Treatment of behavioral disorders in developmental and epileptic encephalopathy

Abstract

The present technology relates to a method of treating behavioral problems and seizures in a subject with developmental and epileptic encephalopathy (DEE) by transdermally administering an effective amount of cannabidiol (CBD) to the subject, wherein the behavioral problems are treated in the subject.

Description

Technical Field

[0001] Related Applications This application claims the benefit of U.S. Provisional Application No. 62 / 901,651, filed on September 17, 2019. The entire disclosure of the above application is incorporated herein by reference.

[0002] The present disclosure relates to a method of treating behavioral problems in pediatric epilepsy disorders by transdermally administering an effective amount of cannabidiol (CBD) to a subject that requires it.

Background Art

[0003] Although individually rare, developmental and epileptic encephalopathies (DEEs), including especially Lennox-Gastaut syndrome and Doose syndrome, impose a substantial collective personal, medical, and financial burden on affected children and their families, healthcare providers, and the healthcare system. Stafstrom et al., "Epileptic Encephalopathy in Infants and Children" Epilepsy Curr 16(4):273-279 (2016). Patients with DEE not only have seizures, as is obvious from the name, but also independently experience cognitive and behavioral problems such as deficits in social communication. Scheffer et al., "ILAE classification of the epilepsies: Position paper of the ILAE Commission for Classification and Terminology" Epilepsia 58(4):512-521 (2017). This affects the overall quality of life of children with DEE from childhood, even when seizures can be addressed by one or a combination of anti-seizure medications. Also, because epileptic encephalopathies are highly resistant to treatment, failure of treatment to improve either seizures or the encephalopathy is common. Vigevano et al., "Therapeutic approach to epileptic encephalopathies" Epilepsia 54:45-50 (2013).

[0004] Cannabinoids are a class of chemical compounds found in the cannabis plant. The two main cannabinoids found in cannabis are cannabidiol, or CBD, and Δ9-tetrahydrocannabinol, or THC. CBD lacks the psychoactive effects of THC. Studies have shown that CBD can be used to treat conditions such as epilepsy, arthritis, and cancer.

[0005] EPIDIOLEX oral CBD solution is approved for the treatment of epilepsy in children with Lennox-Gastaut and Dravet syndromes. However, oral delivery can lead to gastrointestinal (GI) adverse events; for example, EPIDIOLEX label reported somnolence and sedation in 32% of its patients, which were dose-related. (EPIDIOLEX Cannabidiol Oral Solution label, June 2018). Oral CBD also has the potential to degrade to THC in stomach acid, which may be associated with undesirable psychostimulant effects. (Ibid.)

[0006] In patients with DEE, treatment for behavioral problems is required in addition to seizures. Treatment that does not produce undesirable side effects such as somnolence, lethargy, withdrawal, and sedation is also necessary, as these can negate any benefits of behavioral symptoms or worsen the effects of behavioral problems. [Prior art documents] [Non-patent literature]

[0007] [Non-Patent Document 1] Stafstrom et al., “Epileptic Encephalopathy in Infants and Children” Epilepsy Curr 16(4):273-279(2016) [Non-Patent Document 2] Scheffer et al., “ILAE classification of the epilepsies: Position paper of the ILAE Commission for Classification and Terminology” Epilepsia 58(4):512-521 (2017) [Non-Patent Document 3] Vigevano et al., “Therapeutic approach to epileptic encephalopathies” Epilepsia 54:45-50 (2013) [Overview of the Initiative]

[0008] This disclosure relates to a method for treating behavioral problems and seizures in subjects with developmental and epileptic encephalopathy (DEE), comprising administering an effective amount of cannabidiol (CBD) transdermally to the subject, wherein the behavioral problems are treated in the subject. Subjects with developmental and epileptic encephalopathy (DEE) include subjects with SYNGAP1 encephalopathy.

[0009] On Friday, May 31, 2019, the U.S. Food and Drug Administration's Center for Applied Nutritional Safety held a public lecture (Part 15) titled "Scientific Data and Information on Products Containing Cannabis or Cannabis-Derived Compounds." Monica Weldon, President and CEO of Bridge the Gap, a SYNGAP Education and Research Foundation, spoke publicly. Monica Weldon spoke about the need to treat SYNGAP. She began her speech by helping to explain the perspective of parents of children with SYNGAP symptoms: Imagine being told there are no FDA-approved products for your child. Imagine your child suffering from a rare genetic disorder that doctors barely understand, characterized by seizures, mood disorders, and the inability to communicate because the child does not speak. To treat your child's challenges, even if it's just to find out what the problem is, try to think from the perspective of a parent or caregiver, different from your child.

[0010] Now, let's insert CBD. Despite its misleading descriptions, derivative products, ambiguous dosage recommendations, and panacea marketing, it has since created an ambiguous legal environment around it, now giving rise to the Wild West of CBD.

[0011] Like many advocates for rare childhood diseases, the inventors are particularly keen on emerging therapies that aim to help children.

[0012] Patients and their families rely on the inventors for guidance and reliable educational materials regarding potential treatments, especially since the inventors are working closely with researchers to develop targeted therapies for SYNGAP1. The inventors do not have an approved targeted therapy for children. Therefore, the inventors are focusing on short-term repurposing of drug and natural therapies to alleviate SYNGAP1 symptoms.

[0013] CBD-based pharmaceuticals and OTC CBD products are constantly in the spotlight. The biggest challenge for the inventors as an organization is how to address them. At this stage, the inventors believe further scientific investigation is needed regarding safety, efficacy, product integrity, and drug interactions, and that further CBD research will answer many of the inventors' questions.

[0014] This disclosure addresses a need discussed by the President and CEO of Bridge the Gap, a SYNGAP Educational Research Foundation. This disclosure relates to a method for treating DEE, including SYNGAP1 encephalopathy, by transdermal administration of an effective dose of cannabidiol (CBD) to a subject, wherein one or more symptoms, such as behavioral problems, are treated in the subject.

[0015] In some embodiments, seizures are also treated. In some embodiments, seizures are treated so that the subject is a 35% responder, 50% responder, or 90% responder within 30 days.

[0016] The effective dose of CBD may be approximately 250 mg to 1000 mg per day. In some embodiments, the effective dose of CBD is started at approximately 250 mg per day and titrated up to a daily dose of approximately 500 mg or approximately 1000 mg per day. The effective dose of CBD can be started at approximately 50 mg per day and titrated up to approximately 250 mg per day. In some embodiments, the effective dose of CBD is started at 250 mg per day. The effective dose of CBD can be started at 500 mg per day. In some embodiments, the daily doses of 500 mg and 1000 mg are administered to patients weighing more than 25 kg. CBD can be administered in once-daily or twice-daily doses. In some embodiments, the effective dose is 750 mg or 1000 mg per day.

[0017] CBD can be formulated as a gel. In some embodiments, CBD is formulated as a permeability-enhancing gel. The gel can contain 1% (wt / wt) to 7.5% (wt / wt) of CBD. In some embodiments, the gel contains 4.2% (wt / wt) of CBD. In some embodiments, the gel contains 7.5% (wt / wt) of CBD.

[0018] In some embodiments, the transdermal formulation can be a cream, ointment, lotion, or balm. CBD can be delivered by a bandage, pad, or patch.

[0019] CBD can be transdermally administered to the upper arm and shoulder of a subject. In some embodiments, CBD is transdermally administered to the thigh or back of the subject.

[0020] CBD can be synthetic CBD. CBD can be purified CBD. CBD can be plant-derived.

[0021] When an effective amount of cannabidiol (CBD) is transdermally administered, it can reduce the intensity of at least one adverse event or side effect compared to oral administration of CBD. The at least one adverse event or side effect can be a gastrointestinal (GI) adverse event. The at least one adverse event or side effect can be liver function. In some embodiments, the at least one adverse event is drowsiness. In some embodiments, the frequency and intensity of drowsiness decrease as an adverse event.

Brief Description of the Drawings

[0022] [Figure 1] Table of decrease in seizure frequency and responder rate exceeding 50%.

Modes for Carrying Out the Invention

[0023] A method of treating behavioral problems and seizures in a subject having developmental and epileptic encephalopathy (DEE) by transdermally administering an effective amount of cannabidiol (CBD) to the subject, wherein the behavioral problems are treated in the subject, is provided herein. Subjects having developmental and epileptic encephalopathy (DEE) include subjects having SYNGAP1 encephalopathy.

[0024] The study summarized in the examples—a Phase 2 open-label clinical trial—evaluated the safety and efficacy of transdermal administration of CBD in developmental and epileptic encephalopathy (DEE), a heterogeneous group of rare childhood epilepsy syndromes including Dravet syndrome (DS) and Lennox-Gastaut syndrome (LGS). The most common and debilitating seizure types in people with epilepsy are focal impairment and convulsive seizures. Patients experiencing these seizure types achieved a median monthly reduction of 44%–58% in seizures compared to baseline at 2–6 months of treatment. Qualitative assessments by caregivers in the study showed improved mood, social interaction, learning ability, arousal, school attendance, and improved behavioral problems, including cognitive symptoms of DEE.

[0025] definition As used herein, the terms “to treat” or “to cure” mean to alleviate, improve, reduce or mitigate at least one symptom (such as a behavioral symptom) of a condition, disease or disorder in a subject such as a human, or to improve a verifiable measure related to the condition, disease or disorder.

[0026] As used herein, the term “clinical efficacy” refers to the ability to produce the desired effect in humans, as demonstrated through the Food and Drug Administration (FDA) or any corresponding foreign clinical trial.

[0027] As used herein, the terms “cannabidiol” or “CBD” refer to pharmaceutically acceptable derivatives of cannabidiol, including cannabidiol; cannabidiol prodrugs; pharmaceutically acceptable salts of cannabidiol; cannabidiol prodrugs and cannabidiol derivatives. CBD includes 2-[3-methyl-6-(1-methylethenyl)-2-cyclohexen-1-yl]-5-pentyl-1,3-benzenediol and their pharmaceutically acceptable salts, solvates, metabolites (e.g., cutaneous metabolites) and metabolic precursors. The synthesis of CBD is described, for example, in Petilka et al., Helv. Chim. Acta, 52:1102 (1969) and Mechoulam et al., J. Am. Chem. Soc., 87:3273 (1965), which are incorporated herein by reference.

[0028] The term "epileptic encephalopathy" refers to epileptic activity that contributes to severe cognitive and behavioral problems beyond what would be expected from the underlying condition alone (e.g., cortical malformations). The onset of these disorders can occur at any age.

[0029] The term “developmental and epileptic encephalopathy” or “DEE” refers to a severe epileptic disorder that develops in infancy and childhood. DEE is characterized by the presence of multiple focal and generalized seizure types, as well as severe cognitive and behavioral problems. In DEE, cognitive and behavioral problems may occur independently of seizure activity, even before seizures become frequent, suggesting a developmental component in addition to the epileptic component of DEE. Such problems may occur early or worsen over time. Scheffer, “ILAE classification of the epilepsies: Position paper of the ILAE Commission for Classification and Terminology,” Epilepsia 58(4):512-521, 2017. DEE includes hereditary epilepsies such as CDKL5, SCN1A, and STXBP1-related disorders. This includes Lennox-Gastaut syndrome (LGS), Otawara, West, Landau-Klefner, Douse, Dravet syndrome (DS), and infantile seizures (IS).

[0030] As used herein, the term “behavioral problems” means behavioral defects or regressions such as defects or regressions in social communication, mood, confrontational and defiant behavior, tantrums and self-injury, or speech disorders.

[0031] As used herein, the term “administer transdermally” means bringing CBD into contact with the skin of a patient or subject under conditions that are effective for CBD to penetrate the skin.

[0032] The term developmental and epileptic encephalopathy (DEE) was recently introduced by the International League Against Epilepsy (ILAE) Task Force on Classification and Terminology (Scheffer et al., 2017) to more fully describe the clinical manifestations of coexisting developmental disorders and epileptic encephalopathy. Historically, epileptic encephalopathy was used more broadly to encompass both concepts without using the term “developmental.” In 2001, the ILAE recognized epileptic encephalopathy as a distinct category. Engel, “A proposed diagnostic scheme for people with epileptic seizures and with epilepsy: report of the ILAE Task Force on Classification and Terminology,” Epilepsia 42:796-803 (2001). The ILAE defined epileptic encephalopathy as a condition in which “epileptic-like EEG abnormalities themselves are thought to contribute to progressive impairment of brain function.” In 2010, the ILAE redefined epileptic encephalopathy as a condition in which epileptic activity itself can contribute to severe cognitive and behavioral problems beyond those that might be expected from the underlying pathology alone (e.g., cortical malformations), and which may worsen over time. (Berg et al., "Revised terminology and concepts for organization of seizures and epilepsies: report of the ILAE Commission on Classification and Terminology, 2005-2009," Epilepsia 51:676-685 (2010)).

[0033] The latest change to include "developmental" in the description was made to enable a specific distinction between patients presenting with both developmental disorders and epileptic encephalopathy and patients presenting with developmental disorders without a pre-existing developmental background and without high-frequency epileptic activity associated with developmental disorders or epileptic encephalopathy. A key component of this concept is that improvement in epileptic activity may have the potential to improve the developmental outcomes of the disorder (Scheffer et al., 2017).

[0034] The overall incidence and prevalence of developmental epileptic encephalopathy (DEE) are low. Patients with DEE may include, but are not limited to, those with genetic disorders such as Lennox-Gastaut syndrome, Dravet syndrome, Douse syndrome (epilepsy with myoclonic cataplexy (EMAS)), West syndrome (infantile seizures), Landau-Kleffner syndrome, or CDKL5 encephalopathy and CHD2 encephalopathy.

[0035] Seizures in patients with DEE are generally refractory to standard antiepileptic drugs (AEDs). Consequently, more aggressive adjunctive use of AEDs is often considered, as they are thought to be effective in suppressing interictal epileptic discharges (e.g., benzodiazepines, valproic acid, and lamotrigine), immunomodulatory therapies (e.g., corticosteroids, intravenous immunoglobulin [IVIG], plasmapheresis), ketogenic diets, and surgical options.

[0036] Patients with DEE may present with various seizure types and sub-disorders, but the only DEE subtypes for which one or more AEDs are currently approved by the U.S. FDA for adjunctive therapy are Lennox-Gastaut syndrome, Dravet syndrome, and infantile seizures (Table 1).

[0037] [Table 1]

[0038] Given the treatment refractory nature and the limited number of approved drugs for which there is evidence from controlled trials, clinicians are often forced to use standard AEDs on a trial-and-error basis, primarily based on clinical experience or open-label trials. Lennox-Gastaut syndrome and Dravet syndrome were the DEE subtypes for which the most evidence from controlled trials of antiepileptic drugs has been generated.

[0039] Vlaskamp et al. investigated a patient cohort of 57 patients (53% male, median age 8 years) with SYNGAP1 mutations or microdeletions. Vlaskamp et al., "SYNGAP1 encephalopathy: A distinctive generalized developmental and epileptic encephalopathy," Neurology 2019;92:e96-e107 (2019). Table 2 outlines the phenotypic profiles of SYNGAP1 patients with mutations, variants, or microdeletions.

[0040] [Table 2] TIFF0007870724000003.tif87159

[0041] In Table 2, the following abbreviations indicate that EM is blepharoplasty (with or without absence) and ID is intellectual disability. Where patient information was missing, a common factor was added representing the number of patients for whom known information about this variable was available. If no common factor was provided, information was available for all patients. Feeding problems included insufficient intake, uncontrolled eating due to binge eating, eating inedible objects, difficulties in transitioning from liquid to solid foods in infancy, and difficulties with chewing and swallowing.

[0042] Furthermore, regarding Table 2, developmental delay was identified immediately after birth in 55 out of 56 patients (96%), and in all cases it preceded the onset of seizures. In 56 patients, development regressed or stalled with the onset of seizures. Language was severely impaired, and 12 patients were nonverbal between the ages of 2 and 33. ID was present in 55 out of 57 patients, with moderate to severe in 50 and mild in 5. Behavioral problems were observed in 41 out of 56 patients (73%), often severe and accompanied by aggression, self-injurious behavior, and tantrums. ASD was diagnosed in 30 patients (53%).

[0043] University of Washington Caregiver Stress Scale (UW-CSS) The UW-CSS measures the stress experienced by caregivers of children under 18 years of age and was developed to address areas of significant stress for caregivers of children with severe epilepsy. University of Washington Caregiver Stress Scale (UW-CSS) Version 1 User Guide 2017; Jensen et al., "The impact on the lives of caregivers of children with severe epilepsy: Results from expert panel and caregiver focus groups," Epilepsy Behav (2017).

[0044] Quality of Life (ELDQOL) for Epilepsy and Learning Disabilities The Epilepsy and Learning Disability Quality of Life (ELDQOL) scale is a questionnaire that covers seizure severity, seizure-related injuries, AED side effects, behavior, mood, physical, cognitive and social functioning, parental attention, communication, overall quality of life, and overall health.

[0045] Sleep Disturbance Scale for Children (SDSC) The SDSC was created to assess sleep disorders in children and provide a comprehensive measure of sleep disturbance suitable for use in clinical screening and surveys. Developers Bruni et al. developed six categories representing sleep difficulties affecting children aged 6–15 years: sleep onset and maintenance, sleep-disordered breathing, wakefulness / nocturnal sleep, sleep-wake transition, hypersomnolence, and sleep hyperhidrosis (nocturnal sweating). Bruni et al., "The Sleep Disturbance Scale for Children (SDSC)." Development and validation of an instrument for assessing sleep disorders in childhood and adolescence, J Sleep Res 5(4):251-61 (1996). Patients / parents use a 5-point scale to indicate frequency from 1 (never) to 5 (always). Higher scores indicate more acute sleep disturbance. Scores are tallied for each of the six sleep disorder categories to calculate an overall score. Shahid et al. (eds.), STOP, THAT and 100 Other Sleep Scales 82:331-332 (Springer Science+Business Media, LLC 2012).

[0046] Vineland Adaptive Behavior Scale TM (VABS-3) The VABS-3 is a individually administered scale of adaptive behavior in four domains: communication, daily living skills, socialization, and motor skills. It also provides a composite score that summarizes an individual's performance across all four domains. It is widely used in the assessment of individuals with intellectual, developmental, and other disabilities.

[0047] Qualitative caregiver feedback Qualitative assessment of improvement, deterioration, or no change in daily activities, school attendance, and wakefulness for the patient and family, but not limited to these. In the example, clinicians were asked to record qualitative caregiver feedback at week 26 by asking the following questions: (1) "Have there been any improvements for [Patient Name] and their family since [Patient Name] used the gel?"; (2) "Have there been any deteriorations for [Patient Name] and their family since [Patient Name] used the gel?"; (3) "A few specific questions: Let me ask about their daily activities: For example, are they attending school? If so, how? Are they awake? If so, how?"

[0048] Transdermal pharmaceutical composition Transdermal delivery of cannabinoids (e.g., CBD) offers advantages over oral administration because it allows the drug to be absorbed directly into the bloodstream through the skin. This avoids first-pass hepatic metabolism, enabling lower dosage levels of the active pharmaceutical ingredient with higher bioavailability and an improved safety profile. Transdermal delivery also bypasses the gastrointestinal tract, reducing the opportunity for the potential breakdown of CBD to THC by stomach acid, which can be associated with GI-related adverse events and undesirable psychoactive effects. Furthermore, transdermal delivery of CBD reduces the intensity and frequency of somnolence, an adverse event typically present with oral administration of CBD. Transdermal delivery of CBD can also avoid hepatic adverse events typically present with oral administration of CBD. In some embodiments, transdermal administration of an effective dose of CBD reduces the intensity of at least one adverse event by approximately 15% to approximately 95% compared to oral administration of CBD.

[0049] CBD may be in gel form and can be pharmaceutically manufactured as a clear, permeability-enhancing gel designed to provide controlled transdermal drug delivery with once or twice-daily administration. CBD gels may contain 1% (wt / wt) to 7.5% (wt / wt) CBD. For example, a CBD gel may have 4.2% (wt / wt) or 7.5% (wt / wt) CBD. CBD gels can be applied topically by the patient or caregiver to the patient's upper arm and shoulder, back, thigh, or any combination thereof.

[0050] The CBD gel may contain diluents and carriers, as well as other conventional excipients such as wetting agents, preservatives, and suspending and dispersing agents.

[0051] CBD gels may contain solubilizers, permeation enhancers, antioxidants, bulking agents, thickeners, and / or pH adjusters. The composition of a CBD gel may be, for example, a. cannabidiol present in an amount of about 0.1% to about 20% (wt / wt) of the composition; b. a lower alcohol having 1 to 6 carbon atoms present in an amount of about 15% to about 95% (wt / wt) of the composition; c. a first permeation enhancer present in an amount of about 0.1% to about 20% (wt / wt) of the composition; and d. enough water to make the composition total 100% (wt / wt). Other formulations of CBD gels can be found in International Publication No. WO2010 / 127033, the full contents of which are incorporated herein by reference.

[0052] The effective dose of CBD can range from approximately 50 mg to 1000 mg per day, which can be administered once or twice daily. [Examples]

[0053] [Example 1] Trial of ZYN-002 in children with developmental epileptic encephalopathy This was a sequential, multistage, open-label, multinational, multicenter, multiple-dose study to evaluate the long-term safety and tolerability of ZYN002 (transdermal CBD gel) in pediatric and adolescent epilepsy patients aged 3 to 18 years with seizures associated with developmental and epileptic encephalopathy (DEE), according to the International League Against Epilepsy (ILEA) classification (Scheffer et al., 2017). Approximately 55 patients entered a 4-week baseline period, and 50 patients progressed to open-label treatment in period A (including a total of 24 or fewer patients with Lennox-Gastaut syndrome or Dravet syndrome).

[0054] During period A, patients underwent a 4-week baseline period, followed by a 4-week titration period and a 22-week flexible maintenance period. Patients were treated for a total of 26 weeks during period A.

[0055] In Period B, patients continued to receive ZYN002 for up to 46 more weeks at the same maintenance dose they had received at week 26 (e.g., end of Period A). At any point at the end of treatment, patients were required to complete tapering and follow-up periods. After the final tapering dose, patients were followed up by telephone weekly for 4 weeks to complete a short version of the marijuana withdrawal checklist (behavioral checklist). After 4 weeks of follow-up, patients were released from the study.

[0056] Patients received the study drug twice daily (every 12 ± 2 hours) for a 26-week treatment period and a 46-week extension period (total treatment duration of 72 weeks). At the end of treatment, patients were required to complete a tapering period of 1 to 3 weeks (depending on the dose).

[0057] Registered patients received an initial dose of ZYN-002 based on body weight, either 250 mg or 500 mg per day. Patients weighing 25 kg or less could be titrated up to 750 mg per day, while patients weighing over 25 kg could be titrated up to 1,000 mg per day.

[0058] Diagnostics and criteria for inclusion Patients participating in this study had been diagnosed with developmental and epileptic encephalopathy. The patients were between 3 and 18 years old, with body mass indices ranging from 13 to 35 kg / m². 2 Its weight was over 12 kg.

[0059] Patients had been diagnosed with developmental and epileptic encephalopathy (DEE) as defined by the International League Against Epilepsy Classification (Scheffer 2017) and had generalized motor symptoms (i.e., generalized tonic-clonic, tonic seizures, clonic seizures, cataplexy, epileptic spasms), focal motor awareness, focal impaired awareness, or bilateral tonic-clonic seizures originating from a focal point. Registered cases of DEE included, but were not limited to, Dravet syndrome, West syndrome / infant seizures, and Douze syndrome. The diagnosis must have been established for more than one year and must be validated by examination and review of a medical history and appropriate tests, including electroencephalography (EEG), magnetic resonance imaging (MRI) scans, or genetic testing.

[0060] During the baseline period, the patient experienced a total of five or more seizures of the following types: generalized motor (i.e., generalized tonic-clonic, tonic seizure, clonic seizure, atonic seizure, or epileptic convulsion), focal motor, focal impaired consciousness, or bilateral tonic-clonic seizures originating from a focal point. Clusters of epileptic convulsions were counted as single seizures.

[0061] The patient had a history of developmental delay involving regression, slowdown, or stagnation in at least one developmental area following the onset of seizures, as determined by the principal investigator.

[0062] Applicable area The approved application sites for the gel were the left and right upper arms, as shown in Table 3.

[0063] [Table 3]

[0064] If redness occurred at the application site, consult the principal investigator and temporarily apply ZYN002 to the upper thighs of both sides. In patients with a low BMI and / or small arms, ZYN002 was applied to the upper right or upper left thigh. The order of application was one sachet to each upper arm / shoulder and one sachet to each upper thigh.

[0065] When applied to the upper right and / or left thigh, the procedure was the same as that described for the left and right upper arms / shoulders. The caregiver applying the gel wore gloves. The caregiver ensured that the gel was fully rubbed in, that no gel remained on the glove, that the skin surface to which the gel was applied was no longer shiny, and that it was not dry to the touch before dressing. Upon completion of the treatment application, the patient / caregiver discarded the glove(s) and thoroughly washed their hands with soap and warm water. The caregiver was instructed to keep the application site dry from water for 6 hours or to avoid excessive sweating. The caregiver may apply an approved moisturizing lotion 2 hours after administration. The caregiver was instructed to cover the application site to minimize sun exposure when going out during the day.

[0066] Products, dosage, and mode of administration The product was ZYN002 (cannabidiol: CBD), a 4.2% gel for topical use. The drug was supplied in sachets containing 2.98 g of gel, delivering 125 mg of CBD per sachet. To achieve the appropriate total daily dose for each patient based on the treatment group, 1 to 4 sachets were used in the morning and evening.

[0067] The treatment was as follows: Treatment A: 125 mg of CBD Q12H (±2 hours); the total daily dose was 250 mg of CBD (one sachet in the morning and one in the evening).

[0068] Treatment B - 250 mg of CBD Q12H (±2 hours); the total daily dose was 500 mg of CBD (2 packets in the morning, 2 packets in the evening).

[0069] Treatment C-375mg of CBD Q12H (±2 hours); the total daily dose was 750mg of CBD (3 packets in the morning and 3 packets in the evening).

[0070] Treatment D - 500 mg of CBD Q12H (±2 hours); the total daily dose was 1000 mg of CBD (4 packets in the morning, 4 packets in the evening).

[0071] Period A: Baseline period During the 4-week baseline period, parents and / or caregivers recorded the number of seizures of the following types in a seizure diary: • Generalized tonic-clonic seizures ("primary generalized tonic-clonic" seizures) • Focus loss seizures • Focal origin bilateral tonic-clonic seizure • Focused seizures accompanied by motor symptoms • Tonic seizures • Clonic seizures • Cataplexy • Epileptic spasms (clusters of epileptic spasms were counted as single seizures.) The following types of seizures were recorded in a daily log at the same time and for the same duration each day, as determined by the principal investigator (e.g., 10 minutes at 6:00 PM): Myoclonic seizures Absence seizures • Focal conscious seizures without motor signs (e.g., focal sensory seizures) In addition, caregivers assessed their impression of daily absence, myoclonic, and focal sensory seizures using a three-point Likert scale, as instructed by the principal investigator, where 0 = no seizures, 1 = some seizures, and 2 = many seizures. The principal investigator identified the most physically distressing seizure type experienced by the patient. This was based on the principal investigator's clinical assessment.

[0072] Video electroencephalography (video-EEG) sessions of 2, 4, or 24 hours were performed at the start and end of the study. Information recorded via video-EEG included wakefulness and sleep EEG background features, interictal epileptic-like and non-epileptic-like abnormalities, and EEG and clinical features of seizures that occurred during the study. Video-EEG interpretation was completed by an independent reviewer. Where additional consent was required to transfer EEG data to a central reviewer, the principal investigator obtained consent before the EEG left the site. If the subject / caregiver did not consent, the EEG was not provided for central review. Patients continued to meet inclusion / exclusion criteria to proceed to the treatment period.

[0073] Period A: Titration period For patients weighing less than 25 kg, the initial dose was 125 mg of CBD Q12H (±2 hours), with a total daily dose of 250 mg of CBD over a 4-week titration period. At the 4th week visit (visit 4), the dose was either maintained at 250 mg of CBD per day or increased to 250 mg of CBD Q12H (±2 hours) at the discretion of the principal investigator, with a total daily dose of 500 mg of CBD (4 sachets) for the remaining 22 weeks of treatment.

[0074] Patients weighing over 25 kg received 250 mg of CBD Q12H (±2 hours), with a total daily dose of 500 mg of CBD for the 4-week titration period. At the 4th week visit (visit 4), the dose was either maintained at 500 mg of CBD per day or increased to 375 mg of CBD Q12H (±2 hours) at the discretion of the principal investigator, with a total daily dose of 750 mg of CBD (6 sachets) for the remaining 22 weeks of treatment.

[0075] Period A: Maintenance period At week 10, patients taking 500mg of CBD per day were able to increase to 750mg of CBD per day (6 sachets), and patients taking 750mg of CBD per day were able to increase to 1000mg of CBD per day (8 sachets).

[0076] The principal investigator reduced the dose as needed based on safety and tolerability after the patient initiated the maintenance period. Patients taking 250 mg of CBD Q12H (±2 hours) for a total daily dose of 500 mg of CBD were able to reduce their dose to 125 mg of CBD Q12H (±2 hours) for a total daily dose of 250 mg of CBD. Patients taking 375 mg of CBD Q12H (±2 hours) for a total daily dose of 750 mg of CBD were able to reduce their dose to 250 mg of CBD Q12H (±2 hours) for a total daily dose of 500 mg of CBD. Patients taking 500mg of CBD Q12H (±2 hours) with a total daily dose of 1000mg were able to reduce their dose to 375mg of CBD Q12H (±2 hours) with a total daily dose of 750mg, or 250mg of CBD Q12H (±2 hours) with a total daily dose of 500mg. Patients whose weight changed during the study were able to increase or decrease their dose.

[0077] Depending on the patient's dose at the time of discontinuation, a tapering period ranging from 1 to 3 weeks was completed. After tapering, patients were also required to complete a 4-week telephone follow-up period.

[0078] Parents / caregivers were instructed to record the frequency and type of seizures, as well as skin irritation scores, in a daily log. Parents / caregivers have completed this: (1) University of Washington Caregiver Stress Scale for day 1, week 14, and week 26.

[0079] (2) Quality of Life scale for epilepsy and learning disabilities (ELDQOL modified) on day 1, week 14, and week 26.

[0080] (3) Sleep Disturbance Scale for Children (SDSC) on day 1, week 14, and week 26.

[0081] (4) Vineland Adaptive Behavior Scale on day 1 and week 26 TM (VABS-3).

[0082] (5) Parents / caregivers also completed a daily Likert-type "good day / bad day" questionnaire.

[0083] (6) Qualitative caregiver feedback at week 26.

[0084] the purpose The primary objective of this study was to evaluate the safety and tolerability of ZYN002 in pediatric and adolescent epilepsy patients with developmental epilepsy and epileptic encephalopathy (DEE) for up to 72 weeks.

[0085] A secondary objective was to evaluate the effectiveness of ZYN002 in terms of seizure frequency, caregiver stress, quality of life, sleep disturbance, adaptive behavior among epilepsy patients, and overall daily assessment ("good day / bad day").

[0086] Evaluation Criteria Safety: Safety assessment included collection of adverse events (AEs), physical and neurological examinations, 12-lead ECG, laboratory evaluation (hematology, chemistry, and urinalysis), testosterone (men only), Tanner staging scale, pregnancy test (women of childbearing age only), C-SSRS (children), a short form of the marijuana withdrawal checklist (behavioral checklist), and findings from post-treatment skin examinations.

[0087] Skin Integrity: A logbook was provided to the parent / caregiver to complete daily skin check examinations. The parent / caregiver recorded the skin check score in the daily skin check logbook once a day in the evening.

[0088] Seizure frequency: The primary efficacy assessment was the median percentage change from baseline in mean monthly (28-day) seizure frequency (SF28) over 26 weeks (Period A) for the following types ("countable seizures"): • Generalized tonic-clonic seizures ("primary generalized tonic-clonic" seizures) • Focus loss seizures • Focal origin bilateral tonic-clonic seizure Seizure endpoints were summarized monthly.

[0089] Secondary seizure endpoints included the median percentage change from baseline in the following SF28: • All "countable seizures" (individually and in total): • Generalized tonic-clonic seizures (GTCS) • Focal Impairment of Consciousness Seizures (FIAS) • Focal origin bitonic-clonic seizures (BTCS) • Tonic seizure (T) • Clonic seizures (C) • Atonic seizures (AT) • Epileptic spasms (ES) • Focal conscious seizures with motor signs (FM) • Panfocal seizures (FIAS, BTCS, FM) The seizure type identified as the most distressing overall (at baseline): Frequency of the following types of seizures occurring consistently at a countable frequency during the daily observation period: Myoclonic seizures (M) Absence seizure (A) • Focal sensory seizures (FAS) without motor signs Other efficacy endpoints are as follows: • Changes in the University of Washington Caregiver Stress Scale from baseline to 14, 26, and 50 weeks / ET - total score; • Changes in ELDQOL modification subscale scores from baseline to weeks 14, 26, and 50 / ET; • Changes in the total SDSC score and subscale scores from baseline to 14, 26, and 50 weeks / ET; • For each period used to assess seizure frequency, the change from baseline in the "good day / bad day" assessment was evaluated; and • Changes in the VABS-3 composite score and subscale scores from baseline to weeks 26 and 50 / ET.

[0090] In week 26, the clinician recorded qualitative caregiver feedback by asking the following questions: (1) "Have you or your family experienced any improvements as a result of [Patient Name] using the gel?"; (2) "Have you or your family experienced any worsening as a result of [Patient Name] using the gel?"; (3) "A few specific questions: I'd like to ask about their daily activities. For example, do they attend school? If so, how? Are they awake? If so, how?"

[0091] result Data show that ZYN-002 reduced seizure frequency in many types of difficult-to-treat developmental and epileptic encephalopathy. It also improved significant behavioral deficits, arousal, and social interaction, enabling children to attend school more consistently. DEE is the most difficult and poorly controlled form of epileptic disorder, involving many symptoms that negatively impact patient and family functioning.

[0092] These results show a significant reduction in seizures, as well as improvements in many challenging behaviors and symptoms, including seizure intensity, fatigue, social isolation, cognitive impairment, and language deficits.

[0093] Of the 48 patients enrolled, 21 completed the tapering period and discontinued the study treatment, while 27 continued treatment. Only one patient discontinued treatment due to an adverse event.

[0094] Seizures and seizure frequency Of the 48 registered patients, 33 (approximately 70%) had focal impaired consciousness seizures (FIAS; previously known as complex partial seizures) and / or convulsive seizures (focal-origin bilateral tonic-clonic seizures and generalized tonic-clonic seizures, BTCS and GTCS, respectively) at baseline.

[0095] Referring to Figure 1, compared to baseline seizure frequency, these patients experienced a median reduction of 44% or more in seizures from month 2 onward, using 28-day normalized monthly seizure frequency (SF28). Of the 46 patients, 13 had various non-FIAS and non-convulsive seizure types at baseline. 55 percent (55%) of patients with FIAS and / or convulsive seizures experienced a median reduction of 50% or more in seizures at 6 months of treatment. Patients with either DS or LGS who experienced FIAS and / or convulsive seizures (n=11) experienced a median reduction of 51% in FIAS and / or convulsive seizures at 6 months of treatment compared to baseline. 60 percent (60%) of patients with DS or LGS experienced a median reduction of 50% or more in FIAS or convulsive seizures at 6 months of treatment.

[0096] Qualitative caregiver feedback: A qualitative analysis of the effects of ZYN-001 on behavioral and cognitive impairments. Parents and caregivers were asked to provide a qualitative assessment of the child's overall experience with ZYN-002 over the treatment period. Topline results included: 53% reported improved vitality (e.g., alertness / awareness, energy).

[0097] 51% reported improvement in seizures.

[0098] 47% reported improved cognitive and concentration abilities.

[0099] 44% reported improvements in involvement / participation, relationships, speech / communication, and social avoidance behavior.

[0100] 28% reported that their children attended school on time / more frequently.

[0101] • 26% reported difficulty in applying the gel to children (e.g., the time it takes for the gel to dry).

[0102] Two naive, independent coders conducted data analysis in parallel. Coding was completed using Atlas.ti software. Any caregiver reports of signs, symptoms, or other empirical occurrences in children were coded. Responses from 43 participants were coded. The results are shown in Table 4, and the aggregations are based on absolute mentions (i.e., multiple mentions per patient are possible).

[0103] [Table 4] TIFF0007870724000006.tif222170TIFF0007870724000007.tif111170

[0104] Table 5 provides a complete summary of patient mentions.

[0105] [Table 5] TIFF0007870724000009.tif162167

[0106] safety ZYN-002 was well-tolerated. Eight patients discontinued the study; one discontinued as a result of an adverse event (skin reaction), and seven discontinued as a result of withdrawal of consent or recognition of lack of efficacy. During the baseline period (before the start of the study treatment), 14 out of 48 enrolled patients (29.2%) reported a total of 22 adverse events (AEs). Throughout the 6-month treatment period, 96% of patients experienced a treatment-emerging adverse event (TEAE), and 60% experienced a TEAE related to the study treatment. There was no clear trend of increasing AE occurrence with increasing ZYN002 dose levels. TEAEs were reported in 12 out of 21 patients (57.1%) during the tapering period. Most TEAEs were mild to moderate and transient. The most frequently reported TEAEs in favorable terms were upper respiratory tract infection (41.7% of patients), nasopharyngitis (20.8%), somnolence (12.5%), and vomiting (10.4%). The next most frequently reported TEAEs were application site dryness (8.3%), application site pain (8.3%), and somnolence (8.3%). Ten patients (20.8%) reported serious adverse events (SAEs) during the treatment period, and one patient (4.8%) reported a serious adverse event (SAE) during the tapering period; eight were infection-related and two were exacerbations of epilepsy. Two SAEs (lower respiratory tract infection and status epilepticus) were considered potentially treatment-related. There were no patient deaths during the study.

[0107] [Example 2] A trial of four patients with SYNGAP1 In the ZYN2-CL-025 (BELIEVE) trial, there were four patients with SYNGAP1, as shown in Table 5.

[0108] Table 6 provides patient data for four patients with SYNGAP1.

[0109] [Table 6]

[0110] Qualitative feedback was not provided for patients aged 3.5 and 9 years. Qualitative feedback was provided for patients aged 6.5 and 11.5 years. For the 6.5-year-old patient, the qualitative feedback indicated "significant overall improvement." For the 11.5-year-old patient, the qualitative feedback indicated that the patient was "happier, more outgoing, and able to wave to people."

Claims

1. A pharmaceutical composition for the treatment of behavioral problems and seizures in subjects with developmental and epileptic encephalopathy (DEE), and for transdermal administration, wherein the pharmaceutical composition is formulated for transdermal administration of synthetic cannabidiol (CBD), contains an effective amount of CBD, the seizures to be treated are focal impairment of consciousness seizures (FIAS), and the behavioral problems include deficits or regressions in social communication, mood, confrontational and defiant behavior, tantrums, self-injurious behavior, or speech disorders, or a combination thereof. A pharmaceutical composition wherein the effective amount of CBD is 750 mg or 1000 mg per day in total.

2. The pharmaceutical composition according to claim 1, wherein the treatment comprises a significant improvement in quality of life, as measured by an improvement in the Quality of Life (ELDQOL) scale for epilepsy and learning disability within two weeks, four weeks, or eight weeks.

3. The pharmaceutical composition according to claim 1 or 2, wherein the treatment comprises a significant reduction in sleep disturbance as determined by improvement in the Pediatric Sleep Disturbance Scale (SDSC) within two weeks, four weeks, or eight weeks.

4. Treatment is within one or two months of Vineland Adaptive Behavior Scale ＴＭ A pharmaceutical composition according to any one of claims 1 to 3, comprising a significant improvement in adaptive behavior determined by a decrease in -3 (VABS-3).

5. A pharmaceutical composition according to any one of claims 1 to 4, wherein the treatment comprises a significant improvement in caregiver stress, as measured by improvement in the University of Washington Caregiver Stress Scale within two weeks, four weeks, or eight weeks.

6. A pharmaceutical composition according to any one of claims 1 to 5, wherein the treatment includes a significant improvement in daily satisfaction and well-being.

7. A pharmaceutical composition according to any one of claims 1 to 6, wherein the treatment includes a significant improvement in cognition and awareness.

8. A pharmaceutical composition according to any one of claims 1 to 7, wherein the subject does not have erythema or minimal erythema.

9. A pharmaceutical composition according to any one of claims 1 to 8, wherein the treatment significantly reduces the frequency of focused loss of consciousness seizures and convulsive seizures on a monthly basis.

10. A pharmaceutical composition according to any one of claims 1 to 9, wherein the subject has Lennox-Gastaut syndrome or Dravet syndrome and is a 50% responder within 30 days.

11. A pharmaceutical composition according to any one of claims 1 to 10, wherein CBD is administered in a once-daily dose.

12. A pharmaceutical composition according to any one of claims 1 to 11, wherein CBD is administered in a dose twice daily.

13. The pharmaceutical composition according to claim 1, wherein the CBD is synthetic CBD.

14. The pharmaceutical composition according to claim 1, wherein the CBD is purified.

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