Treatment of SYNGAP1 encephalopathy

Abstract

The present invention relates to the treatment of SYNGAP1 encephalopathy, in particular to a method of treating SYNGAP1 encephalopathy by transdermally administering to a subject an effective amount of cannabidiol (CBD) wherein a SYNGAP1 symptom is treated in the subject.

Description

[0001] This invention is a divisional application of Chinese Patent Application No. 202080065120.3, filed on September 16, 2020, entitled “Treatment of SYNGAP1 Encephalopathy”. Technical Field

[0002] This disclosure relates to a method of treating SYNGAP1 encephalopathy by transdermal administration of an effective amount of cannabidiol (CBD) to a subject in need. Background Technology

[0003] Cannabinoids are a class of compounds found in the cannabis plant. The two main cannabinoids found in cannabis are cannabidiol (CBD) and Δ9-tetrahydrocannabinol (THC). CBD lacks the psychoactive effects of THC. Studies have shown that CBD may be used to treat conditions such as arthritis and cancer.

[0004] EPIDIOLEX oral CBD solution has been approved for pediatric treatment. However, oral delivery has been associated with gastrointestinal (GI) adverse events; for example, the EPIDIOLEX label reports drowsiness and sedation in 32% of its patients, and these are dose-related. (EPIDIOLEX cannabidiol oral solution label, June 2018). Oral CBD also has the potential to degrade into THC in gastric acid, which may be associated with undesirable psychoactive effects. Summary of the Invention

[0005] There is a need to treat the symptoms of SYNGAP1 encephalopathy, including seizures and behavioral problems. Furthermore, autism spectrum disorder is a common comorbidity in SYNGAP1 patients and should be treated. A treatment is required that does not produce undesirable side effects such as lethargy, avoidance, or sedation, which could negate any benefits of the behavioral symptoms or exacerbate the behavioral problems.

[0006] On Friday, May 31, 2019, the United States Food and Drug Administration (FDA) held a public hearing (Part 15) on food safety and applied nutrition entitled “Scientific Data and Information about Products Containing Cannabis or Cannabis-Derived Compounds.” Monica Weldon, president and CEO of Bridge the Gap, the SYNGAP Education Research Foundation, spoke at the hearing. Weldon highlighted the need to treat SYNGAP. She began her speech by helping parents describe the perspectives of children with SYNGAP symptoms: Imagine being told there are no FDA-approved products for your child. Imagine seeing your child suffer from a rare genetic disorder. Transmissible sexual dysfunction, which doctors barely understand, manifests as epileptic seizures, mood disorders, and childhood... The children are unable to communicate because they have become unable to speak. Standing beside their children is different. From the perspective of parents or caregivers ([sic]), address their child's problems, or even simply find out... What went wrong? Now insert CBD. Due to all its confusing descriptions, derivatives, vague dosage recommendations, and... Cure-all marketing, and then you create a vague legal environment around it, and now... You have just created the Wild West of the CBD. Like many advocates for rare childhood diseases, we are particularly interested in emerging therapies designed to help our children. Don't be sensitive. Patients and their families expect guidance on potential treatments and credible educational materials, especially when we work with researchers. We are working closely with our staff to develop targeted therapies for SYNGAP1. We have not yet approved it for our children. Targeted therapy. Therefore, we focus on the short-term regeneration of pharmaceuticals and natural medications. Use (short-term repurposing) to relieve SYNGAP1 symptoms. CBD-based drugs and OTC CBD products have been a recurring topic of discussion. This is our biggest challenge as an organization. It's about how to address them. At this stage, when it comes to safety, efficacy, When discussing product integrity and drug interactions, we need to... Further scientific research, and further research on CBD, will answer many of our questions.

[0007] This disclosure addresses a need discussed by Bridge the Gap, President and CEO of the SYNGAP Educational Research Foundation. This disclosure relates to a method for treating SYNGAP1 encephalopathy, including SYNGAP1 symptoms of behavioral problems and SYNGAP1 seizures, comprising transdermal administration of an effective amount of cannabidiol (CBD) to a subject, wherein one or more SYNGAP1 symptoms of the subject, such as behavioral problems, are treated.

[0008] Treatment of one or more behavioral problems may involve the reduction of one or more behavioral problems. These one or more behavioral problems include social avoidance, attention deficit, impulsivity, mood disturbances, inattention, impulsivity, or physical aggression.

[0009] In some embodiments, the SYNGAP1 symptom being treated is a seizure. In some embodiments, SYNGAP1 seizures are treated such that the subject is a 35%, 50%, or 90% responder within 30 days. In some embodiments, the treatment comprises a reduction of SYNGAP1 seizures by about 25% to about 45%. SYNGAP1 seizures can be at least one of focal impaired awareness seizures (FIAS) or atonic seizures (AT).

[0010] Two or more SYNGAP1 symptoms can be treated. In some implementations, the two or more SYNGAP1 symptoms treated are behavioral problems and SYNGAP1 seizures. Treatment of behavioral problems includes a reduction in one or more behavioral problems, and treatment of SYNGAP1 seizures includes a reduction in SYNGAP1 seizures of approximately 25% to approximately 45%. SYNGAP1 seizures can be at least one of focal sensory impairment seizures (FIAS) or atonic seizures (AT).

[0011] In some implementations, treatment includes daily improvements in satisfaction and well-being. Treatment can be improvements in cognition and awareness. Treatment can also be a meaningful monthly reduction in focal perceptual impairment seizures and convulsive seizures.

[0012] An effective dose of CBD can be between about 250 mg and about 1000 mg daily. In some embodiments, an effective dose of CBD starts at about 250 mg daily and increases to about 500 mg daily or about 1000 mg daily. An effective dose of CBD can start at about 50 mg daily and increase to about 250 mg daily. In some embodiments, an effective dose of CBD starts at 250 mg daily. An effective dose of CBD can start at 500 mg daily. In some embodiments, 500 mg daily and 1000 mg daily doses are administered to patients weighing more than 25 kg. CBD can be administered as a single daily dose or two daily doses. In some embodiments, an effective dose is 750 mg daily or 1000 mg daily.

[0013] CBD can be formulated as a gel. In some embodiments, CBD is formulated as a permeation-enhanced gel. The gel may contain between 1% (wt / wt) and 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.

[0014] In some embodiments, the transdermal preparation can be a cream, salve, lotion, or ointment. CBD can be delivered via bandage, pad, or patch.

[0015] CBD can be applied transdermally to a patient's upper arm and shoulder. In some implementations, CBD is applied transdermally to the subject's thigh or back.

[0016] CBD can be synthetic. CBD can be purified. CBD can be botanically derived.

[0017] Compared to oral administration of cannabidiol (CBD), transdermal administration of an effective amount of CBD can reduce the intensity of at least one adverse event or side effect. The at least one adverse event or side effect may be a gastrointestinal (GI) adverse event. The at least one adverse event or side effect may be liver function-related. In some embodiments, the at least one adverse event is drowsiness. In some embodiments, the frequency and intensity of drowsiness are reduced as adverse events. Attached Figure Description

[0018] Figure 1 This is a table showing a decrease in the frequency of epileptic seizures and a greater than 50% response rate. Detailed Implementation

[0019] This article provides a method for treating SYNGAP1 encephalopathy symptoms in a subject by transdermal administration of an effective amount of cannabidiol (CBD), wherein the subject's one or more behavioral problems or SYNGAP1 seizures are treated.

[0020] The trial summarized in this example—a Phase 2 open-label clinical trial—evaluated the safety and efficacy of transdermal CBD administration in SYNGAP1 encephalopathy and in a heterogeneous group of other rare developmental and epileptic encephalopathies (DEEs) including, but not limited to, Dravet syndrome (DS) and Lennox-Gastaut syndrome (LGS). Some of the most common and debilitating seizure types in SYNGAP1 encephalopathy are focal sensory-impairing and convulsive seizures. Patients with SYNGAP1 encephalopathy experiencing these seizure types, such as SYNGAP1 seizures, experienced a reduction in seizures of up to 73% during a 26-week treatment period. In the study, caregiver qualitative assessments indicated improvements in behavioral problems, including improved mood, interpersonal communication, learning ability, alertness, school attendance, and cognitive symptoms. definition

[0021] As used herein, the term “treating” or “treatment” means to reduce, improve, alleviate, or weaken at least one symptom (e.g., a behavioral symptom) of a subject’s, such as a person’s, condition, disease, or symptom, or a measurably measurable improvement in relation to the condition, disease, or symptom.

[0022] As used herein, the term “clinical efficacy” refers to the ability to produce a desired effect in a human body, as demonstrated by clinical trials conducted by the Food and Drug Administration (FDA) or any foreign counterparts.

[0023] As used herein, the terms “cannabidiol” or “CBD” refer to cannabidiol; cannabidiol prodrugs; pharmaceutically acceptable derivatives of cannabidiol, including pharmaceutically acceptable salts, cannabidiol prodrugs, and cannabidiol derivatives. CBD comprises 2-[3-methyl-6-(1-isopropenyl)-2-cyclohexen-1-yl]-5-pentyl-1,3-benzenediol (2-[3-methyl-6-(1-methylethenyl)-2-cyclohexen-1-yl]-5-pentyl-1,3-benzenediol) and its pharmaceutically acceptable salts, solvates, metabolites (e.g., skin 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.

[0024] As used in this article, the term “behavioral problems” refers to behavioral deficits or regressions, such as deficits or regressions in social communication, emotions, oppositional and defective behaviors, anger and self-harm, or language disorders.

[0025] The term “transdermal administering” as used in this article refers to the contact of CBD with the skin of a patient or subject under conditions where CBD can effectively penetrate the skin.

[0026] As used herein, the term “SYNGAP1 seizures” refers to seizures in SYNGAP1 subjects. These seizures fall under the seizure group described herein and include, but are not limited to: generalized tonic-clonic seizures (“primary generalized tonic-clonic”); focal perceptual impairment seizures; focal to bilateral tonic-clonic seizures; focal aware seizures with motor signs; tonic seizures; clonic seizures; and tonic seizures.

[0027] Located on chromosome 6p21.32, SYNGAP1 is primarily expressed in the postsynaptic synapse of excitatory neurons. SYNGAP1 is a complex protein, an abundant component of the postsynaptic density (PSD) of excitatory glutamatergic neurons, where it exists as part of the N-methyl-D-aspartate receptor (NMDAR) complex. SYNGAP1 is one of several genes encoding proteins that regulate synaptic structure and function. Loss of SYNGAP1 has major consequences for neuronal homeostasis and development, which are important for learning and memory, seizure thresholds, and behavioral problems. SYNGAP1 is essential for synaptic development, structure, function, and plasticity (Sheng and Kim, 2011).

[0028] The neuronal pathways and brain regions most severely disrupted by SYNGAP1 dysfunction contain presynaptic CB1 receptors and retrograde endocannabinoid signaling systems. Cannabidiol and other cannabinoid therapeutics can target these signaling systems to promote neuronal homeostasis and synaptic plasticity recovery, thereby increasing neuronal function in the regulation of learning, memory, and emotional behavior.

[0029] SYNGAP1 intellectual disability is a neurological disorder characterized by moderate to severe intellectual disability that is evident in early childhood. The earliest features are delayed development of speech and motor skills, such as sitting, standing, and walking. Many people with this condition have weak muscle tone (hypotonia), which leads to difficulties in motor skills. Some affected individuals lose skills they have already acquired (developmental regression).

[0030] Patients with severe SYNGAP1 variants may have very low IQs (<50), primarily nonverbal, and several comorbid conditions, such as impulsivity and challenging behavior. SYNGAP1 is caused by de novo (spontaneous, non-hereditary) mutations. Other behavioral abnormalities include inattention, impulsivity, and physical aggression (hitting, biting). Mood swings, depression, and rigidity have also been reported in many children.

[0031] SYNGAP1 seizures are often difficult to treat with standard antiepileptic drugs (AEDs). Therefore, more aggressive adjunctive use of AEDs is often considered, which are considered effective in suppressing interictal epileptiform discharges (e.g., benzodiazepines, valproic acid, and lamotrigine), immunomodulatory therapies (e.g., corticosteroids, intravenous immunoglobulin [IVIG], plasmapheresis), ketogenic diets, and surgical options.

[0032] Given the treatment incompatibility and the limited number of approved drugs with evidence from controlled trials, clinicians are often left with no choice but to use standard AEDs in an error-fashion manner, primarily based on clinical experience or publicly labeled trials.

[0033] Vlaskamp et al. examined a 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 1 summarizes the phenotypic profile of SYNGAP1 patients with mutations, variants, or microdeletions. Table 1: Characteristics of SYNGAP1 patients (Vlaskamp 2019)

[0034] For Table 1, the following abbreviations indicate: EM represents blepharotic syndrome with or without absence of twitching, and ID represents intellectual disability. If patient information is lacking, a denominator representing the number of patients with known information on that variable is provided. If no denominator is provided, information exists for all patients. Eating problems include insufficient intake, uncontrolled gulping, eating inedible objects, difficulty transitioning from liquids to solids in early childhood, and difficulties with chewing and swallowing.

[0035] Further regarding Table 1, 55 out of 56 patients (96%) were diagnosed with developmental delay shortly after birth, and this preceded the onset of epilepsy in all patients. In all 56 patients, developmental regression or arrest occurred concurrently with the onset of epilepsy. Language impairment was severe, with 12 patients exhibiting nonverbal impairment, ranging in age from 2 to 33 years. Developmental delay was present in 55 out of 57 patients, with 50 being moderate to severe and 5 mild. Behavioral problems were observed in 41 out of 56 patients (73%), often presenting as severe opposing and deficit behaviors, including aggression, self-harm, and rage. ASD was diagnosed in 30 patients (53%). The University of Washington Caregiver Stress Scale (UW-CSS)

[0036] The UW-CSS measures stress experienced by caregivers of children under 18 years of age and was developed to pinpoint stress areas important for caregivers of children with severe epilepsy. (University of Washington Caregiver Stress Scale (UW-CSS) Version 1 User Guide, 2017; Jensen et al., “Life impact of caregiving for severe childhood epilepsy: Results of expert panels and caregiver focus groups”, Epilepsy Behav (2017).) Quality of Life for Epilepsy and Learning Disabilities (ELDQOL)

[0037] The Epilepsy and Learning Disabilities Quality of Life (ELDQOL) scale is a questionnaire that covers seizure severity, seizure-related injury, AED side effects, behavior, mood, physical, cognitive and social functioning, parental attention, communication, overall QOL and overall health. The Sleep Disturbance Scale for Children (SDSC)

[0038] The Sleep Disturbance Scale for Children (SDSC) was created to evaluate sleep disorders in children and to provide a general measure of sleep disorders suitable for clinical screening and research. Developer Bruni and colleagues developed six categories representing sleep difficulties affecting children aged 6 to 15 years: initiating and maintaining sleep, sleep breathing disorders, arousal / nightmares, sleep-wake transition, excessive somnolence, and sleep hyperhidrosis (night sweats). Bruni et al., “The Sleep Disturbance Scale for Children (SDSC). Construction and validation of an instrument to evaluate sleep disturbances in childhood and adolescence” J Sleep Res 5(4):251-61 (1996). Patients / parents used a five-point scale to indicate the frequency from 1 (never) to 5 (always). Higher scores indicated more acute sleep disorders. Scores for each of the six sleep disorder categories were recorded, and a total score was calculated. Shahid et al. (des.), STOP, THAT and One Hundred Other Sleep Scales 82:331-332 (Springer Science + Business Media, LLC 2012). Qualitative Caregiver Feedback

[0039] Qualitative assessment of improvement, deterioration, or no change in the patient and family, including but not limited to daily activities, school attendance, and alertness. In this example, clinicians were asked to capture qualitative caregiver feedback at week 26 and ask the following questions: (1) “Have there been any improvements for [Patient Name] and your family since [Patient Name] started using the gel?”; (2) “Have there been any worsening conditions for [Patient Name] and your family since [Patient Name] started using the gel?”; and (3) “Let me ask just a few specific things: daily activities, e.g., going to school? If so, how? alertness? If so, how?”. Transdermal Pharmaceutical Compositions

[0040] Transdermal delivery of cannabinoids (such as CBD) offers advantages over oral dosing because it allows the drug to be absorbed directly into the bloodstream through the skin. This avoids first-pass liver metabolism, resulting in lower dose levels of the active pharmaceutical ingredient, higher bioavailability, and improved safety. Transdermal delivery also avoids the gastrointestinal tract, reducing GI-related adverse events and the likelihood of CBD being degraded to THC by gastric acid, which may be associated with undesirable psychoactive effects. Furthermore, transdermal delivery of CBD reduces the intensity and frequency of drowsiness adverse events, which are generally present with oral CBD administration. Transdermal delivery of CBD avoids hepatic adverse events, which are generally present with oral CBD administration. In some embodiments, transdermal administration of an effective amount of CBD reduces the intensity of at least one adverse event by about 15% to about 95% compared to oral administration.

[0041] CBD can be in gel form and can be a pharmaceutically-produced, transparent, permeation-enhancing gel designed to provide transdermal controlled drug delivery in one or two daily doses. CBD gels can range from 1% (wt / wt) CBD to 7.5% (wt / wt) CBD. (CBD gels may have, for example, 4.2% (wt / wt) or 7.5% (wt / wt) CBD.) CBD gel can be applied topically by the patient or caregiver to the patient's upper arm and shoulder, back, thigh, or any combination thereof.

[0042] CBD gels may contain diluents and carriers, as well as other conventional excipients such as wetting agents, preservatives, suspending agents, and dispersants.

[0043] CBD gels may contain a solubilizing agent, a permeation enhancer, a solubilizer, an antioxidant, a building agent, a thickener, and / or a pH adjuster. 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 1-6 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. water, in an amount sufficient to bring the composition to 100% (wt / wt) total. Other dosage forms of CBD gels can be found in International Publication No. WO 2010 / 127033, the entire contents of which are incorporated herein by reference.

[0044] The effective dose of CBD can be between approximately 50 mg and approximately 1000 mg per day, and it can be administered as one or two doses per day.

[0045] Children with SYNGAP1 encephalopathy may develop different types of seizures (referred to as SYNGAP1 seizures in this article), which are difficult to control with antiepileptic drugs. Common types of generalized seizures may include (Vlaskamp et al., 2019): myoclonic seizures; atonic seizures; eyelid myoclonus that develops into myoclonic atonic seizures; absence eyelid myoclonus; atypical and typical absence seizures; and generalized tonic-clonic seizures.

[0046] SYNGAP1 seizures can be triggered by certain types of flashing light or patterns, a condition known as photosensitivity. Other types of triggers, such as eating, can also induce SYNGAP1 seizures.

[0047] Patients with SYNGAP1 encephalopathy typically have developmental arrest or regression, which can occur before the onset of epileptic seizures. Most patients with SYNGAP1 have at least one of the following symptoms: intellectual disability, behavioral problems, high pain threshold, eating problems, sleep problems, autism spectrum disorder, and ataxia or gait abnormalities.

[0048] SYNGAP1 loss-of-function variants are surprisingly common, with a reported incidence of 1–4 per 10,000 individuals, or approximately 0.5–1.0% of all ID cases. However, the number of patients diagnosed with SYNGAP1 is significantly lower than the estimated prevalence. Bridge the Gap, the SYNGAP advocacy organization in the United States, reports only >350 patients diagnosed worldwide. Based on conversations with Bridge the Gap, a more accurate prevalence might be represented by 1 in 20,000 patients; however, the majority remain undiagnosed. Example Example 1: Study of ZYN-002 in Children with Developmental Epileptic Encephalopathies

[0049] This was a continuous, multi-phase, open-label, multinational, multicenter, multi-dose study to evaluate the long-term safety and tolerability of ZYN002 (transdermal CBD gel) in children and adolescents aged 3 to 18 years with epilepsy and 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 the 4-week baseline period, of whom 50 further received open-label treatment in Period A (including no more than 24 patients with Lennox-Gastaut syndrome or Dravet syndrome in total).

[0050] In Phase A, patients experienced a 4-week baseline period, followed by a 4-week titration period, and a 22-week flexible dosing maintenance period. Patients in Phase A received a total of 26 weeks of treatment.

[0051] In Phase B, patients continued receiving the same maintenance dose of ZYN002 they received at week 26 (e.g., at the end of Phase A) for an additional 46 weeks. At any point, upon termination of treatment, patients were required to complete a tapering and follow-up period. After the final tapered dose, patients were followed up weekly by telephone for four weeks to complete the Marijuana Withdrawal Checklist shortform. After the four-week follow-up, patients were discharged from the study.

[0052] During the 26-week treatment period and the 46-week extension period (total treatment duration of 72 weeks), patients received the study drug twice daily (every 12 hours ± 2 hours). At the end of treatment, patients were instructed to complete a gradual tapering period of one to three weeks (depending on the dose).

[0053] Recruited patients received an initial dose of ZYN-002 based on weight, either 250 mg or 500 mg daily. Patients weighing <25 kg could have their dose increased to 750 mg daily, and patients weighing >25 kg could have their dose increased to 1,000 mg daily. Diagnosis and Criteria for Inclusion

[0054] Patients participating in this study had been diagnosed with developmental and epileptic encephalopathy. Their ages ranged from 3 to 18 years, and their body mass index (BMI) was between 13 and 35 kg / m². 2 Between, and with a weight of not less than 12kg.

[0055] The patient has a diagnosis of developmental and epileptic encephalopathy (DEE) as defined by the International League Against Epilepsy (Scheffer 2017), which includes generalized motor seizures (i.e., generalized tonic-clonic, tonic, clonic, atonic, epileptic spasms), focal aware motor seizures, focal perceptual impairment, or focal extension to bilateral tonic-clonic seizures. Examples of DEE include, but are not limited to, Lennox-Gastaut syndrome, Dravet syndrome, West syndrome / infantile spasms, and Doose syndrome. The diagnosis must have been established for ≥1 year and be substantiated by a review of history and examinations, as well as appropriate studies including electroencephalogram (EEG), magnetic resonance imaging (MRI) scans, or genetic testing.

[0056] The patient experienced a total of five or more seizures of the following types during the baseline period: generalized motor (i.e., generalized tonic-clonic, tonic, clonic, atonic, or epileptic spasms), focal motor, focal perceptual impairment, or focal extension to bilateral tonic-clonic seizures. A cluster of epileptic spasms is counted as a single seizure.

[0057] As determined by the researchers, the patient had a history of developmental delay in at least one developmental area following the onset of epileptic seizures, accompanied by regression, slowing or arrest. Application Sites

[0058] The approved application sites for the gel are the right upper arm and left upper arm as specified in Table 2.

[0059] If redness occurs at the application site, ZYN002 may be temporarily applied to the right and upper left thighs after consulting with the investigator. Patients with low BMI and / or small arms are permitted to apply ZYN002 to the right or upper left thigh. The application sequence is one sachet for each upper left and right upper arm / shoulder, and one sachet for each upper right and left thigh.

[0060] If applied to the upper right and / or left thigh, the procedure is the same as described for the left and right upper arm / shoulder. Parents / caregivers should use gel-wearing gloves. Parents / caregivers should ensure the gel is thoroughly rubbed in, with no gel residue remaining on the gloves, and that the skin surface to which the gel is applied is no longer shiny and dry to the touch before application. Once the patient / caregiver has finished the treatment application, they should discard the gloves and thoroughly wash their hands with soap and warm water. Parents / caregivers are instructed to keep the application site dry for 6 hours, avoiding contact with water or excessive sweating. Parents / caregivers may apply an approved moisturizing lotion 2 hours after administration. Parents / caregivers are instructed to cover the application site to minimize sun exposure when outdoors during the day. Product, dosage and administration method

[0061] The product is ZYN002 (cannabidiol: CBD), 4.2% gel, for topical use. The medication is provided in sachets containing 2.98g of gel to deliver 125mg CBD per sachet. Apply one (1) to four (4) sachets in the morning and evening to achieve the appropriate total daily dose based on each patient in the treatment group.

[0062] The following steps will be taken: Treatment A: 125mg CBD Q12H (±2 hours); Total daily dose of 250mg CBD (1 sachet in the morning and 1 sachet in the evening). Treatment B - 250mg CBD Q12H (±2 hours); Total daily dose of 500mg CBD (2 sachets in the morning and 2 sachets in the evening). Treatment C - 375mg CBD Q12H (±2 hours); Total daily dose of 750mg CBD (3 sachets in the morning and 3 sachets in the evening). Treatment D - 500mg CBD Q12H (±2 hours); total daily dose of 1000mg CBD (4 sachets in the morning and 4 sachets in the evening). Period A: Baseline Period

[0063] During the 4-week baseline period, parents and / or caregivers recorded the number of the following types of seizures in a seizure diary: Generalized tonic-clonic seizures (“primary generalized tonic-clonic” seizures) Focal sensory impairment seizures • Focal extension to bilateral tonic-clonic seizures Focal sensory seizures with motor signs Tonic-clonic seizures Clonic epileptic seizures ●Atonic seizures • Epileptic spasms (a cluster of epileptic spasms is counted as a single epileptic seizure)

[0064] The following types of seizures were captured in a daily diary at the same time and for the same duration each day, as determined by the researcher (e.g., 6:00 PM, 10 minutes): Myoclonic seizures ●Absence seizures Focal aware seizures without motor signs (e.g., focal...) Sensory epileptic seizures

[0065] In addition, caregivers assessed their impressions of absence, myoclonic, and focal sensory seizures daily as instructed by the researchers using a 3-point Likert-type scale (0 = no seizures, 1 = some seizures, 2 = numerous seizures). The researchers identified the most disabling seizure types experienced by patients. This was based on the researchers' clinical observations.

[0066] Video electroencephalograms (video-EGGs) lasting 2, 4, or 24 hours were performed at the start and end of the study. Information was captured via video-EGGs and included wakeful and sleep EEG backgrounds, features of interictal epileptiform and non-epileptiform abnormalities, and EEG and clinical features of seizures that occurred during the study. Video-EGG interpretation was performed by an independent reviewer. When additional consent was required to transmit EEG data to the central reviewer, the investigator obtained consent before the EEG left the site. If the subject / caregiver did not provide consent, the EEG was not provided to the central reviewer. Patients continued to meet inclusion / exclusion criteria to continue treatment. Phase A: Increased dosage period

[0067] For patients <25kg, the initial dose is 125mg CBD Q12H (±2 hours), resulting in a total daily dose of 250mg CBD over the four-week escalation period. At the fourth week visit (Visit 4), based on researcher discretion, the dose may be maintained at 250mg CBD daily or increased to 250mg CBD Q12H (±2 hours), resulting in a total daily dose of 500mg CBD (4 sachets) for the remaining 22 weeks of treatment.

[0068] Patients weighing >25 kg received 250 mg CBD Q12H (±2 hours), bringing the total daily dose to 500 mg CBD over the four-week escalation period. At the fourth week visit (Visit 4), based on the investigator's judgment, the dose could be maintained at 500 mg CBD daily or increased to 375 mg CBD Q12H (±2 hours), bringing the total daily dose to 750 mg CBD (6 sachets) for the remaining 22 weeks of treatment. Phase A: Maintenance Period

[0069] In week 10, patients using 500 mg CBD daily can increase their dosage to 750 mg CBD daily (6 sachets), and patients using 750 mg CBD daily can increase their dosage to 1000 mg CBD daily (8 sachets).

[0070] After patients began the maintenance period, investigators reduced the dose as needed based on safety and tolerability. Patients using 250 mg CBD Q12H (±2 hours) could reduce their dose from a total daily dose of 500 mg CBD to 125 mg CBD Q12H (±2 hours); the total daily dose was 250 mg CBD. Patients using 375 mg CBD Q12H (±2 hours) could reduce their dose from a total daily dose of 750 mg CBD to 250 mg CBD Q12H (±2 hours); the total daily dose was 500 mg CBD. Patients using 500 mg CBD Q12H (±2 hours) could reduce their dose from a total daily dose of 1000 mg CBD to 375 mg CBD Q12H (±2 hours); the total daily dose was either 750 mg or 250 mg CBD Q12H (±2 hours); the total daily dose was 500 mg CBD. Patients whose weight changed during the study could have their dose increased or decreased.

[0071] Based on the patient's initial dose at the time of discontinuation, a gradual tapering period ranging from one to three weeks is followed. After the tapering, the patient is required to complete a four-week telephone follow-up period.

[0072] Parents / caregivers were instructed to record the frequency and type of seizures, as well as skin irritation scores, in a daily diary. Parents / caregivers also completed: (1) The University of Washington Caregiver Stress Scale on day 1, week 14 and week 26. (2) Epilepsy and Learning Disabilities Quality of Life Scale (ELDQOL-modified) at day 1, week 14 and week 26. (3) Childhood Sleep Disorders Scale (SDSC) on day 1, week 14 and week 26. (4) Vineland Adaptive Behavior Scale-3 (VABS-3) on day 1 and week 26. (5) Parents / caregivers also completed a daily Likert-type “good day / bad day” questionnaire. (6) Qualitative caregiver feedback in week 26. Purpose

[0073] The primary objective of this study was to evaluate the safety and tolerability of ZYN002 in children and adolescents with developmental and epileptic encephalopathy (DEE) lasting up to 72 weeks.

[0074] The secondary objective was to evaluate the efficacy of ZYN002 in terms of seizure frequency, caregiver stress, quality of life, sleep disturbances, adaptive behavior in patients with epilepsy, and overall daily assessments (“good days / bad days”). Evaluation criteria

[0075] Safety: Safety assessment includes collection of adverse events (AEs), physical and neurological examination, 12-lead ECG, clinical laboratory assessment (hematology, chemistry and urinalysis, testosterone (male only), Tanner staging scale, pregnancy test (female only), C-SSRS (children), cannabis withdrawal checklist (behavioral checklist), and results of post-treatment skin examination.

[0076] Skin Integrity: Provide parents / caregivers with a diary to complete daily skin checks. Parents / caregivers record the skin check score once each evening in the daily skin check diary.

[0077] Seizure frequency: The primary efficacy assessment was the median percentage change in the frequency (SF28) of the mean monthly (28-day) seizures of the following types over a 26-week (Phase A) period compared to baseline, totaling (“countable seizures”): Generalized tonic-clonic seizures (“primary generalized tonic-clonic” seizures) Focal sensory impairment seizures ● Focal extension to bilateral tonic-clonic seizures

[0078] Summarize seizure endpoints monthly.

[0079] Secondary seizure endpoints include the following median percentage change in SF28 from baseline: • All “countable seizures” (individual and total): —Generalized tonic-clonic seizures (GTCS) —Focal sensory impairment seizures (FIAS) —Focal extension to bilateral tonic-clonic seizures (BTCS) —Tonic seizure (T) —Clonic epileptic seizure (C) —Atonic seizures —Epileptic spasm (ES) —Focal sensory seizures (FM) with motor signs • All focal-onset seizures (FIAS, BTCS, FM)

[0080] The type of epileptic seizure was identified (at baseline) as the most disabling overall: The frequency of the following types of epileptic seizures during the daily observation period, which occurred continuously at a countable frequency: Myoclonic seizures (M) Absence seizures (A) Focal sensory seizures without motor signs (FAS)

[0081] Other epileptic endpoints include: ● If a patient's Red SF is ≥35%, 50%, or 90%, the patient's percentage within a given period is defined as 35%, 50% or 90% of respondents. • Number of days without seizures (select countable seizures). • Use a 3-point Likert scale (no, some, and many seizures) captured in a diary to assess uncountable seizures (myoclonic, absence, and focal sensory seizures).

[0082] Other efficacy endpoints include: • Changes in the total score of the University of Washington Caregiver Stress Scale from baseline to weeks 14, 26, and 50 / ET; • Changes in ELDQOL-improved subscale scores from baseline to weeks 14, 26, and 50 / ET; • Changes in total subscale scores of the SDSC from baseline to weeks 14, 26, and 50 ET; ● For each cycle used to assess seizure frequency, assess the change from baseline in the "good day / bad day" assessment; and ● Changes in VABS-3 combination and subscale scores from baseline to week 26 and week 50 / ET.

[0083] At week 26, clinicians captured qualitative caregiver feedback and asked the following questions: (1) “Have there been any improvements for [Patient Name] and your family since [Patient Name] started using the gel?”; (2) “Have there been any worsening conditions for [Patient Name] and your family since [Patient Name] started using the gel?”; and (3) “Let me ask just a few specific things: daily activities, such as going to school? If so, how? alertness? If so, how?”. result

[0084] Data shows that ZYN-002 reduces the frequency of seizures in many types of developmental and epileptic encephalopathy that are difficult to treat. It also improves significant behavioral deficits, alertness, social connection, and enables children to attend school more consistently and healthily. DEE is one of the most challenging and poorly controlled epilepsy disorders, with many symptoms that adversely affect patient and family functioning.

[0085] These results indicate a significant reduction in seizures and improvements in many difficult behaviors and symptoms, such as seizure intensity, fatigue, social isolation, poor cognitive and language deficits.

[0086] Of the 48 patients recruited, 21 have completed the tapering phase and discontinued treatment, while 27 have continued. Only one participant discontinued treatment due to an adverse event. Seizures and frequency of seizures

[0087] Of the 48 patients recruited, 33 (approximately 70%) had focal sensory impairment seizures (FIAS; formerly known as complex partial seizures) and / or convulsive seizures at baseline (focal extension to bilateral tonic-clonic seizures and generalized tonic-clonic seizures, BTCS and GTCS, respectively).

[0088] refer to Figure 1 Compared to baseline seizure frequency, using monthly seizure frequency standardized to 28 days (SF28), these patients experienced a median reduction of ≥44% in seizure frequency starting from month 2. Thirteen of the 46 patients had various non-FIAS and non-convulsive seizure types at baseline. Fifty-five percent (55%) of patients with FIAS and / or convulsive seizures experienced a median seizure reduction of ≥50% at month 6 of treatment. At month 6 of treatment, patients with DS or LGS experiencing FIAS and / or convulsive seizures (n=11) experienced a median reduction of 51% in FIAS and / or convulsive seizures compared to baseline. At month 6 of treatment, sixty percent (60%) of patients with DS or LGS experienced a median reduction of ≥50% in FIAS or convulsive seizures. Qualitative Caregiver Feedback: A Qualitative Analysis of the Impact of ZYN-002 on Behavioral and Cognitive Impairment

[0089] Parents and caregivers were asked to provide a qualitative assessment of their child's overall experience with ZYN-002 throughout the treatment period. Top-line results included: ●53% reported improved vitality (e.g., alertness / awareness, energy). ●51% reported an improvement in seizure frequency. • 47% reported improvements in cognition and concentration. • 44% reported improvements in engagement, relationships, and speaking / participation. Communication and social avoidance behaviors. • 28% reported that their children attended school on time / more frequently. ●26% reported difficulties applying the gel to their children (e.g., the time it takes for the gel to dry).

[0090] Data analysis was performed in parallel by two naive independent coders. Coding was done in Atlas.ti software. Reports from any caregivers regarding their child's physical signs, symptoms, or other experiences were coded. Responses from 43 participants were also coded. Results are shown in Table 3. The methodology was based on absolute statements (allowing each patient to submit multiple statements). Table 3: Qualitative Caregiver Feedback Results Table 3: Qualitative Caregiver Feedback Results Table 3: Qualitative Caregiver Feedback Results

[0091] Table 4 provides a complete record of patient mentions. Security

[0092] ZYN-002 was well tolerated. Eight patients discontinued the study; one due to an adverse event (skin reaction), and seven due to consent to withdrawal or perceived lack of efficacy. At baseline (before starting study treatment), 14 of the 48 enrolled patients (29.2%) reported a total of 22 adverse events (AEs). After six months of treatment, 96% of patients experienced a treatment emergencies (TEAE), and 60% experienced study-related TEAEs. There was no significant trend toward an increase in the incidence of AEs as ZYN002 dose levels increased. During the tapering period, 12 of the 21 patients (57.1%) reported TEAEs. Most TEAEs were mild to moderate and transient. The most frequently reported TEAEs according to preferred terminology were respiratory tract infection (41.7%), nasopharyngitis (20.8%), somnolence (12.5%), and vomiting (10.4%). The next most frequently reported treatment-associated adverse events (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 treatment, and one patient (4.8%) reported a serious adverse event during gradual dose reduction; eight patients experienced infection-related events, and two experienced exacerbations of epilepsy. Two SAEs (lower respiratory tract infection and status epilepticus) were considered potentially treatment-related. No patient deaths occurred during the study period. Example 2: A study of four patients with SYNGAP1

[0093] In the ZYN2-CL-025(BELIEVE) study, there were four patients with SYNGAP1, as shown in Table 5.

[0094] Table 5 provides patient data for four patients with SYNGAP1. Table 5: Patient data of patients with SYNGAP1 in the BELIEVE clinical trial

[0095] No qualitative feedback was given to patients aged 3.5 and 9 years. Qualitative feedback was given to patients aged 6.5 and 11.5 years. For the 6.5-year-old patient, the qualitative feedback indicated "significant overall improvement." And for the 11.5-year-old patient, the qualitative feedback indicated that the patient was "happier, more engaged, and now able to wave to people."

Claims

1. A method for treating SYNGAP1 encephalopathy, the method comprising: An effective amount of cannabidiol (CBD) was administered transdermally to the subject, wherein the subject's SYNGAP1 symptoms were treated.

2. The method according to claim 1, wherein, The effective dose of CBD is 250 mg, 500 mg, 750 mg or 1000 mg per day.

3. The method according to claim 1, wherein, The effective dose of CBD is 750 mg total per day.

4. The method according to claim 1, wherein, The effective dose of CBD is 1000 mg total per day.

5. The method according to any one of the preceding claims, wherein, The SYNGAP1 symptoms described in the treatment are one or more behavioral problems.

6. The method according to claim 5, wherein, The treatment of one or more behavioral problems involves the reduction of one or more behavioral problems.

7. The method according to claim 6, wherein, The aforementioned one or more behavioral problems include social avoidance, attention deficit, impulsivity, mood disorders, inattention, impulsivity, or physical aggression.

8. The method according to any one of claims 1-4, wherein, The SYNGAP1 symptom for which treatment is applied is epileptic seizures.

9. The method according to claim 8, wherein, Treatment includes a reduction of approximately 25% to approximately 45% in SYNGAP1 seizures.

10. The method according to claim 9, wherein, The SYNGAP1 seizure is at least one of focal sensory impairment seizure (FIAS) or atonic seizure (AT).

11. The method according to any one of claims 1-4, wherein, Two or more SYNGAP1 symptoms are treated.

12. The method according to claim 11, wherein, Symptoms of SYNGAP1 that require two or more treatments include behavioral problems and SYNGAP1 seizures.

13. The method according to claim 12, wherein, The treatment of the behavioral problems includes the reduction of one or more behavioral problems, and the treatment of the SYNGAP1 seizures includes a reduction of SYNGAP1 seizures by approximately 25% to approximately 45%.

14. The method according to claim 13, wherein, The behavioral problems mentioned include social avoidance, attention deficit, impulsivity, mood disorders, inattention, impulsivity, or physical aggression.

15. The method of claim 13, wherein, The SYNGAP1 seizure is at least one of focal sensory impairment seizure (FIAS) or atonic seizure (AT).

16. The method according to any one of the preceding claims, wherein, The treatment includes improvements in daily satisfaction and well-being.

17. The method according to any one of the preceding claims, wherein, The treatment includes improvements in cognition and awareness.

18. The method according to any one of the preceding claims, wherein, Treatment includes a meaningful monthly reduction in focal sensory impairment seizures and convulsive seizures.

19. The method according to any one of the preceding claims, wherein, The CBD is administered once or twice daily.

20. The method according to any one of the preceding claims, wherein, The CBD mentioned is synthetic CBD.

21. The method according to claim 20, wherein, The CBD was purified.

22. The method according to any one of claims 1-19, wherein, The CBD mentioned is of plant origin.

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