome, or other forms of epileptic encephalopathy, where the patient also has a disease or disorder associated with cognitive decline.

[0132] Cognitive impairment can be observed in patients suffering from symptoms of epilepsy such as disruption of both basic cognitive function and "higher-order" executive function. Executive function has conventionally included cognitive abilities of working memory, self-regulation, inhibitory control, and attentional control, and is often evaluated using laboratory-based ability scales or tests such as the Behavior Rating Inventory of Executive Function (BRIEF). It has been discovered and described herein that treatment with fenfluramine can improve cognitive function (e.g., as measured by the BRIEF).

[0133] The present disclosure provides methods and compositions for improving a patient's cognitive function (e.g., as measured by BRIEF, Wechsler Memory Test, MOCA, EXAMINER, or other metrics), particularly in pediatric and young adult patients. In some embodiments, the patient is also being treated for a seizure disorder or condition, such as Dravet syndrome and / or Lennox-Gastaut syndrome. The present disclosure relates to meeting such needs, since it relates to the discovery that administration of fenfluramine over a period of time is associated with improvement in cognitive function, as measured, for example, by BRIEF, Wechsler Memory Test, MOCA, EXAMINER, or other metrics. As described herein, it has been discovered that administration of fenfluramine may be beneficial in treating diseases and conditions that affect cognitive function.

[0134] A particular aspect of the invention includes treating a pediatric patient (including up to 18 years of age, including adolescence up to 18 years of age) with fenfluramine to improve the pediatric or adolescent's ability with respect to BRIEF or other metrics of cognitive function in daily life at school, work, or home.

[0135] Another particular aspect of the invention includes treating an adult patient (over 18 years of age) with fenfluramine to improve the adult's ability with respect to BRIEF, Wechsler Memory Test, MOCA, EXAMINER, or other measurements of cognitive function in daily life at school, work, or home.

[0136] Aspects of the present disclosure include methods of improving and / or measuring improvement of cognitive function in a patient, including the step of administering fenfluramine or a pharmaceutically acceptable salt thereof to the patient. In some embodiments, fenfluramine may be administered over a period of several months or years (e.g., 1, 2, 3, 6, 9, 12, 15, 18, 21 months, etc., e.g., up to 3 years, including 3 years). Measures of cognitive function may include administering the BRIEF test, the Wechsler Memory Test, the MOCA, the EXAMINER, or other measures to the patient both before and after fenfluramine treatment (e.g., every 3 months, every 6 months, every 1 year after the start of fenfluramine treatment, and continuously throughout the treatment) as qualitative and quantitative measures of improvement of cognitive function.

[0137] In some embodiments, the patient is diagnosed with a disease or condition selected from epilepsy or epileptic encephalopathy (e.g., Dravet syndrome, Doose syndrome, infantile spasms, Lennox-Gastaut syndrome); attention disorders (e.g., attention deficit disorder (ADD) or attention deficit hyperactivity disorder (ADHD)); developmental disorders such as autism spectrum disorder (ASD) including autism, Asperger syndrome, pervasive developmental disorder not otherwise specified (PDD) (PDD-NOS); oppositional defiant disorder (ODD); learning disorders (e.g., dyslexia, dyscalculia); Tourette syndrome; traumatic brain injury; lead exposure; anxiety and / or depressive states; and low birth weight, or any combination thereof.

[0138] In some embodiments, the patient is diagnosed with Dravet syndrome.

[0139] In some embodiments, the patient is diagnosed with epileptic encephalopathy.

[0140] In some embodiments, the symptoms of epileptic encephalopathy are seizures, where fenfluramine is formulated with a pharmaceutically acceptable carrier and the effective dose is less than 10.0 mg / kg / day, or less than 1.0 mg / kg / day, or approximately 0.8 mg / kg / day, or approximately 0.5 mg / kg / day, or approximately 0.2 mg / kg / day, or approximately 0.01 mg / kg / day.

[0141] In some embodiments, fenfluramine is administered in a dosage form selected from the group consisting of oral, injectable, transdermal, inhaled, nasal, rectal, intravaginal, and parenteral delivery.

[0142] In some embodiments, the dosage form is an oral composition in an amount selected from the group consisting of 30 mg / day or less, 20 mg / day or less, 10 mg / day or less, and 5 mg / day or less. In some embodiments, the oral composition is a solution.

[0143] In some embodiments of this method, fenfluramine is the only pharmaceutically active ingredient administered to the patient.

[0144] In some embodiments of this method, fenfluramine is used as adjuvant therapy in a patient. In some embodiments of this method, fenfluramine is used as adjuvant therapy in a patient having epilepsy or epileptic encephalopathy. In some embodiments of this method, fenfluramine is used as adjuvant therapy in a patient having Dravet syndrome or Lennox-Gastaut syndrome (LGS).

[0145] In some embodiments, at least one co-therapeutic agent is administered, where the agent is selected from the group consisting of brivaracetam, bromides (e.g., potassium bromide, sodium bromide), cannabidiol, carbamazepine, clonidine, ergenyl chrono, ethosuximide, felbamate, fosphenytoin, lacosamide, lamotrigine, levetiracetam, levocarnitine, mesuximide, nitrazepam, oxcarbazepine, perampanel, phenobarbital, pregabalin, progabide, pyridoxine, rufinamide, sulthiame, tizanidine, topiramate, stiripentol, sodium valproate semisodium, sodium valproate, valproic acid, verapamil, zonisamide, and benzodiazepines, such as clobazam, clonazepam, diazepam, ethyl loflazepate, lorazepam, and midazolam, and pharmaceutically acceptable salts or bases thereof.

[0146] In some embodiments, the fenfluramine treatment continues in an amount and for a period such that it improves cognitive function as evaluated via BRIEF, the Wechsler Memory Scale, MOCA, EXAMINER, or other clinical and / or metric scores. In some embodiments, the patient's score on the cognitive function test is improved to a statistically significant percentage. In some embodiments, the patient's Clinical Global Impression of Improvement (CGI-I rating) is improved. In some embodiments, at least one parameter of the patient's score is improved by 5% or more, 10% or more, 15% or more, 25% or more, 50% or more, or 75% or more, or by one or more levels of the evaluation scale.

[0147] In some embodiments, the patient is also being treated for epilepsy or epileptic encephalopathy.

[0148] In some embodiments, the patient diagnosed with epilepsy is under 18 years of age. In some embodiments, the patient diagnosed with epilepsy is an adult over 18 years of age.

[0149] Another aspect of the disclosure includes a kit comprising a fenfluramine formulation, packaging, and a package insert for use in improving cognitive function in a patient.

[0150] Another aspect of the disclosure includes a container comprising a plurality of dosages of a formulation comprising a pharmaceutically acceptable carrier and an active ingredient comprising fenfluramine; and instructions for treating a patient with the formulation and for assessing the cognitive function of the patient (e.g., by obtaining a score according to the BRIEF, Wechsler Memory Test, MOCA, EXAMINER, or other scales) before and after treatment with the formulation, a kit comprising.

[0151] Dosage by weight (mg / kg / day): In aspects of the present invention, any effective dosage of fenfluramine can be utilized. However, it has been found by the inventors that surprisingly low dosages of fenfluramine are effective for suppressing or eliminating seizures, particularly in epileptic patients. In some cases, in preferred aspects of the present invention, less than about 10 mg / kg / day, such as less than about 9 mg / kg / day, less than about 8 mg / kg / day, less than about 7 mg / kg / day, less than about 6 mg / kg / day, less than about 5 mg / kg / day, less than about 4 mg / kg / day, less than about 3.0 mg / kg / day, less than about 2.5 mg / kg / day, less than about 2.0 mg / kg / day, less than about 1.5 mg / kg / day, less than about 1.0 mg / kg / day, such as about 0.95 mg / kg / day, about 0.9 mg / kg / day, about 0.85 mg / kg / day, about 0.8 mg / kg / day, about 0.75 mg / kg / day, about 0.7 mg / kg / day, about 0.65 mg / kg / day, about 0.6 mg / kg / day, about 0.55 mg / kg / day, about 0.5 mg / kg / day, about 0.45 mg / kg / day, about 0.4 mg / kg / day, about 0.350 mg / kg / day, about 0.3 mg / kg / day, about 0.25 mg / kg / day, about 0.2 mg / kg / day, about 0.15 mg / kg / day to about 0.1 mg / kg / day, about 0.075 mg / kg / day, about 0.05 mg / kg / day, about 0.025 mg / kg / day, about 0.0225 mg / kg / day, about 0.02 mg / kg / day, about 0.0175 mg / kg / day, about 0.015 mg / kg / day, about 0.0125 mg / kg / day, or about 0.01 mg / kg / day of daily dosage is utilized.

[0152] In other words, the preferred dosage is from less than about 10 to about 0.01 mg / kg / day. In some cases, the dosage is from less than about 10.0 mg / kg / day to about 0.01 mg / kg / day, such as from less than about 5.0 mg / kg / day to about 0.01 mg / kg / day, from less than about 4.5 mg / kg / day to about 0.01 mg / kg / day, from less than about 4.0 mg / kg / day to about 0.01 mg / kg / day, from less than about 3.5 mg / kg / day to about 0.01 mg / kg / day, from less than about 3.0 mg / kg / day to about 0.01 mg / kg / day, from less than about 2.5 mg / kg / day to about 0.01 mg / kg / day, from less than about 2.0 mg / kg / day to about 0.01 mg / kg / day, from less than about 1.5 mg / kg / day to about 0.01 mg / kg / day, or from less than about 1.0 mg / kg / day to 0.01 mg / kg / day, such as less than about 0.9 mg / kg / day, less than about 0.8 mg / kg / day, less than about 0.7 mg / kg / day, from less than about 0.6 mg / kg / day to about 0.01 mg / kg / day, from less than about 0.5 mg / kg / day to about 0.01 mg / kg / day, from less than about 0.4 mg / kg / day to about 0.01 mg / kg / day, from less than about 0.3 mg / kg / day to about 0.01 mg / kg / day, or from less than about 0.2 mg / kg / day to about 0.01 mg / kg / day.

[0153] As indicated above, the dosage is based on the patient's weight. However, for convenience, the dosage may be pre-adjusted to an amount such as 1.0 mg, 2.5 mg, 5 mg, 10 mg, 15 mg, 20 mg, 30 mg, 40 mg, or 50 mg. In a particular example, the dosage may be pre-adjusted to an amount from about 0.25 mg to about 5 mg, such as about 0.25 mg, about 0.5 mg, about 0.75 mg, about 1.0 mg, about 1.25 mg, about 1.5 mg, about 1.75 mg, about 2.0 mg, about 2.25 mg, about 2.5 mg, about 2.75 mg, about 3.0 mg, about 3.25 mg, about 3.5 mg, about 3.75 mg, about 4.0 mg, about 4.25 mg, about 4.5 mg, about 4.75 mg, or about 5.0 mg.

[0154] Generally, the minimum effective dosage should be used for a particular patient.

[0155] The dosages described in this specification may be administered one or more times a day, for example, once a day, twice a day, three times a day, or four or more times a day, to provide a daily dosage.

[0156] In certain embodiments, the dosage is a daily dose of 30 mg or less, for example, about 30 mg, about 29 mg, about 28 mg, about 27 mg, about 26 mg, about 25 mg, about 24 mg, about 23 mg, about 22 mg, about 21 mg, about 20 mg, about 19 mg, about 18 mg, about 17 mg, about 16 mg, about 15 mg, about 14 mg, about 13 mg, about 12 mg, about 11 mg, about 10 mg, about 9 mg, about 8 mg, about 7 mg, about 6 mg, about 5 mg, about 4 mg, about 3 mg, about 2 mg, or about 1 mg. Generally, the minimum effective dose should be used for a particular patient. In some cases, the dosage is generally far lower than the dosage used in weight loss.

[0157] Route of administration: The dosages of phentermine administered by the methods of the present invention can be administered systemically or locally. The methods of administration can include administration via enteral routes such as oral, buccal, sublingual, and rectal; topical administration such as transdermal and intradermal; and parenteral administration. Suitable parenteral routes include injection via a subcutaneous needle or catheter, for example, intravenous, intramuscular, subcutaneous, intradermal, intraperitoneal, intraarterial, intracerebroventricular, intrathecal, and intracameral injection, and non-injection routes such as intravaginal, rectal, or nasal administration. In certain embodiments, it may be desirable to locally administer one or more compounds of the present invention to the site in need of treatment. This can be achieved, for example, by local injection upon topical application, by injection, by means of a catheter, by means of a suppository, or by means of an implant made from a material including a membrane or fiber such as a silicone membrane, for example, a porous, non-porous, or gelatinous material.

[0158] Route of Administration / Form of Administration: The dose of fenfluramine administered in the method of the present invention can be formulated into any pharmaceutically acceptable form of administration including, but not limited to, (a) oral administration forms such as tablets including orally disintegrating tablets, capsules, and lozenges, oral solutions or syrups, oral emulsions, oral gels, oral films, buccal solutions, for example powders for suspensions; (b) injectable administration forms; (c) transdermal administration forms such as transdermal patches, ointments, creams; (c) inhalable administration forms; and / or (e) nasal, (f) rectal, (g) vaginal administration forms.

[0159] Dosage Form / Frequency of Administration: Such forms of administration can be formulated for once-daily administration or multiple daily administrations (e.g., 2, 3, or 4 times a day). Alternatively, for convenience, the forms of administration can be formulated for less frequent administration (e.g., monthly, biweekly, weekly, every three days, every two days, or daily), and formulations that facilitate sustained release are known in the art.

[0160] Form of Administration / Preparation, Ingredients: The forms of administration of fenfluramine utilized in the method of the present invention can be prepared by combining fenfluramine or a pharmaceutically acceptable salt thereof with one or more pharmaceutically acceptable diluents, carriers, adjuvants, etc. by methods known to those skilled in the art of pharmaceutical formulations.

[0161] Oral Administration Form / Suitable Dosage Forms and Their Components: In some embodiments, formulations suitable for oral administration include: (a) a liquid solution such as an effective amount of a compound dissolved in a diluent such as water or physiological saline; (b) capsules, sachets, or tablets each containing a predetermined amount of the active ingredient (fenfluramine) as a solid or granule; (c) a suspension in a suitable liquid; and (d) a suitable emulsion. Tablet forms may include lactose, mannitol, corn starch, potato starch, microcrystalline cellulose, acacia, gelatin, colloidal silicon dioxide, croscarmellose sodium, talc, magnesium stearate, stearic acid, and one or more other excipients, colorants, diluents, buffers, wetting agents, preservatives, flavoring agents, and pharmaceutically compatible excipients. Lozenge forms may typically contain the active ingredient in a flavoring agent such as sucrose and acacia or tragacanth; similarly, troches may contain the active ingredient in an inert base such as gelatin and glycerin, or in sucrose and acacia, and emulsions and gels, etc., may contain, in addition to the active ingredient, excipients as described herein.

[0162] Oral Administration Form / Excipients: For oral solid pharmaceutical formulations, suitable excipients include pharmaceutical-grade carriers such as mannitol, lactose, glucose, sucrose, starch, cellulose, gelatin, magnesium stearate, sodium saccharin, and / or magnesium carbonate. For use in oral liquid formulations, the composition may be prepared as a solution, suspension, emulsion, or syrup and may be supplied, for example, in solid form or liquid form suitable for hydration in an aqueous carrier such as aqueous physiological saline, aqueous dextrose, glycerol, or ethanol, preferably water or physiological saline. Desirably, the composition may also contain small amounts of non-toxic auxiliary substances such as wetting agents, emulsifying agents, or buffers.

[0163] As an example, the fenfluramine composition is mixed with a conventionally pharmaceutically acceptable carrier and excipient (i.e., vehicle) and can be used in the form of an aqueous solution, tablet, capsule, elixir, suspension, syrup, and oblatum. Such pharmaceutical compositions contain, in certain embodiments, from about 0.1% to about 90% by weight of the active compound, more commonly from about 1% to about 30% by weight of the active compound. The pharmaceutical compositions may contain common carriers and excipients such as corn starch or gelatin, lactose, dextrose, sucrose, microcrystalline cellulose, kaolin, mannitol, dibasic calcium phosphate, sodium chloride, and alginic acid. Disintegrants commonly used in the formulations of the present invention include croscarmellose, microcrystalline cellulose, corn starch, sodium starch glycolate, and alginic acid.

[0164] Formulations suitable for topical administration may be presented as creams, gels, pastes, or foams containing, in addition to the active ingredient, a carrier as appropriate. In some embodiments, topical formulations contain one or more components selected from structuring agents, thickening or gelling agents, and emollients or lubricants. Frequently used structuring agents include long-chain alcohols such as stearyl alcohol, as well as its glyceryl ethers or esters and oligo(ethylene oxide) ethers or esters. Examples of thickening and gelling agents include polymers of acrylic or methacrylic acid and their esters, polyacrylamide, and naturally occurring thickening agents such as agar, carrageenan, gelatin, and guar gum. Examples of emollients include triglyceride esters, fatty acid esters and amides, waxes such as beeswax, spermaceti wax, or carnauba wax, phospholipids such as lecithin, and their sterol and fatty acid esters. Topical formulations may further include other components such as, for example, astringents, fragrances, dyes, skin penetration enhancers, sunscreens (e.g., sun protection agents), and the like.

[0165] Certain formulations of the present invention are in the form of an oral liquid. The liquid may be a solution or a suspension, and may be an oral solution or syrup contained in a bottle with a graduated syringe for the milligram amounts obtainable in a given volume of solution. The liquid solution is capable of adjusting the volume of solution for appropriate administration to small children, who are administered fenfluramine in any amount between 1.25 mg and 30 mg and in incremental amounts of 0.25 mg, and thus may be administered in amounts such as 1.25 mg, 1.5 mg, 1.75 mg, 2.0 mg, etc.

[0166] Fenfluramine may be co-administered with other known drugs such as co-therapeutic agents selected from the group consisting of brivaracetam, bromides (e.g., potassium bromide, sodium bromide), cannabidiol, carbamazepine, clonidine, ergoline chrono, ethosuximide, felbamate, fosphenytoin, lacosamide, lamotrigine, levetiracetam, levocarnitine, mesuximide, nitrazepam, oxcarbazepine, perampanel, phenobarbital, pregabalin, progabide, pyridoxine, rufinamide, sulthiame, tizanidine, topiramate, stiripentol, sodium valproate semisodium, sodium valproate, valproic acid, verapamil, zonisamide, and benzodiazepines, such as clobazam, clonazepam, diazepam, ethyl loflazepate, lorazepam, and midazolam, and pharmaceutically acceptable salts or bases thereof.

[0167] The co-therapeutic agents have recommended dosages. Those recommended dosages are specifically for the co-therapeutic agents listed above, and more specifically for the dosages recommended for those drugs, both of which are incorporated herein by reference within the latest edition of the Physician’s Desk Reference (PDR) or provided online at emedicine.medscape.com.

[0168] In connection with the present invention, the co-therapeutic agent can be used at the recommended dosage, or in the range of 1 / 100 to 100 times, 1 / 10 to 10 times, 1 / 5 to 5 times, 1 / 2 to 2 times of the recommended dosage, or in any amount in 1 / 10 increments between those ranges.

[0169] As specific examples of the combination of the co-therapeutic agent and fenfluramine, the co-therapeutic agent may be any one, any two, or all three of strychnopentol, clobazam, and valproate. Fenfluramine may be administered at a daily dose of 0.8 mg / kg per kg of the patient's body weight. When fenfluramine is co-administered with 20 mg of clobazam and / or 25 mg / kg of valproate or without them, and with 50 mg / kg / day of strychnopentol, it may be administered at a daily dose of 0.5 mg / kg per kg of the patient's body weight. Each such amount may be increased to an amount that is 2 times, 3 times, 5 times, or 10 times that amount, or decreased by 10%, 50%, or 75%.

[0170] In an alternative embodiment, the dispensing device may be a syringe or graduated pipette useful for delivering various doses of fenfluramine solution. In another embodiment, the dispensing device is a metered-dose device capable of dispensing a fixed volume of fenfluramine solution. In one exemplary embodiment, the dose delivered by the metered-dose device is adjustable.

[0171] The formulation may be a solution or suspension and is prepared such that a given volume of the formulation contains a known amount of active fenfluramine.

[0172] For example, in one aspect of this aspect, the dispensing device is a graduated syringe in 1 milliliter increments, and the liquid fenfluramine formulation is characterized in that 1 milliliter in the volume of the formulation strictly contains 1 milligram of fenfluramine. Thus, the patient can be accurately administered the desired milligram dosage of fenfluramine based on the volume of the liquid formulation administered orally to the patient.

[0173] In an alternative embodiment, the dispenser is a syringe connected to and configured to withdraw a liquid formulation from a container, graduated in several steps indicating the volume of the withdrawn formulation, or a fixed-dose dispenser for delivering a predetermined volume of the formulation to a patient, or a metering dispenser calibrated to deliver a predetermined volume of liquid enabling simple, consistent, and accurate administration.

[0174] In some embodiments of this method, fenfluramine is the only pharmaceutically active ingredient administered to the patient.

[0175] In some embodiments of this method, fenfluramine is used as adjuvant therapy in a patient. In some embodiments of this method, fenfluramine is used as adjuvant therapy in a patient having epilepsy or epileptic encephalopathy. In some embodiments of this method, fenfluramine is used as adjuvant therapy in a patient having Dravet syndrome or Lennox-Gastaut syndrome (LGS).

[0176] In the method of the present invention, fenfluramine can be utilized as concomitant therapy in the treatment of epilepsy. Fenfluramine can be co-administered in a single dosage formulation with fenfluramine, or separately in one or more individual dosage formulations, in combination with one or more pharmaceutically active agents that can be provided separately. When separate pharmaceutical dosage formulations are used, the subject composition and the one or more additional agents can be administered simultaneously or separately at different times, i.e., sequentially.

[0177] In one aspect, the agent is a co-therapeutic agent such as an anti-seizure agent. Suitable co-therapeutic agents include brivaracetam, bromides (e.g., potassium bromide, sodium bromide), cannabidiol, carbamazepine, clonidine, ergenyl chrono, ethosuximide, felbamate, fosphenytoin, lacosamide, lamotrigine, levetiracetam, levocarnitine, mesuximide, nitrazepam, oxcarbamazepine, perampanel, phenobarbital, pregabalin, progabide, pyridoxine, rufinamide, sulthiame, tizanidine, topiramate, stiripentol, valproic acid semisodium, valproic acid sodium, valproic acid, verapamil, zonisamide, and benzodiazepines such as clobazam, clonazepam, diazepam, ethyl loflazepate, lorazepam, and midazolam, and can be selected from the group consisting of these. The use of pharmaceutically acceptable salts of the co-therapeutic agent is also contemplated.

[0178] In some aspects, the subject / patient may have been previously treated with an agent prior to treatment with fenfluramine, where the previous agent is selected from acetazolamide, brivaracetam, carbamazepine, clobazam, clonazepam, diazepam, ergenyl chrono, ethosuximide, felbamate, gabapentin, lacosamide, lamotrigine, levetiracetam, lorazepam, mesuximide, oxcarbamazepine, perampanel, phenobarbital, phenytoin, phenytoin sodium, pregabalin, rufinamide, stiripentol, sulthiame, topiramate, valproic acid semisodium, valproic acid sodium, valproic acid, vigabatrin, zonisamide, and pharmaceutically acceptable salts or bases of any of these.

[0179] Fenfluramine can be administered in the form of the free base or in the form of a pharmaceutically acceptable salt selected from the group consisting of, for example, hydrochloride, hydrobromide, hydroiodide, maleate, sulfate, tartrate, acetate, citrate, tosylate, succinate, mesylate and besylate. Further exemplary pharmaceutically acceptable salts are recognized in Berge et al., J. Pharm Sci. (1977) 68(1): 1-19.

[0180] Fenfluramine for use in the methods of the present invention can be made by any pharmaceutically acceptable process known to those skilled in the art. Examples of processes for synthesizing fenfluramine are provided in the following documents: GB1413070, GB1413078, and EP441160.

[0181] The dosage of fenfluramine to be used in the methods of the present invention can be provided in the form of a kit including instructions for using the dosage in one or more of the methods of the present invention. In certain embodiments, the kit can additionally include a dosage form comprising one or more co-therapeutic agents.

[0182] The methods of the present invention can be practiced on any appropriately diagnosed patient. In alternative exemplary embodiments of the present invention, the age of the patient is about 18 years or less, about 16 years or less, about 14 years or less, about 12 years or less, about 10 years or less, about 8 years or less, about 6 years or less, or about 4 years or less to about 0 months of age or more, about 1 month of age or more, about 2 months of age or more, about 4 months of age or more, about 6 months of age or more, or about 1 year of age or more. Thus, in some embodiments, the diagnosed patient is about 1 month of age to about 18 years old when treated.

[0183] In some embodiments, the patient is an adult over 18 years of age.

[0184] The present invention is further illustrated in the following examples.

Examples

[0185] Example 1 Examination for treatment with fenfluramine and improvement of cognitive function evaluated by BRIEF - Doose syndrome Catarino et al. reported the results of a retrospective study of 22 adult patients with Doose syndrome and found improvement in seizure control after switching to an appropriate antiepileptic drug (AED), and three patients who experienced improvement in cognitive function (Catarino CB, Liu JY, Liagkouras I, et al., 2011, Brain 134:2982 - 3010). Furthermore, in a recently published trial of cannabidiol in Doose syndrome, the active treatment group did not achieve a significant difference from placebo in cognitive function (Devinsky, NEJM 2017). To date, no prospective placebo - controlled trials of AEDs in Doose syndrome (or any other epileptic encephalopathy) have been able to demonstrate such benefits; the present disclosure is the first to demonstrate improvement in cognitive function in a prospective randomized comparative trial of fenfluramine treatment in pediatric Doose patients.

[0186] Although not limited to theory, in this study, it was hypothesized that in children and adults with epileptic encephalopathy, cognitive impairment may be caused by seizures, underlying genetic abnormalities, or a combination of both. Historically, for example, a significant reduction in the monthly convulsion seizure frequency (MCSF) due to fenfluramine treatment may contribute to the improvement of cognitive function (Brunklaus A, Zuberi SM. “Dravet syndrome--from epileptic encephalopathy to channelopathy.” Epilepsia 2014, 55:979-84; Catarino et al., “Dravet syndrome as epileptic encephalopathy: evidence from long-term course and neuropathology.” Brain 2011, 134:2982-3010). However, considering that the improvement of cognitive function has not been reported in previous placebo-controlled trials, the ability of fenfluramine to improve cognitive function may not be limited to its effect of reducing seizure frequency, and may be a complex interaction of other factors including the reduction of MCSF and genetic factors. The direct mechanism of action has not been excluded.

[0187] In this disclosure, a study was conducted in which fenfluramine HCl oral solution was used as adjuvant therapy for 22 weeks in children and young adults with Dravet syndrome, and a follow-up of 3 to 6 months after the final administration of the test drug was performed for final safety monitoring.

[0188] The results for the first 119 consecutive subjects who were enrolled and randomly assigned (out of a total of 240 subjects planned) in any of the trials before a pre-determined cut-off date are presented as "Study 1" in this example.

[0189] Selection Criteria and Exclusion Criteria Human patients aged 2 to 18 years, including the border, with a recorded medical history that supports the clinical diagnosis of Dravet syndrome and a history of seizures (either generalized tonic-clonic or unilateral or bilateral clonic, and any of the protracted ones) were recruited and selected for inclusion in the study according to criteria including age, physical and mental characteristics, and (optionally) the combination of resistance to treatment by conventional therapies. The selected subjects were evaluated over the course of this 22-week study. The study protocol was reviewed and approved by the clinical research review committee or ethics committee at each clinical research facility before any study activation at the clinical research facility. All patients or their legal representatives signed an informed consent / consent document before registering for the clinical trial.

[0190] In some patients, seizures induced by long-term exposure to high temperatures, and / or seizures are associated with fever caused by disease or vaccine, hot baths, high levels of activity, and sudden temperature changes, and / or seizures are induced by strong natural light and / or fluorescent light, and certain visual patterns.

[0191] Subjects had ≥4 seizure episodes (tonic, atonic, tonic-clonic, clonic) per 4 weeks during the past 12 weeks before screening, as reported by a parent / guardian to the investigator or from the investigator's medical records.

[0192] All drug therapies or interventions for epilepsy (including ketogenic diet [KD] and vagus nerve stimulation [VNS]) were stable for at least 4 weeks before screening and were expected to remain stable throughout the study period.

[0193] The parents / caregivers of the subjects were willing and able to keep diary records, attend scheduled visits, and manage the study drug records.

[0194] Subjects are excluded if it is known that they are allergic to either fenfluramine or an excipient in the investigational drug; have a history of pulmonary arterial hypertension; have a concurrent or prior history of cardiovascular or cerebrovascular disease (e.g., valvular heart disease, myocardial infarction, or stroke); are currently being treated with stiripentol within 21 days prior to screening with a central-acting appetite suppressant, monoamine oxidase inhibitor, or any central-acting drug with serotonin agonist or antagonist properties; or have a positive urine test for tetrahydrocannabinol or a positive whole blood test for cannabidiol at the time of screening. Eligibility for enrollment was approved by the Epilepsy Study Consortium (http: / / epilepsyconsortium.org / ).

[0195] Subject candidates participated in a 6-week baseline to confirm seizure frequency and determine eligibility. Seizures were recorded by the parent or caregiver in an electronic study diary for date, time, duration, and type of seizure. To meet eligibility for randomization, each subject must have had ≥6 convulsive seizures with ≥2 seizures in the first 3 weeks and ≥2 seizures in the last 3 weeks during the baseline period. In this study, convulsive seizures were defined as unilateral clonic, tonic, clonic-tonic, tonic-atonic, generalized tonic-clonic, and focal with clear observable motor signs. The 6-week baseline period began with a screening visit, followed by an observation period to evaluate the subject for baseline seizure activity based on daily seizure activity entries in the diary. At the end of the baseline period, eligible patients were randomly assigned 1:1:1 in double-blind fashion to receive the first dose of fenfluramine HCl (“ZX008” buffered to pH 5) (not exceeding doses of 0.2 mg / kg / day, 0.8 mg / kg / day, 30 mg / day).

[0196] Randomization was performed in double-blind fashion and stratified by age group (<6 years, ≥6 years) between treatment groups. A placebo solution with the same appearance and taste was also provided. The daily dose was administered with meals in two equal doses, one in the morning and one in the evening approximately 12 hours apart. During the first 2 weeks (titration period), patients in the fenfluramine 0.8 mg / kg / day group were blindly titrated to their final dose, starting at 0.2 mg / kg / day for 4 days, then 0.4 mg / kg / day for 4 days, and then reaching the final dose. The other groups received a dummy titration to maintain blindness. Patients were maintained at their final dose for an additional 12 weeks (maintenance period). Near the end of the treatment period (titration plus maintenance), patients eligible to continue in any open-label extension (OLE) trial received a 2-week transition period, while patients who ended the trial received a 2-week taper and follow-up.

[0197] ZX008 was supplied as an oral solution at concentrations of 1.25, 2.5, and 5 mg / mL. Subjects were randomized to receive either one of two doses of ZX008 (0.2 mg / kg / day, 0.8 mg / kg / day; maximum 30 mg / day) or placebo. The study drug was administered with meals in equally divided doses twice daily (BID). For the placebo group, an oral solution without fenfluramine was administered as a negative control.

[0198] In some embodiments, the BRIEF, BRIEF-A or BRIEF-P (depending on the age of the patient) is administered to establish a cognitive function baseline measure in patients prior to treatment with fenfluramine.

[0199] The BRIEF (BRIEF-A or BRIEF-P) was administered at randomization of the patient (at the 3rd visit, which was 1 day before the start of treatment (day 1 of the trial, “-1” day of the trial)); the BRIEF was administered again at the 8th visit (day 43 of the trial) and at the end of the trial (12th visit, day 99 of the trial) to evaluate cognitive function. Initially, the BRIEF was included as a safety measure to evaluate whether the treatment had any negative effects on cognitive function. However, surprisingly, in addition to no negative effects on cognitive function, furthermore, a statistically significant improvement was observed in some of the BRIEF executive function index scores, and it was even more unexpectedly observed that the placebo treatment group deteriorated in all three indices (i.e., the Behavior Regulation Index (BRI), the Metacognition Index (MI), and the Global Executive Composite Score (GEC)). Compared to baseline, randomized subjects receiving phentermine HCl (“ZX008”) at 0.8 mg / kg / day were observed to have a statistically significant improvement in both the BRIEF BRI index (P<0.05) and the BRIEF GEC index (P<0.05) compared to placebo, and the control in the ZX008 0.2 mg / kg / day group was observed to have a significant improvement in the BRI (P<0.05).

[0200] Example 2 Examination of treatment with phentermine and overall functional improvement evaluated by CGI-I - tardive dyskinesia In a series of Phase III trials of fenfluramine, CGI-S and CGI-I evaluations were performed by clinical trial physicians and parents / caregivers. CGI changes in two randomized comparative trials were measured, and the results are reported in this example. Test 1 was conducted as described in Example 1, and CGI evaluations were performed according to a pre-established visit schedule adjusted to the clinic. Tables of the results of the CGI evaluations of Test 1 at the 12th visit (Day 113) and bar graphs of the statistical analysis are provided in Figures 1-4. The evaluations showed a clinically significant improvement in the CGI-I score (increase in scores for moderate improvement and marked improvement). At either a dose of 0.2 mg / kg / day or 0.8 mg / kg / day, significantly more parents / caregivers rated their child as "markedly improved" or "moderately improved" than was the case in the placebo group. Similar results were obtained in the CGI-I evaluations by the treating physicians.

[0201] In Study 1504, a randomized, double-blind, placebo-controlled, parallel-group evaluation of the efficacy, safety, and tolerability of ZX008 as adjunctive antiepileptic therapy to stiripentol treatment in children and young adults with Dravet syndrome also included CGI measurements during the baseline period and at specified visits.

[0202] Patient Selection and Administration: The 6-week baseline period consisted of a screening visit followed by the initial determination of eligibility during the observation period, where subjects were evaluated for baseline seizure activity based on a log of daily seizure activity to confirm the baseline convulsive seizure frequency (CSF). At the end of the baseline period, eligible subjects were randomly assigned (1:1) in double-blind fashion to receive ZX008 (at a dose of 0.5 mg / kg / day, maximum 20 mg / day) or placebo.

[0203] Randomization was stratified by age group (≥2 to <6 years and ≥6 years) to ensure balance between treatment arms. Patients were titrated to their target dose over 3 weeks and then maintained at that fixed dose for 12 weeks. Titration was done in three steps, starting with ZX008 (or an equivalent placebo) at a dose of 0.2 mg / kg / day on Days 1 to 7 of the study, increasing to a dose of 0.4 mg / kg / day on Days 8 to 14 of the study, and then increasing to a dose of 0.5 mg / kg / day on Days 15 to 21 of the study. The maximum daily dose at any point was 20 mg / day. The duration of the titration period was 21 days. After titration, subjects continued treatment for 12 weeks of maintenance with ZX008 0.5 mg / kg / day (maximum 20 mg / day) or their randomly assigned dose of placebo.

[0204] Eighty-seven patients were randomized to treatment and placebo arms with a median age of 9 years (range, 2 to 19 years) across study sites in Europe, the United States, and Canada. After a 6-week baseline observation period to establish baseline CSF, patients were randomized to one of two treatment groups that added ZX008 (n = 43) or placebo (n = 44) to their stable background regimen of stiripentol + other antiepileptic drugs. The 0.5 mg / kg / day (maximum 1-day dose of 20 mg) ZX008 dose in this study was due to a drug-drug interaction between stiripentol and ZX008.

[0205] Figures 5 and 6 are graphical summaries of the percentage of patients in Study 1504 showing improvement in CGI compared to patients on placebo.

[0206] Study 1503 was an open-label long-term safety study of ZX008 in subjects with Prader-Willi syndrome who had successfully completed 14 weeks of treatment in Cohorts 1 and 2 of 1501, 1502, or 1504. Patients enrolled in Study 1503 all received phentermine treatment for up to 24 months after participation in the open-label phase. CGI-S (baseline score) was determined at entry into 1503 (i.e., after completion of the 16-week blinded study), and then again at the final visit for each patient. Figures 7 and 8 and Tables 3 and 4 show the number of patients with each of the 7-point ratings and the statistical calculations of improvement.

[0207] Table 1 and Figure 4 present the CGI-I caregiver / parent ratings at baseline and final visit when the subject completed participation in the core study. At the final visit, 204 subjects (82.3%) had a CGI-I caregiver / parent rating of improvement (mild improvement, moderate improvement, or marked improvement), and 155 subjects (62.5%) had a CGI-I caregiver / parent rating of moderate / marked improvement or marked improvement. Table 4 and Figure 8 present the CGI-I investigator ratings at baseline and final visit. At the final visit, 217 subjects (85.4%) had a CGI-I investigator rating of improvement (mild improvement, moderate improvement, or marked improvement), and 163 subjects (64.2%) had a CGI-I investigator rating of moderate / marked improvement. The improvement in CGI-I scores seen in the open-label extension (OLE) was an improvement over the score improvement seen in the core study, demonstrating both continued improvement and persistence of the treatment effect with phentermine.

[0208] Safety The incidence of treatment-emergent adverse events (TEAEs) occurring under the administration of the investigational drug was continuously monitored over the study period. TEAEs were graded by the study physicians as mild, moderate, or severe, and related or unrelated to the investigational drug. Vital signs, height, weight, and clinical laboratory evaluations were performed at each study visit. The Behavior Rating Inventory of Executive Function (BRIEF) was administered periodically at baseline and throughout the treatment period to evaluate any effects of the treatment on cognitive function. Doppler echocardiogram (ECHO) and 12-lead electrocardiogram (ECG) were performed at screening / baseline, 6 weeks after treatment, and 14 weeks after treatment at the end of the maintenance period. ECG and ECHO were evaluated by two independent cardiologists blinded to the random assignment of treatment. In the event of a disagreement, the decision was referred to a third cardiologist.

[0209] Statistical analysis The standard deviation of the percentage change in monthly seizure frequency was estimated to be 55% based on the results from previous randomized clinical trials of stiripentol and cannabidiol for the treatment of seizures in patients with Dravet syndrome. Based on this premise, a sample size of 40 patients per arm was determined to provide 90% power to detect a difference in the mean change from baseline in monthly seizure frequency of 40% using a two-sided test at the α = 0.05 significance level.

[0210] The monthly convulsion frequency (MCSF) was presented every 28 days. The primary evaluation item was the change in the average MCSF between the baseline period, the incremental period, and the combined period of the maintenance period in the subjects treated with ZX008 at 0.8 mg / kg / day compared with the group treated with placebo. Five important secondary evaluation items were determined in advance: the comparison between the ZX008 0.2 mg / kg / day group and placebo regarding the change in MCSF between the baseline period, the incremental period, and the combined period of the maintenance period; the comparison between both ZX008 groups (independently) and placebo regarding the proportion of subjects who achieved a ≥50% decrease in MCSF from the baseline; and the comparison between both ZX008 groups and placebo regarding the longest seizure-free period observed in each group. Using the serial gatekeeping method, the simultaneous type 1 error rate was maintained at α = 0.05 between the analyses of the primary evaluation item and the five important secondary evaluation items. The analyses of the primary evaluation item and all secondary evaluation items were performed on the mITT population defined as all subjects who received at least one dose of the test drug and had seizure diary data after at least one week of treatment.

[0211] The primary evaluation item was analyzed using an analysis of covariance (ANCOVA) model that used treatment and age group (<6 years, ≥6 years) as factors, log baseline MCSF as a covariate, and log MCSF in the combined period of the incremental period and the maintenance period as a response. The estimated treatment difference and CI evaluation items were exponentiated to obtain the estimated value of the percentage difference between groups. The comparison between ZX008 at 0.2 mg / kg / day and placebo regarding the change in MCSF from the baseline period to the combined period of the incremental period and the maintenance period was analyzed similarly. The treatment groups were compared regarding the proportion of patients who achieved a ≥50% decrease in MCSF using a logistic regression analysis that incorporated the same factors as the primary evaluation item analysis. The groups were compared regarding the longest seizure-free period using the Wilcoxon rank-sum test, and the 95% CI of the median difference between groups was calculated using the Hodges–Lehmann estimator.

[0212] Additional secondary evaluation items Using the logistic regression described above, each ZX008 dose group was compared to placebo with respect to the percentage of patients who experienced a ≥25% and ≥75% decrease in MCSF. The Clinical Global Impression of Improvement (CGI-I) was evaluated by the study physicians and parents / caregivers using a 7-point Likert scale in response ranging from "very much improved" to "unchanged" to "very much worse". This evaluation was conducted during the blinded trial phase as well as during the open-label extension (OLE) trial with a treatment period of up to 24 months. The percentage of subjects rated as "very much improved" or "moderately improved" in each fenfluramine dose group was compared to placebo using Cochran-Mantel-Haenszel tests stratified by age group.

[0213] The percentage of patients in each ZX008 dose group who experienced seizure freedom or near-seizure freedom, defined as having ≤1 seizure over the entire treatment period, was compared to placebo.

[0214] All subjects received ZX008 or a matching amount of placebo for up to approximately 16 weeks in Study 1 (escalation period = 2 weeks; maintenance period = 12 weeks; taper / transition period = 2 weeks). After completion of the maintenance period, eligible subjects could enroll in an open-label extension (OLE) trial after completion of the transition. Subjects who did not enroll in the OLE trial had the study drug tapered (doses were administered blindly as in the escalation, i.e., doses decreased by 4 days each). Follow-up cardiovascular safety evaluations, including ECG and ECHO, were performed 3 - 6 months after the final dose of the study drug.

[0215] In Study 1, subjects were evaluated using the Clinical Global Impression (CGI), which allows for evaluation of improvement by parents / caregivers and the study responsible physician, as well as the Quality of Life in Childhood Epilepsy (QOLCE) scale and the Pediatric Quality of Life Inventory (PedsQL) scale to measure changes in the quality of life of the subjects. Comparisons between treatment groups were made using the Wilcoxon rank-sum test.

[0216] Missing data were not attributed to the analysis of the validation assessment items.

[0217] The CGI scale measures the change in the clinical state of the subject at a specific point in time, i.e., from the baseline period (and is also called the CGI-S, initial rank of severity). The CGI assessment scale enables an overall assessment of the improvement of the subject over time. The severity of the patient's condition is evaluated on a 7-point scale from 1 (marked improvement) to 7 (marked deterioration) as follows. 1 = Marked improvement 2 = Moderate improvement 3 = Mild improvement 4 = No change 5 = Mild deterioration 6 = Moderate deterioration 7 = Marked deterioration

[0218] In 2003, Varni and colleagues published a study aimed at determining the feasibility, reliability, and validity of the 23-item PEDSQL 4.0 (Pediatric Quality of Life Scale) Generic Core Scale as a measure of pediatric and adolescent pediatric public health. This instrument was given to over 10,000 families with children aged 2 - 16 years in the state of California. According to Varni, et al., parents reported changes and aggregate scores for each scale that could be considered clinically significant, with a cut-off point of >1 SEM or change in the standard error of measurement.

[0219] In both effective treatment groups, a significant improvement in quality of life based on the PEDSQL total score was experienced. Both effective treatment groups experienced significant improvement in all four core scores and three aggregate scores compared to placebo.

[0220] Scores in the effective treatment groups were observed to be improved compared to scores in the placebo group, indicating that fenfluramine had an effect on cognitive function measured using the BRIEF scale.

[0221] Results A total of 173 patients were screened for eligibility, 119 patients were enrolled, and randomly assigned to treatment. Fifty-four patients had screening failures, and the two most common reasons for screening failure were the presence of cardiovascular or cardiorespiratory abnormalities (mainly traces of mitral regurgitation and / or traces of aortic regurgitation) (n = 23, 43%) and failure to meet the randomization criteria (n = 19, 35%). Nine patients withdrew before the end of the trial, three in the placebo group (lack of efficacy (n = 1), subject / caregiver decision (n = 2)), and six in the ZX008 0.8 mg / kg / day group (adverse events (n = 5), subject / caregiver decision (n = 1)). A total of 112 patients from Study 1 participated in the OLE trial.

[0222] Patient demographics and baseline seizure frequencies are shown in Table 1. The mean age of the patients was 9.0 ± 4.7 years, and the mean MCSF was 41.9 ± 65. Patients had been treated previously, on average, 2.4 ± 1.0 (mean, 2; range, 0 - 5). AEDs most commonly included valproate (59.7%), clobazam (58.8%), topiramate (25.2%), and levetiracetam (21.8%). Fifty-eight (48.7%) subjects had been treated previously with stiripentol. Non-convulsive seizures were reported in 24 patients (60%) in the ZX008 0.8 mg / kg / day group, 23 patients (59%) in the ZX008 0.2 mg / kg / day group, and 21 patients (53%) in the placebo group. Overall mean medication compliance with the investigational drug was >90% in each treatment group.

[0223] Seizure frequency The trial met its primary efficacy evaluation item with high statistical significance. Compared with placebo, the ZX008 0.8 mg / kg / day group showed a substantial 63.9% decrease in mean MCSF over the 14-week treatment period (P<0.001, Table 2). The ZX008 0.2 mg / kg / day group also showed a significant 33.7% substantial decrease in mean MCSF compared with placebo (P = 0.019, Table 2). Clinically significant decreases in mean MCSF from baseline were recorded at all time points measured during the maintenance period of the 0.8 mg / kg / day group: -62.4%, -61.8%, and -62.2% at 6, 10, and 14 weeks after treatment, respectively. Smaller but similarly well-persisting decreases were observed in the 0.2 mg / kg / day group: -26.3%, -22.4%, and -22.2% at the same time points. A significantly greater proportion of subjects treated with any dose of ZX008 showed a clinically significant decrease (≧50%) or substantial decrease (≧75%) in MCSF during the treatment period compared with subjects in the placebo group (Table 2). The median longest seizure-free period was significantly longer in the ZX008 0.8 mg / kg / day group (20.5 days; p<0.001) and the ZX008 0.2 mg / kg / day group (14 days; p = 0.011) compared with placebo (9 days; Table 2). Seizure freedom over the entire 14-week treatment period was experienced by 3 subjects (7.5%) in the ZX008 0.8 mg / kg / day group and 3 subjects (7.7%) in the ZX008 0.2 mg / kg / kg group, and no subjects in the placebo group.

[0224] Given the high rate of seizures in patients with Dravet syndrome, a post hoc analysis was performed to investigate the treatment effect on achieving a state close to seizure freedom defined as experiencing 0 or only 1 seizure during the 14-week treatment period. A state close to seizure freedom was shown in 10 subjects (25%) in the ZX008 0.8 mg / kg / day group, 5 subjects (12.8%) in the ZX008 0.2 mg / kg / day group, and 0 subjects in the placebo group.

[0225] Quality of life Subjects in both active treatment groups experienced a significant improvement in quality of life based on the total score of the Pediatric Quality of Life Measure (PEDS-QL) (Table 2). However, no significant changes were seen in the QOLCE.

[0226] Safety TEAEs were reported in 65% of subjects in the placebo group and 95% of subjects in each ZX008 dose group. A summary of non-cardiovascular adverse events occurring in ≥10% of patients in either treatment group is shown in Table 3. The most common non-cardiovascular adverse events reported in patients treated with ZX008 were decreased appetite, diarrhea, pharyngitis, somnolence, drowsiness, and fever. Of the patients with TEAEs, 93% had mild to moderate severity; 24 (92.3%) of 26 patients, 35 (94.6%) of 37 patients, and 35 (92.1%) of 38 patients in the placebo, 0.2 mg / kg / day, and 0.8 mg / kg / day groups, respectively.

[0227] Since fenfluramine was sold as an appetite suppressant at high doses, weight was monitored over the study period, and any change of ≥7% from baseline was considered clinically significant. Overall, in the placebo group, 1 subject (2.5%) lost weight (up to 8.0% at the 8th visit), and 9 subjects (22.5%) had weight gain in the range of 7.4% - 17.1% predicted for pediatric studies. In the ZX008 0.2 mg / kg / day group, 5 subjects (12.8%) had weight loss in the range of 8.4% - 21.9%; 1 subject with 21.9% weight loss received nutritional guidance to manage her weight during the clinical trial. Another subject with 15.3% weight loss was diagnosed with diabetes immediately prior to enrollment in the study and was also managed for weight loss. 1 subject in the 0.2 mg / kg / day group had 10.3% weight gain during the study. In the ZX008 0.8 mg / kg / day group, 8 subjects (20.0%) had weight loss in the range of 7.2% - 11.4% of baseline weight. 1 subject in the ZX008 0.8 mg / kg / day group discontinued due to, among other adverse events, decreased appetite and weight loss. However, the weight loss was less than 1 kg. There were no deaths in this trial.

[0228] Serious adverse events occurred in 4 subjects (10.0%) in the placebo group, 4 subjects (10.3%) in the ZX008 0.2 mg / kg / day group, and 5 subjects (12.5%) in the ZX008 0.8 mg / kg / day group. These adverse events were mainly hospitalizations related to the disease under study, including status epilepticus in 2 placebo subjects (5.0%), 1 ZX008 0.2 mg / kg / day subject (2.6%), and 2 ZX008 0.8 mg / kg / day patients (5%).

[0229] Compared to baseline, subjects randomly assigned to ZX008 0.8 mg / kg / day achieved statistically significant improvements in both the BRIEF Behavior Regulation Index (BRI) (P<0.05) and the Global Executive Composite (GEC) (P<0.05) compared to placebo, and subjects in the ZX008 0.2 mg / kg / day group achieved a significant improvement in the BRI (P<0.05; Table 2). The BRI represents the ability of children to shift cognitive set via appropriate inhibitory control and regulate affect and behavior, and the GEC is an aggregate score incorporating all 8 clinical scales of the BRIEF. No changes in the BRIEF-P were seen.

[0230] During the course of Study 1, 5 subjects (12.5%), 7 subjects (17.9%), and 9 subjects (22.5%) in the placebo, ZX008 0.2 mg / kg / day, and ZX008 0.8 mg / kg / day groups, respectively, had at least 1 echocardiogram finding with evidence of mitral regurgitation and / or aortic regurgitation. No cases of clinically or FDA-defined valvular heart disease (mild or severe aortic regurgitation or moderate or severe mitral regurgitation) or pulmonary hypertension were observed. No clinically significant signs or symptoms characteristic of cardiovascular disease were seen at any time point.

[0231] Discussion Dravet syndrome is a severe, treatment-resistant, childhood-onset epilepsy condition characterized by high seizure burden with significant comorbidities of neurodevelopmental abnormalities, movement abnormalities, and behavioral abnormalities. In addition, the syndrome is characterized by a high mortality rate, most commonly due to status epilepticus and SUDEP. A Dravet-specific SUDEP rate of 9.32 per 1,000 person-years has been reported, which is substantially higher than that reported in the general population of patients with epilepsy.

[0232] In this trial, ZX008 showed a highly statistically significant and clinically meaningful dose-dependent decrease in the frequency of early-onset and sustained seizures. In particular, the significantly higher response rates compared to placebo in patients showing a ≥50% and ≥75% decrease in the frequency of seizures further support the strong antiseizure efficacy of ZX008 in subjects with Dravet syndrome. These effects were evaluated as clinically important by both treating physicians and parents / caregivers who assessed a significantly higher proportion of ZX008-treated subjects as having "moderate improvement" or "marked improvement" compared to subjects in the placebo group.

[0233] Neurological comorbidities, including in particular developmental delay, cognitive dysfunction, and behavioral problems, are common in patients with Dravet syndrome, and the latest literature supports the concept that the seizure frequency may be at least partly related to the magnitude of these neurological deficits. In this trial, ZX008 was associated with a marked decrease in mean MCSF in 45% of subjects in the 0.8 mg / kg / day group who experienced a ≥75% reduction. In this trial, a significant improvement in some measures of quality of life began to emerge. The BRIEF was included as a safety measure to assess whether the treatment had any negative effect on cognitive function. The results showed that this was not the case. Rather, a statistically significant improvement was recorded in some of the BRIEF executive function index scores, and the placebo group deteriorated on all three indices. There is a hypothesis that the magnitude of the decrease in MCSF may contribute to the improvement in cognitive function. This concept is supported by a report from Catarino et al. who conducted a retrospective study of a cohort of 22 adult patients with Dravet syndrome and found 3 patients who had experienced an improvement in seizure control as well as an improvement in cognitive function after switching to an appropriate AED. Further analysis of the entire Phase 3 patient population, including long-term evaluations from the safety extension trial, confirms that it is sufficient to characterize the impact of the treatment on quality of life and executive function.

[0234] ZX008 generally showed good tolerability in this trial. The safety profile of ZX008 for non-cardiovascular events was similar to that reported for fenfluramine from the Belgian cohort, and somnolence and decreased appetite were commonly reported in this trial in patients treated with ZX008 compared to placebo. Since fenfluramine was previously marketed as an appetite suppressant, it is not unexpected that 21% - 38% of subjects in the active treatment groups experienced a decrease in appetite, but little meaningful weight loss was reported (13% and 20% in the ZX008 0.2 and 0.8 mg / kg / day groups, respectively). Serious adverse events occurred at similar frequencies between treatment groups, and most were related to DS symptoms.

[0235] Cardiovascular safety remains a major concern in the use of ZX008 for the treatment of patients with Prader-Willi syndrome. Fenfluramine was marketed as a weight loss treatment from the 1960s through the late 1990s, typically at doses of 60-120 mg / day, often in off-label combination with phentermine, another appetite suppressant. Concerns about cardiovascular safety emerged in the 1990s when the use of fenfluramine was reported to be associated with an increased risk of primary pulmonary hypertension and valvular heart disease. Based on these reports, fenfluramine was withdrawn from the worldwide market in early 1997. The magnitude of the risk of valvular heart disease associated with fenfluramine is complicated by the fact that the pre-treatment prevalence of heart valve disease in the obese adult population was unknown and that phentermine was often used in combination with fenfluramine. A recent review of nine comparative trials of fenfluramine and related drugs in adults treated for obesity reported that the prevalence of mild or severe aortic regurgitation was 9.6% compared to 3.9% in the control group, and the prevalence of moderate and severe mitral regurgitation was 3.1% compared to 2.5% in the control group. Higher doses of fenfluramine were reported by Li et al. to have resulted in an increased risk of valve dysfunction, as analyzed in the original cases cited by the FDA and described as having a significantly higher relative risk of severe valvular heart disease in obese adults taking ≥60 mg / day compared to those taking <40 mg / day.

[0236] In this study, all subjects were treated with ZX008 at ≤30 mg / day and were carefully monitored regularly to identify functional changes in heart valves. During the 14-week treatment period and the 2-week transition period, no cases of valvulopathy or pulmonary hypertension were observed at any time point or in any subject at the end of the maintenance period. Only traces of mitral regurgitation and / or traces of aortic regurgitation, which are commonly found in the general population and not recognized as abnormal by current guidelines, were observed. The prevalence of traces of regurgitation in young patients with Dravet syndrome is unknown, but 23 out of 173 patients (13.3%) screened for participation in this study were excluded due to the presence of traces of mitral regurgitation at ECHO screening.

[0237] (Table 1) Demographics and baseline seizure frequency TIFF2025113312000005.tif132169

[0238] (Table 2) Analysis of secondary evaluation items TIFF2025113312000006.tif199170TIFF2025113312000007.tif193170 a Since only a small number of subjects showed a 100% reduction in seizure frequency, model statistics such as odds ratios are not reported. b The results of QOLCE did not show a statistically significant change from placebo. c An increase in the total score indicates improvement. d BRIEF was a safety evaluation item. e Since some countries do not have a normative population for BRIEF, only the raw scores are presented here. f A negative score indicates improvement. g The results of BRIEF-P revealed no statistical difference from placebo.

[0239] (Table 1) Clinical Global Impression of Improvement, Parent / Caregiver Assessment at Baseline (Start of Study 1503) and at Final Visit (mITT Population) TIFF2025113312000008.tif164162TIFF2025113312000009.tif118162Abbreviations: CGI = Clinical Global Impression; CI = Confidence Interval; Max = Maximum; mITT = Modified Intention-to-Treat Population; Min = Minimum; OL = Open Label; SE = Standard Error. a Exact Clopper-Pearson two-sided CI for percentage of subjects with that response

[0240] (Table 2) Clinical Global Impression of Improvement, Investigator Assessment at Baseline (Start of OLE) and at Final Visit (mITT Population) TIFF2025113312000010.tif52162TIFF2025113312000011.tif225162Abbreviations: CGI = Clinical Global Impression; CI = Confidence Interval; Max = Maximum; mITT = Modified Intention-to-Treat Population; Min = Minimum; OL = Open Label; SE = Standard Error. a Exact Clopper-Pearson two-sided CI for percentage of subjects with that response

[0241] Example 3 Examination of Treatment with Fenfluramine and Improvement in Cognitive Function Evaluated by BRIEF in Lennox-Gastaut Syndrome (LGS) In this two-part study of fenfluramine HCl in pediatric and adult patients with LGS, Part 1 is a randomized double-blind placebo-controlled trial of two fixed doses of oral solution of fenfluramine HCl as adjunctive therapy for seizures in pediatric and adult patients with LGS; Part 2 is open label.

[0242] Extension to Evaluate Long-Term Safety of ZX008 in Pediatric and Adult Patients with LGS

[0243] In this study conducted in LGS patients, the BRIEF is administered on the 15th visit, on the first day of the study.

[0244] The ZX008 formulation is an oral aqueous solution of fenfluramine hydrochloride buffered to pH 5 and provided at concentrations of 1.25 mg / mL, 2.5 mg / mL, and 5 mg / mL. The excipients selected are approved for use in the formulations of currently marketed drugs and are considered safe. The solution formulation is appropriately flavored and contains preservatives and thickeners. The formulation is sugar-free and is intended to be compatible with KD.

[0245] The first part of the formulation is provided in bottles with child-resistant safety caps. The clinical trial material is supplied in a single-bottle size with a nominal fill volume of 120 mL. A matching placebo is also provided. The doses to be tested include ZX008 0.2 mg / kg / day and ZX008 0.8 mg / kg / day divided into twice-daily doses (BID) up to a maximum of 30 mg / day (subjects taking the concomitant agent STP receive up to 20 mg / kg / day, either 0.2 mg / kg / day or 0.5 mg / kg / day). An intermediate dose of 0.4 mg / kg / day is used for dose escalation. To ensure blinding, the concentration of the ZX008 oral solution (1.25 mg / mL, 2.5 mg / mL, and / or 5 mg / mL) received by the subjects is randomly assigned across the three available concentrations.

[0246] In the second part, the doses to be tested include 0.2 mg / kg / day, 0.4 mg / kg / day, 0.6 mg / kg / day, and 0.8 mg / kg / day divided into twice-daily doses up to a maximum of 30 mg / day (subjects taking the concomitant agent STP receive up to 20 mg / kg / day, either 0.2 mg / kg / day, 0.4 mg / kg / day, or 0.5 mg / kg / day). The ZX008 formulation is provided at a concentration of 2.5 mg / mL in a single-bottle size with a nominal fill volume of 120 mL.

[0247] The foregoing merely illustrates the principles of the present invention. It is understood that those skilled in the art can devise various adaptations that embody the principles of the present invention and are within the spirit and scope thereof, although not explicitly described or shown herein. Further, all examples and conditional descriptions set forth herein are principally intended to assist the reader in understanding the principles of the present invention and the concepts contributing to the advancement of the art made by the inventors, and are to be construed as not limiting to such specifically described examples and conditions. Additionally, all descriptions in this specification that state the principles, aspects, and embodiments of the present invention, as well as the specific examples thereof, are intended to encompass both their structural and functional equivalents. Moreover, such equivalents are intended to include both currently known equivalents and equivalents developed in the future, i.e., any element developed that performs the same function regardless of structure. Accordingly, the scope of the present invention is not intended to be limited to the exemplary embodiments shown and described herein. Rather, the scope and spirit of the present invention are embodied by the appended claims.

Claims

Claim 1 A formulation for use in improving neurological function, evaluated by observing at least one rank level of statistically significant improvement in a patient using BRIEF examination, said formulation comprising fenfluramine or a pharmaceutically acceptable salt thereof and wherein said use is for said repeated administration over several days until the patient shows improvement in the BRIEF score as compared to a previous BRIEF score obtained prior to said repeated administration said formulation for said use Claim 2 The formulation for use according to claim 1, wherein the patient is diagnosed with a disease or condition selected from epilepsy or epileptic encephalopathy (e.g., Dravet syndrome, Doose syndrome, infantile spasms, Lennox-Gastaut syndrome); attention disorders (e.g., attention deficit disorder (ADD) or attention deficit hyperactivity disorder (ADHD)); autism spectrum disorder (ASD) including autism, Asperger's syndrome, pervasive developmental disorder (PDD) and pervasive developmental disorder not otherwise specified (PDD-NOS); oppositional defiant disorder (ODD); learning disorders (e.g., dyslexia, dyscalculia); Tourette syndrome; traumatic brain injury; lead exposure; anxiety and / or depressive states; and low birth weight, or any combination thereof Claim 3 The formulation for use according to claim 1, wherein the patient is diagnosed with either Dravet syndrome or Lennox-Gastaut syndrome Claim 4 The formulation for use according to any one of claims 1 to 3, further comprising a co-therapeutic agent Claim 5 The formulation for use according to any one of claims 1 to 4, wherein fenfluramine is formulated with a pharmaceutically acceptable carrier and administered at an effective dose selected from less than about 10.0 mg / kg / day, less than 1.0 mg / kg / day, about 0.8 mg / kg / day, about 0.5 mg / kg / day, about 0.2 mg / kg / day, and about 0.01 mg / kg / day Claim 6 The formulation for use according to any one of claims 1 to 5, wherein fenfluramine is administered in an administration form selected from the group consisting of oral, injectable, transdermal, inhaled, nasal, buccal, rectal, intravaginal, and parenteral delivery Claim 7 The formulation for use according to any one of claims 1 to 6, wherein the administration form is an oral composition administered in an amount selected from the group consisting of 30 mg / day or less, 20 mg / day or less, 10 mg / day or less, and 5 mg / day or less Claim 8 A preparation for use according to any one of claims 1 to 7, wherein at least one co-therapeutic agent is administered, and the agent is selected from the group consisting of brivaracetam, bromides (e.g., potassium bromide, sodium bromide), cannabidiol, carbamazepine, clonidine, ergogenil chrono, ethosuximide, felbamate, fosphenytoin, lacosamide, lamotrigine, levetiracetam, levocarnitine, mesuximide, nitrazepam, oxcarbazepine, perampanel, phenobarbital, pregabalin, progabide, pyridoxine, rufinamide, sulthiame, tizanidine, topiramate, stiripentol, semisodium valproate, sodium valproate, valproic acid, verapamil, zonisamide, and benzodiazepines, e.g., clobazam, clonazepam, diazepam, ethyl loflazepate, lorazepam, and midazolam, and pharmaceutically acceptable salts or bases thereof.

9. The administration continues for a period such as to improve cognitive function as indicated by improvement in at least one BRIEF score, the period being selected from the group consisting of 1 month, 2 months, 3 months, 6 months, 9 months, 12 months, 15 months, 18 months, 21 months, 2 years, and 3 years, The improvement in cognitive function is evaluated by observing a statistically significant improvement in at least one BRIEF score at an improvement rate selected from the group consisting of 5% or more, 10% or more, 15% or more, 25% or more, 50% or more, or 75% or more, a preparation for use according to any one of claims 1 to 8.

10. A fenfluramine preparation; Packaging; and A package insert including instructions for use in improving cognitive function as evaluated by improvement in at least one BRIEF score in a patient comprising a kit.

11. A container containing multiple doses of a preparation comprising a pharmaceutically acceptable carrier and an active ingredient comprising fenfluramine; and Instructions for treating a patient with the preparation and for evaluating the patient's BRIEF score before and after treatment with the preparation comprising a kit.

12. A preparation for use in improving the Behavioral Rating Inventory of Executive Function (BRIEF) score in a patient, the preparation comprising fenfluramine or a pharmaceutically acceptable salt thereof and the use being for repeated administration once or twice daily over a period of time, The period is selected from the group consisting of 1 month, 2 months, 3 months, 6 months, 9 months, 12 months, 15 months, 18 months, 21 months, 2 years, and 3 years and 3 months, A formulation for said use, wherein the improvement in the BRIEF score is obtained as compared to the patient's previous BRIEF score obtained prior to at least some of the repeated administrations. **Claim 13** A formulation for use in the treatment of a patient, the formulation comprises a therapeutically effective amount of fenfluramine or a pharmaceutically acceptable salt, base, or acid thereof and the use is for repeated administration over several days until the patient shows an improvement in the Clinical Global Impression (CGI) rank as compared to the previous CGI obtained prior to repeated administration of the formulation. A formulation for said use. **Claim 14** A formulation for use in the treatment of a patient diagnosed with Dravet syndrome, the formulation comprises a therapeutically effective amount of fenfluramine or a pharmaceutically acceptable salt, base, or acid thereof in an amount of 0.2 mg / kg / day or more and up to 30 mg / day; a co-therapeutic agent and the co-therapeutic agent and fenfluramine are for use in repeated administration over several weeks until the patient shows an improvement in the Clinical Global Impression (CGI) rank as compared to the previous CGI obtained prior to repeated daily administration of the formulation, and is a liquid formulation. A formulation for said use. **Claim 15** The formulation for use according to claim 14, wherein the co-therapeutic agent is selected from the group consisting of carbamazepine, ethosuximide, phenytoin, lamotrigine, levetiracetam, phenobarbital, topiramate, valproic acid, valproate, verapamil, and benzodiazepines, such as clobazam, clonazepam, diazepam, lorazepam, and midazolam, and pharmaceutically acceptable salts or bases thereof.

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