CN116782891A - Treatment of refractory seizures with cannabidiol - Google Patents

Abstract

The present application provides methods of treating refractory seizures in a human subject (e.g., a child) comprising administering an effective amount of Cannabidiol (CBD), e.g., in the form of a transdermal gel.

Description

Treatment of refractory seizures with cannabidiol

Cross Reference to Related Applications

The present application claims priority from U.S. provisional application 63/121,076 entitled "treatment of refractory seizure (Treatment of Refractory Seizures)" filed on month 12 of 2020, and U.S. provisional application 61/142,820 entitled "treatment of refractory seizure" filed on month 28 of 2021. The contents of which are incorporated herein by reference in their entirety.

Technical Field

The present disclosure relates to methods of treating epileptic seizures (seizure) in a patient by transdermally administering an effective amount of Cannabidiol (CBD) to a subject in need thereof. More specifically, the present disclosure relates to the treatment of refractory seizures in children by transdermal administration of an effective amount of a CBD.

Background

Developmental and Epileptic Encephalopathy (DEE) is a serious group of neurological developmental disorders characterized by seizures and abnormal electroencephalogram activity that have a negative impact on development. For refractory seizures (such as DEE children), a safe and effective treatment is needed. Treatment is particularly difficult when the subject is suffering from autism spectrum disorder, and the like.

Disclosure of Invention

EPIDIOLEX oral CBD solutions have been approved for the treatment of epilepsy in children with Lennox-Gastaut and Dravet syndrome. However, oral administration has been translated into Gastrointestinal (GI) adverse events, e.g., EPIDIOLEX brand reports that 32% of its patients develop somnolence and sedation, and is dose dependent. EPIDIOLEX cannabidiol oral solution brand (month 6 of 2018). Oral CBD also has the potential to degrade to THC in gastric acid, which may be associated with undesirable psychoactive effects. As above.

Children diagnosed with autism spectrum disorders need effective therapeutic methods for specific target (refractory) seizure types (e.g., refractory seizures for treatment of autism spectrum disorders). Quality of life (QoL) of drug resistant epileptic infants decreases with increasing numbers of ASMs, increasing seizure frequency and decreasing intelligence, further emphasizing the need for new therapies. There is also a need for a treatment that does not produce adverse side effects such as drowsiness, comatose, withdrawal or sedation.

The present disclosure relates to a method of treating refractory seizures in a subject comprising transdermally administering to the subject an effective amount of a CBD. The CBD may be ZYN002, a transdermal synthetic CBD gel formulation. The subject may be a child, including a child suffering from one or more diseases such as Autism Spectrum Disorder (ASD), developmental and Epileptic Encephalopathy (DEE), or epilepsy. For example, the subject may be a child suffering from both ASD and epilepsy. Effective treatments also include improving sleep quality, onset of sleep, and maintenance of sleep in children.

In some examples, the disclosure relates to a method of treating a human suffering from Autism Spectrum Disorder (ASD). The method may comprise administering to a human in need thereof an effective amount of Cannabidiol (CBD) effective to treat refractory seizures in patients with ASD.

In some examples, the type of refractory seizure is focal perception damaging seizure (FIAS), generalized tonic-clonic seizure (GTCS), or focal progression to bilateral tonic-clonic seizure (FBTCS).

In some examples, the CBD may be administered transdermally. The effective amount of CBD may vary from about 250mg to about 1000mg total daily. An effective amount of CBD may be 250mg total daily. An effective amount of CBD may be a total daily amount of 500mg. An effective amount of CBD may be 750mg total daily. An effective amount of CBD may be 1000mg total daily. CBD may be administered in a single daily dose. CBD may also be administered in two doses per day.

In some examples, the treatment includes improvement of sleep-related impairment. Improvements in sleep related impairment include improvements in sleep quality, onset of sleep, overall sleep, falling asleep and maintaining sleep, sleep-wake transitions, or arousal and nightmare disorders.

In some examples, the CBD is a synthetic CBD. The CBD may be a purified CBD. CBDs may be of plant origin. The cannabidiol may be (-) -cannabidiol.

In some examples, the CBD is formulated as a gel. CBDs can be formulated as permeation-enhanced gels.

In some examples, circadian rhythms are maintained or improved after administration of an effective amount of CBD begins. In some examples, administering an effective amount of CBD does not addict and the human subject does not experience excessive sleepiness (excessive somnolence).

The present disclosure relates to a method of treating refractory seizures in a human suffering from Autism Spectrum Disorder (ASD). The method comprises administering to a human in need thereof an effective amount of Cannabidiol (CBD) effective to treat refractory seizures in a human having an ASD. The human subject may include a child diagnosed with ASD. The human subject may also include a human subject having ASD and a complication of refractory epilepsy.

The present disclosure relates to a method of treating refractory seizures in children with Developmental and Epileptic Encephalopathy (DEE). The method may comprise administering to a child in need thereof an effective amount of Cannabidiol (CBD) effective to treat refractory seizures in DEE children.

Drawings

Fig. 1 shows a study design and treatment method of cannabidiol transdermal gel in accordance with the present disclosure.

Fig. 2 shows the scoring results of the good/bad day evaluation.

Fig. 3 is a graph showing the results of the therapeutic effect during the treatment period.

Fig. 4 is a graph showing the results of the percentage of patients with reduced seizures.

Fig. 5 is a graph showing the results of median percent of seizure frequency reduction at 28 days from baseline.

Fig. 6 is a graph showing the results of percentage of patients with reduced seizures combined with Autism Spectrum Disorder (ASD) at baseline.

Figure 7 shows the percentage of patients (DEE) that exceeded the clinically significant sleep problem threshold according to the pediatric Sleep Disorder Scale (SDSC) at baseline and week 26 of ZYN002 treatment.

Figure 8 shows the percentage of patients (DEE) at baseline and 26 th week threshold t-score >70, corresponding to clinically significant sleep problems.

Figure 9 shows that the percentage of patients (DEE) who incorporated ASD was above the threshold for clinically significant sleep problems at baseline and week 26 of ZYN002 treatment according to the pediatric Sleep Disorder Scale (SDSC).

Figure 10 shows the percentage of pooled ASD patients (DEE) at baseline and week 26, shi Yuzhi t-score >70, corresponding to clinically significant sleep problems.

Figure 11 shows a profile of the good/bad day scores at baseline and month 6 of ZYN002 treatment.

Detailed Description

Provided herein are methods of treating a seizure, e.g., refractory seizure, in a subject by transdermally administering to the subject an effective amount of a CBD. The subject may have ASD and epilepsy (DEE) at the same time.

Trial summarized in the examples-phase 2 open label clinical trial-safety, tolerability, and efficacy of transdermally administered CBD in DEE, a heterogeneous group of rare pediatric epileptic syndromes including, but not limited to, dravet Syndrome (DS), lennox-Gastaut syndrome (LGS), and West syndrome.

Fourteen children in the DEE study were predictably identified as simultaneously diagnosed with ASD. While it is believed that seizures can be more easily controlled medically in the general population of ASDs, refractory seizures in ASDs are also rare populations and can also be used as therapeutic indications, with treatment being difficult and/or refractory seizures-generalized for all children in DEE studies. Refractory epilepsy is drug resistant and treatment of refractory epilepsy does not provide significant degrees of seizure freedom. Similarly, refractory seizures are resistant to drugs, and treatment of refractory seizures does not provide significant degrees of seizure freedom.

Of the 14 ASD children with DEE, 11 showed global evidence of positive therapeutic benefit on total seizure count, and 11 patients were diagnosed with seizure types of focal perceptually impaired seizures (FIAS) or tonic-clonic seizures (TCS), including generalized tonic-clonic seizures (GTCS) or focal progression to bilateral tonic-clonic seizures (FBTCS). Of 11 ASD children with FIAS or TCS, 8 showed improvement of seizures during open label treatment of ZYN002 as adjuvant therapy to stable standard of care.

Transdermal administration of an effective amount of CBD has a positive effect on sleep in children with DEE, such as children with ASD co-morbid with epilepsy (DEE). For example, transdermal CBD administration can be used to treat sleep onset and sleep maintenance Disorders (DIMS) in ASD patients with epilepsy. Transdermal administration of an effective amount of CBD may increase the number of good days and decrease the number of bad days in pediatric patients.

Definition of the definition

As used herein, the term "treating" or "treatment" refers to alleviating, ameliorating, reducing, or alleviating at least one symptom (e.g., behavioral symptom) of a condition, disease, or disorder in a subject (e.g., a human), or ameliorating a determinable parameter associated with the condition, disease, or disorder.

The terms "clinical efficacy", "clinically effective", and the like as used herein refer to efficacy as demonstrated in clinical trials conducted by the Food and Drug Administration (FDA) or any foreign counterpart, such as the European Medicines Agency (EMA).

As used herein, the term "cannabidiol" or "CBD" refers to cannabidiol; cannabidiol prodrugs; pharmaceutically acceptable derivatives of cannabidiol, including pharmaceutically acceptable salts of cannabidiol, prodrugs of cannabidiol, and derivatives of cannabidiol. CBD includes 2- [ 3-methyl-6- (l-methylvinyl) -2-cyclohexen-l-yl ] -5-pentyl-l, 3-benzenediol, and pharmaceutically acceptable salts, solvates, metabolites (e.g., skin metabolites) and metabolic precursors thereof. The synthesis of CBDs is described, for example, in Petilka et al, helv.Chim.acta,52:1102 (1969) and Mechoulolam et al, J.am.chem.Soc.,87:3273 (1965), hereby incorporated by reference.

ZYN002 is a pharmaceutically-prepared transdermal CBD gel for reducing seizures in a patient and improving behavioral symptoms in a patient. Patients may have ASD, epilepsy, DEE, fragile X Syndrome (FXS), and other diseases. Some patients may suffer from complications of various diseases, such as ASD and epilepsy. In some examples, the human subject with ASD includes a child diagnosed with ASD, and the human subject may have a co-disease of ASD and epilepsy, such as refractory epilepsy. In some examples, the term "child" refers to a patient aged 3-18 years.

The term "epileptic encephalopathy" refers to epileptic activities that themselves contribute to serious cognitive and behavioral problems beyond what can be expected from underlying pathologies (e.g., cortical deformities) alone. The occurrence of these disorders may occur at any age.

The term "developmental and epileptic encephalopathy" or "DEE" refers to severe epileptic conditions that occur during infancy and childhood. DEE is characterized by the presence of multifocal and generalized seizure types and serious cognitive and behavioral problems. In DEE, cognitive and behavioral problems can occur independently of epileptic activity, even before seizures occur frequently, suggesting that DEE has developmental components in addition to epileptic components. Such damage may occur early or worsen over time. Scheffer, "ILAE classification of the epilepsies: position paper of the ILAE Commission for Classification and Terminology" Epilepia 58 (4): 512-521,2017.DEE includes hereditary seizures such as CDKL5, SCN 1A-and STXBP 1-related disorders. It also includes Lennox-Gastaut syndrome (LGS), ohtahara, west, landau-Kleffner, doose, dravet Syndrome (DS) and Infantile Spasticity (IS). The incidence of DEE at onset for less than or equal to 18 months is 1 person per 2000 live infant.

The term "transdermal administration" as used herein refers to contacting the CBD with the skin of a patient or subject under conditions effective for the CBD to penetrate the skin.

The terms Developmental and Epileptic Encephalopathy (DEE) were introduced by the international antiepileptic consortium (ILAE) classification and the term working group (Scheffer et al, 2017) to more fully describe the clinical manifestations of co-existing developmental disorders and epileptic encephalopathy. Historically, epileptic encephalopathy, the term "developmental" was not used in a broader sense to cover both concepts. In 2001, ILAE considered epileptic encephalopathy as a unique category. Engel, "Aproposed diagnostic scheme for people with epileptic seizures and with epilepsy: report of the ILAE Task Force on Classification and Terminology" Epilepia 42:796-803 (2001). ILAE defines epileptic encephalopathy as a condition in which an epileptic EEG abnormality itself is thought to lead to a progressive disorder of brain function. In 2010, the redefinition of epileptic brain disease as epileptic activity itself may lead to serious cognitive and behavioral problems beyond what can be expected from underlying pathology (e.g. cortical deformity) alone, and can 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" Epilepiaa51:676-685 (2010).

The term "developmental" changes are included in the specification to specifically identify patients who have both developmental disorders and epileptic encephalopathy, as well as patients who have developmental disorders without frequent epileptic activity associated with developmental disorders or epileptic encephalopathy without pre-existing developmental disorders. A key part of this concept is that an improvement in epileptic activity may have the potential to improve the developmental consequences of the disease (Scheffer et al, 2017).

The overall incidence and prevalence of developmental and epileptic encephalopathy is low. Patients with DEE may include, but are not limited to, patients with: lennox-Gastaut syndrome, dravet syndrome, doose syndrome (myoclonus-tension-loss Epilepsy (EMAS)), west syndrome (infantile spasticity), landau-Kleffner syndrome, or hereditary diseases such as CDKL5 encephalopathy and CHD2 encephalopathy.

Seizures are often refractory to anti-seizure drugs (ASM) such as standard anti-epileptic drugs (AED). For example, seizures in patients with DEE are often refractory to AEDs. Accordingly, more aggressive adjunctive use of AEDs (e.g., benzodiazepines, valproic acid, and lamotrigine), immunomodulatory therapies (e.g., corticosteroids, intravenous immunoglobulins [ IVIG ], plasmapheresis), ketogenic diets, and surgical regimens that are believed to be effective in inhibiting inter-seizure epileptic-like discharges is often considered. In addition, oral administration of AEDs can be difficult due to behavioral and cognitive disorders.

While patients with DEE may develop various seizure types and sub-conditions, the current one or more AED approved by the us FDA for adjunctive therapy for DEE subtype is only Lennox-Gastaut syndrome, dravet syndrome, and infantile spasticity (table 1). Children with DEE may be medically fragile and have a variety of co-diseases including motor and cognitive disorders, ASD and sleep disorders, which further increase disability. In some examples, children are defined as 3 years to less than 18 years of age.

Table 1: currently, the U.S. FDA approved drugs for DEA subtype

In view of the difficulty of treatment and limited evidence of control trials of approved drugs, clinicians typically use standard AEDs in a trial-and-error manner based primarily on clinical experience or open label trials. Lennox-Gastaut syndrome and Dravet syndrome are the DEE subtypes, with the most evidence of control trials of antiepileptic drugs.

Similar to DEE, children with ASD have refractory seizure types. For example, there is a need for treatment of refractory epilepsy in ASD.

Table 2 shows an overview related to QoL assessment of the belie study (fig. 1, discussed further below, shows study design and treatment of the belie study). QoL assessment was assessed by caregivers, including ELDQOL scale, daily "good/bad day" assessment, and qualitative feedback (table 2 and fig. 2).

Table 2: qoL assessment

ELDQOL: quality of life for epilepsy and learning disorders; qoL: quality of life.

^a ELDQOL is modified according to the written permissions of the developer; the modification does not affect the effectiveness of the questionnaire.

Table 3 shows an overview of the child Sleep Disorder Scale (SDSC), with the caregivers evaluating the child sleep disorder.

Table 3: sleep assessment

Transdermal pharmaceutical composition

Transdermal delivery of cannabidiol (e.g., CBD) has benefits over oral administration because it allows the drug to be directly absorbed into the blood stream through the skin. This avoids first pass liver metabolism, resulting in lower dosage levels of active pharmaceutical ingredient, higher bioavailability and improved safety. Transdermal delivery also avoids the gastrointestinal tract, reduces the chance of adverse events associated with the gastrointestinal tract, and reduces the likelihood of degradation of CBD to THC by gastric acid, which may be associated with undesirable mental effects. Furthermore, transdermal delivery of CBD reduces the intensity and frequency of sleepiness adverse events, which are typically present in oral administration of CBD. Transdermal delivery of CBD may avoid adverse liver function events, which are typically present in oral administration of CBD. In some embodiments, transdermally administering an effective amount of CBD reduces the intensity of at least one adverse event by about 15% to about 95% relative to orally administered CBD. Cannabidiol transdermal delivery systems are illustratively described in U.S. patent nos. 8,435,556 and 8,449,908, both of which are incorporated herein by reference.

The CBD may be in gel form and may be a pharmaceutically prepared transparent gel, such as a permeation enhancing gel designed to provide transdermal delivery of a controlled drug once or twice daily. The CBD gel may be 1% (wt/wt) CBD to 7.5% (wt/wt) CBD. The CBD gel may have, for example, a CBD of 4.2% (wt/wt) or a CBD of 7.5% (wt/wt). The CBD gel may be applied topically to the upper arm and shoulder, back, thigh, or any combination thereof of a patient by the patient or caregiver.

CBD gels may include diluents and carriers as well as other conventional excipients, such as wetting agents, preservatives and suspending and dispersing agents. The CBD may be a synthetic CBD. The CBD may be a purified CBD. CBDs may be of plant origin. The CBD may be (-) -cannabidiol.

The transdermal formulation may be a cream, ointment, lotion or salve. CBD may be delivered by bandages, pads (pads) or patches.

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

The CBD gel may comprise solubilising agents, penetration enhancers, solubilising agents, antioxidants, fillers, thickeners and/or pH adjusting agents. The composition of the 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. lower alcohols having 1-6 carbon atoms in an amount of about 15% to about 95% (wt/wt) of the composition; c. a first penetration enhancer present in an amount of from about 0.1% to about 20% (wt/wt) of the composition; water in an amount sufficient to bring the composition to a total of 100% (wt/wt). Other formulations of CBD gels can be found in international publication No. WO 2010/127033, the entire contents of which are incorporated herein by reference.

In some examples, the CBD gel may be provided in other ways, such as by a pump or as an alternative transdermal formulation.

An effective amount of CBD may be about 250mg to about 1000mg, which may be administered in a single daily dose or in two daily doses. For example, an effective amount of CBD may be about 250, 500, 750, or 1000mg total daily, which may be administered in a single daily dose or in two daily doses. To illustrate this, a total daily dose of 1000mg may be administered twice a day in a dose of 500 mg.

In some examples, circadian rhythms are maintained or improved upon initial administration of an effective amount of CBD. At least some, if not all, patients will not be addicted to administering an effective amount of CBD. In addition to the benefit of not producing craving at the beginning of administration of an effective amount of CBD, a human subject, such as a patient, may experience no excessive sleepiness.

Examples

Example 1: ZYN-002 study in children with DEE

This is a continuous, multi-stage, open-label, multi-national, multi-central, multi-dose study to evaluate the long-term safety, tolerability, and efficacy of ZYN002 (transdermal CBD gel) in children and adolescent epileptics with seizures associated with Developmental and Epileptic Encephalopathy (DEE) in the 3-18 years of age according to the international antiepileptic consortium (ILEA) classification (Scheffer et al, 2017). This study was performed to evaluate the efficacy of ZYN002 in DEE patients with ASD. The purpose of this study also included evaluating the effect of ZYN002 transdermal CBD gel on the qualitative assessment of QoL, sleep and caregivers in children and adolescent patients suffering from DEE.

Fig. 1 shows the study design and treatment method of example 1 of cannabidiol transdermal gel in belie (ZYN 2-CL-025) according to the present disclosure. ZYN 002A total daily dose of 250mg-1000mg was administered during the first 26 weeks of treatment (phase A) followed by an extension to 46 weeks (phase B). Results for month 12 of phase a and phase B and safety results for week 72 are discussed herein.

Approximately 48 patients entered group a, with 40 patients completing open label treatment at a. In phase a, the patient underwent a baseline period of 4 weeks, followed by a dosing period (dosing period) of 4 weeks, and an elastic dose maintenance period of 22 weeks. Patients received a total of 26 weeks of treatment during phase a.

Approximately 29 patients entered stage B, with 28 patients participating in their entirety. One patient withdrawn the consent on week 42, and at stage B, the patient continued to receive ZYN002 for the same maintenance dose they received on week 26 (e.g., end of stage a) for another 46 weeks.

During the 26-week treatment period and 46-week extended period (72-week total treatment duration), the patient received administration of study drug twice daily (every 12 hours ± 2 hours).

Patients entered into the group received an initial dose of ZYN-002, 250mg daily or 500mg daily on a weight basis. Patients weighing less than or equal to 25kg may be dosed to 750mg daily, and patients weighing >25kg may be dosed to 1,000mg daily.

Diagnostic and inclusion criteria

Patients participating in this study were diagnosed with developmental and epileptic encephalopathy. The patient is male and female, 3-18 years old, and has body mass index of 13-35kg/m ² The weight is not less than 12kg.

Patients have a diagnosis of Developmental and Epileptic Encephalopathy (DEE) defined by the international antiepileptic consortium classification (Scheffer 2017), which has global motor (i.e. global tonic-clonic, tonic, clonic, dystonic, epileptic spasticity), focal perceptual motor, focal perceptual impairment, or focal progression to bilateral tonic clonic seizures. Examples of DEEs involved include, but are not limited to: lennox-Gastaut syndrome, dravet syndrome, west syndrome/infantile spasticity and Doose syndrome. Diagnosis must have been established for 1 year or more and demonstrated by history and examination and review of appropriate studies including electroencephalogram (EEG), magnetic Resonance Imaging (MRI) scans or genetic testing.

Stabilization regimens of 1 to 4 ASMs in the patient were maintained throughout the study, starting at baseline.

The patient experienced five or more total seizures of the following types during the baseline period: global locomotion (i.e., global tonic clonic, tonic, clonic, dystonic or epileptic spasticity), focal sensorial motion, focal sensorial impairment or focal progression to bilateral tonic clonic seizures. A group of epileptic spasms were counted as a single seizure.

As determined by the investigator, the patient has a history of developmental delay with degradation, slowing or arrest in at least one developmental area after onset of the seizure.

Exclusion criteria

Study patient exclusion, including for the following reasons: tetrahydrocannabinol or CBD product was used less than or equal to 12 weeks prior to screening; treatment with strong inhibitors/inducers of CYP3 A4; changing ASM regimen or epileptic diet therapy during the first 4 weeks; or alanine aminotransferase, aspartate aminotransferase or total bilirubin levels greater than or equal to 3X upper normal limit (ULN).

Application site

Approved gel application sites are the upper right and upper left arms as specified in table 4.

Table 4: quantitative administration

If the application site became red, ZYN002 was temporarily applied to the upper left and right thighs after consultation with the researcher. Allowing low BMIs and/or forearm patients to apply ZYN002 to the right or left upper thigh. The order of administration was 1 pouch on each of the left and right upper arms/shoulders, and 1 pouch on each of the upper right and left thighs.

If applied to the right and/or left upper thigh, the procedure is the same as that described for the left and right upper arms/shoulders. Parents/caregivers use gel gloves. The parent/caregiver is sure that the gel is rubbed completely, no gel remains on the glove, and the skin surface to which the gel was applied is no longer shiny and dry to the touch prior to dressing. The parent/caregiver can apply the approved moisturizing lotion 2 hours after application.

Product, dose and mode of administration

The product was ZYN002 (cannabidiol: CBD), 4.2% gel, for topical application. And the drug was provided in a pouch containing 2.98g of gel to deliver 125mg CBD per pouch. Administered in one (1) to four (4) bags in the morning and evening to achieve the appropriate total daily dose for each patient based on the treatment group.

The treatment is as follows:

treatment A-125mg CBD Q12H (+ -2 hours); the total daily dose of CBD was 250mg (1 pouch in the morning, 1 pouch in the evening).

Treatment B-250mg CBD Q12H (+ -2 hours); the total daily dose of CBD was 500mg (2 sachets in the morning, 2 sachets in the evening).

Treatment of C-375mg CBD Q12H (+ -2 hours); the total daily dose of CBD was 750mg (3 sachets in the morning, 3 sachets in the evening).

Treatment D-500mg CBD Q12H (+ -2 hours); the total daily dose of CBD was 1000mg (4 sachets in the morning, 4 sachets in the evening).

Stage a: baseline period

During the 4-week baseline period, parents and/or caregivers record the following types of seizure numbers in the seizure diary:

general tonic-clonic ("primary general tonic-clonic") seizures

Focal perception damaging seizures

Focal progression to bilateral tonic clonic seizures

Focal perceptual seizure with motor signs

Tonic seizure

Clonic seizures

Seizure due to tension loss

Epileptic seizure (counting a group of epileptic seizures as a single seizure)

Seizures of the following types were captured in the daily diary at the same time and for the same duration of the day as determined by the investigator (e.g., 6:00pm,10 minutes):

myoclonus seizures

Seizure due to absence of spirit

Focal perceptual seizures without motor signs (e.g. focal sensory seizures)

Stage a: dosing period

For < 25kg patients, the initial dose was 125mg CBD Q12H (+ -2 hours) and the total daily dose for the four week dosing period was 250mg CBD. At Visit four weeks (Visit 4), based on the discretion of the investigator, the dose could be maintained at 250mg CBD daily or increased to 250mg CBD q12h (±2 hours) for the remaining 22 weeks of the treatment period with a total daily dose of 500mg CBD (4 sachets).

Patients weighing > 25kg received 250mg CBD Q12H (. + -. 2 hours) with a total daily dose of 500mg CBD for the four week dosing period. At Visit four weeks (visual 4), based on the discretion of the investigator, the dose could be kept at 500mg CBD per day or increased to 375mg CBD q12h (±2 hours) for the remaining 22 weeks of the treatment period with a total daily dose of 750mg CBD (6 sachets).

Stage a: maintenance period

On week 10, patients with 500mg CBD per day may be increased to 750mg CBD per day (6 sachets) and patients with 750mg CBD per day may be increased to 1000mg CBD per day (8 sachets).

After the patient begins the maintenance period, the investigator reduces the dose as needed based on safety and tolerability. Patients with CBD 250mg of Q12H (. + -.2 hours); the total daily dose of 500mg CBD can be reduced to 125mg CBD Q12H (+ -2 hours); the total daily dose was 250mg CBD. Patients with CBD 375mg of q12h (±2 hours); the total daily dose of 750mg CBD can be reduced to 250mg CBD Q12H (+ -2 hours); the total daily dose was 500mg CBD. Patients with CBD 500mg of Q12H (. + -. 2 hours); the total daily dose of 1000mg CBD can be reduced to 375mg CBD Q12H (+ -2 hours); the total daily dose is 750mg CBD, or 250mg CBD Q12H (+ -2 hours); the total daily dose was 500mg CBD. Patients with weight changes during the course of the study can increase or decrease their dose.

Depending on the dose at which the patient is stopped, a taper period ranging from one week to three weeks is completed. Following the taper, the patient is also required to complete a 4 week telephone follow-up period.

Evaluation criteria

Security assessment: security assessment includes AE collection, physical and neurological examination, vital signs, electrocardiography (ECG), skin examination (investigator) and recording (parent/carer) and laboratory testing.

Endpoint (endpoint)

Seizure frequency efficacy assessment endpoint is the median percent change from baseline in frequency of average monthly (28 days) seizures (SF 28) over 26 weeks (phase a), totaling ("countable seizures"):

focal perception damaging seizures (FIAS)

Tonic Clonic Seizures (TCS), comprising:

general Tonic Clonic Seizures (GTCS)

Focal progression to bilateral tonic clonic seizures (FBTCS)

Record FIAS and TCS reduction to 35% and 50% patient numbers.

QoL efficacy endpoint:

ELDQOL change from baseline to end of phase A

Changes in "good/bad day" assessment from baseline:

sleep efficacy endpoint:

SDSC change from baseline to end of phase A

Qualitative caregiver endpoint:

qualitative statement of parents and caregivers at the end of phase A

Analysis population: the safety analysis group included all patients who received 1 or more doses of study drug. Patients receiving study medication for > 80 days and completing > 80% of seizure recordings were included in the efficacy analysis and identified as improved intent-to-treat (mITT) populations.

Results

The data indicate ZYN-002 reduces seizure frequency in many types of refractory developmental and epileptic brain disorders, including refractory seizure types such as focal perceptive impairment seizures (FIAS), generalized tonic-clonic seizures (GTCS), or focal progression to bilateral tonic-clonic seizures (FBTCS).

These results indicate a meaningful reduction in seizures and improvement in many difficult behaviors and symptoms, such as sleep-related impairment, seizure intensity, fatigue, social isolation, poor cognitive ability, and language deficits. For example, a patient experiences an improvement in sleep-related impairment, including an improvement in sleep quality, onset of sleep, overall sleep, falling asleep and maintaining sleep, sleep-wake transitions, or arousal and nightmare disorders.

Of the 48 patients enrolled in BELIEVE (ZYN 2-CL-025), 40 completed phase A and 28 completed phase B for 12 months (Table 5). Only one subject withdrawn consent during phase B.

Table 5: cases of patients in ZYN2-CL-025

Baseline characteristics and seizure frequency

The average age was 10.5 years (see table 6) among 48 patients entered into the group belie and included in the safety analysis group. One-fourth of patients suffer from Lennox-Gastaut syndrome (LGS) or Dravet syndrome.

Clinically significant co-morbidities exist in all patients, including gait and movement disorders (45.8%), sleep disorders (39.6%), chronic respiratory disorders/infections (37.5%), ASD (29.2%), and percutaneous endoscopic gastrostomy (14.6%).

The mtt population included 46 patients (2 patients were excluded from efficacy analysis because they did not complete 80% of the record or use study medication for 80 days). 33 patients had FIAS and/or TCS at baseline and constituted a population that measured seizure frequency efficacy assessment endpoints.

Table 6: baseline population statistics and disease characteristics, safety analysis group

ASD: autism spectrum disorder; ASM: antiepileptic drugs.

^a At a baseline period of 4 weeks.

^b For seizure type, n=33. Thirty-three patients with focal perceptive impairment and/or tonic clonic seizures; the patient may have more than one seizure type.

^c Including generalized epileptic encephalopathy, focal DEE, multifocal DEE, unclassified DEE.

^d According to ASD diagnosis by researchers.

^e For seizure type, n=11. Eleven patients with focal perceptive impairment and/or tonic clonic seizures; the patient may have more than one seizure type.

Seizure frequency efficacy assessment endpoint

Fig. 3 is a graph showing efficacy during a treatment period. Specifically, figure 3 shows the median percentage of decrease in FIAS and TCS frequency from baseline over time points for patients with FIAS and/or TCS at baseline for 28 days. The median percentage decrease in the monthly frequency of FIAS and TCS from baseline during the treatment period of 12 months ranged from 44% at 3 months to 73% at 12 months.

Median reductions of FIAS, GTCS, and FBTCS at month 6 compared to baseline were 45%, 60%, and 59%, respectively, when analyzed by seizure type. Median reductions for FIAS, GTCS and FBTCS were 100%, 83% and 59% at month 12, respectively.

Fig. 4 is a graph showing the percentage of patients with reduced seizures. Specifically, fig. 4 shows the percentage of patients with FIAS and/or TCS at baseline that decreased by 35% and 50% at time points FIAS and TCS. By month 3, a relatively high percentage of patients achieved a reduction of FIAS and TCS of 35% or more and 50% or more and continued until month 12, e.g., the percentage of patients reaching 35% or more increased from 58% at month 3 to 89% at month 12; similarly, the percentage of patients reaching ≡50% increased from 46% at month 3 to 83% at month 12.

Figure 5 is a graph showing the median percentage of the 28-day seizure frequency reduction from baseline. Specifically, figure 5 shows the median percentage of time-point decrease in 28-day frequency of FIAS and TCS from baseline for patients with co-morbid ASD at baseline. In patients with co-morbid ASD, the median percentage of decrease in frequency of FIAS and TCS per month from baseline over a treatment period of 12 months ranged from 44% at 3 months to 68% at 12 months.

Fig. 6 is a graph showing patient percentile for seizure reduction of co-morbid Autism Spectrum Disorder (ASD) at baseline. Specifically, fig. 6 shows the percentage of patients with 35% and 50% decrease in FIAS and TCS at time points for co-morbid ASD patients at baseline. The percentage of patients with FIAS and TCS decreases by > 35% and > 50% increases over time. For example, the percentage of patients reaching ≡35% increases from 65% at month 3 to 88% at month 12; similarly, the percentage of patients reaching 50% or more increased from 41% on month 3 to 75% on month 12, with eight (8/9) of the parents/caregivers providing feedback about improvement and one-ninth (1/9) of the parents/caregivers indicating no improvement. Improvements reported by caregivers include less attention, participation, alertness, and academic drowsiness.

ELDQOL

A statistically significant decrease from baseline was observed in the mean ELDQOL subtyping scores for seizure severity, behavior, and emotion at week 26 (table 7).

Table 7: variation of the mITT population average ELDQOL sub-grade score from baseline (n=40) ^a

^a Table 7 includes patients who completed ELDQOL evaluations at both baseline and week 26; the 6 patients completed the baseline evaluation, but did not complete the week 26 evaluation.

^b Negative deviation from baseline reflection has an improving effect.

Sleep scoring

Sleep disorders affect many patients with DEE, ASD, or both. Sleep disorders include, but are not limited to: sleep onset or maintenance Disorders (DIMS), sleep respiratory disorders (SBD), wake/nightmare Disorders (DA), sleep Wake Transition Disorders (SWTD), excessive sleepiness Disorders (DOES), and sleep hyperhidrosis. Sleep onset or maintenance Disorders (DIMS) are disorders in which it is difficult for a patient to go to sleep or remain asleep (e.g., insomnia). Sleep disordered breathing (SBD) is a disorder that involves dyspnea during sleep (e.g., obstructive sleep apnea). A wake/nightmare (DA) disorder is a mental or motor event that occurs during non-REM sleep. Typical DA's include dream and nightmare. In most cases, the patient will not remember after full wake-up of the DA event. Sleep-wake transition disorders (SWTDs) include events that occur during the transition from sleep to wakefulness, and may include rhythmic movement disorders, dreaminess, and leg cramps. Excessive sleepiness Disorder (DOES) is characterized by sleepiness (excessive sleepiness) during the time of normal wakefulness. The hyperhidrosis is characterized by excessive sweating during sleep or at night.

Figure 7 shows the percentage of all patients above the clinically significant sleep problem threshold based on the pediatric Sleep Disorder Scale (SDSC) at baseline and week 26 of ZYN002 treatment. In fig. 7, the left column is the baseline percentage of patients and the right column is the 26 th week percentage of patients (see also table 8). Figure 8 shows the percentage of patients with a threshold t-score > 70 at baseline and week 26, corresponding to clinically significant sleep problems. In fig. 8, the left column is the baseline percentage of patients and the right column is the 26 th week percentage of patients. In total score, sleep onset or maintenance sleep Disorder (DIMS), wake/nightmare Disorder (DA) and sleep-wake transition disorder (SWTD), statistically significant improvement in sleep score over baseline was observed (see also table 9).

Figure 9 shows the percentage of co-morbid ASD patients (DEE) above the clinically significant sleep problem threshold based on the pediatric Sleep Disorder Scale (SDSC) at baseline and week 26 of ZYN002 treatment. In fig. 9, the left column is the baseline percentage of patients and the right column is the 26 th week percentage of patients (see also table 10). Figure 10 shows the percentage of co-morbid ASD patients (DEE) with a threshold t-score > 70 at baseline and week 26, which corresponds to clinically significant sleep problems. In fig. 10, the left column is the baseline percentage of patients and the right column is the 26 th week percentage of patients. In total score, sleep onset or maintenance sleep Disorder (DIMS), wake/nightmare Disorder (DA) and sleep-wake transition disorder (SWTD), statistically significant improvement in sleep score over baseline was observed (see also table 11).

Table 8: changes in all patients (DEE) -SDSC from baseline

^a Negative deviation from baseline reflection has an improving effect. The bias value is based on a corrected baseline average determined from the patient completing the study. Patients not completing the study were not included in the determination of the corrected baseline average.

Table 9: DEE patient > 70 total score (t score) -SDSC change from baseline

^a Negative deviation from baseline reflection has an improving effect. The bias value is based on a corrected baseline average determined from the patient completing the study. Patients not completing the study were not included in the determination of the corrected baseline average.

Table 10: DEE-ASD patient-SDSC change from baseline

^a Negative deviation from baseline reflection has an improving effect. The bias value is based on a corrected baseline average determined from the patient completing the study. Patients not completing the study were not included in the determination of the corrected baseline average.

Table 11: DEE-ASD patient > 70 total score (t-score) -SDSC change from baseline

^a Negative deviations from baseline reflect an improvement. The bias value is based on a corrected baseline average determined from the patient completing the study. Patients not completing the study were not included in the determination of the corrected baseline average.

Assessment of good/bad days

Figure 11 shows a profile of the baseline and the good/bad day ratings at month 6 of ZYN002 treatment. In fig. 11, the baseline ratio for the patients was 3.00% very poor, 9.30% poor, 35.70% general, 45.70% good, and 6.30% very good. Patient proportions at month 6 were 0.50% very poor, 3.20% poor, 25.90% normal, 59.80% good and 10.60% very good. When baseline was compared to month 6, the combined proportion of "good day" and "very good day" reports increased from 52.0% at baseline to 70.4%, and the combined proportion of "very bad day" and "bad day" reports decreased from 12.3% at baseline to 3.7% (fig. 11).

Qualitative feedback of caregivers

A qualitative caregiver assessment was made for parents/caregivers of 43 patients in the mITT population 46 patients. 84% (n=36) of parents/caregivers provided statement of > 1 regarding disease improvement, and 60% (n=26) provided statement of > 1 regarding disease deterioration (table 8). The summary index of the most qualitative assessment of most patients is improved:

any improvement: 84% (n=36)

-vigor improvement: 58% (n=25)

-improvement of seizures: 51% (n=22)

-improved cognition/attention: 47% (n=20)

-improved social avoidance behavior: 44% (n=19)

Improvement of irritability: 33% (n=14)

-school improvement: 28% (n=12)

-medical improvement: 14% (n=6)

Table 12 shows the most frequent positive and negative qualitative statements made by parents and caregivers (n.gtoreq.8) in the group of mITT groups (N=43) during phase A.

Table 12: in phase A, the most frequent positive and negative qualitative statements made by parents and caregivers (n.gtoreq.8) among the mITT population (N=43)

Safety of

ZYN-002 is well tolerated in the BELIEVE clinical trial at ZYN 002. Most treatment-emergent adverse events (TEAEs), any event, whether unrelated to study drug phase, are mild or moderate. During the 72 week treatment period, a total of 30 serious adverse events occurred in 14 patients, two of which (lower respiratory tract infection and status epilepticus) were considered likely to be drug-related. One patient with a history of keratosis discontinued study drug treatment due to AE (severe erythema at the site of administration); skin patch trials showed that this was not allergic contact dermatitis caused by ZYN002 and could be irritating contact dermatitis caused by secondary bacterial infection. There were no clinically significant changes in vital signs, ECG, or laboratory test results for other patients except that 1 patient had a benign, isolated elevated alkaline phosphatase (1.69 x ULN) at week 26, which was considered unrelated to study drug treatment.

BELIEVE is the first clinical trial of ZYN002 (percutaneous CBD) in DEE. The data show a significant decrease in FIAS and TCS after 12 months of treatment with ZYN 002. ZYN002 significantly reduced FIAS and TCS seizures in a subset of patients with ASD, with most children reaching 35% or 50% of the responder thresholds at month 3 and 6, respectively.

Treatment with ZYN002 may bring about clinical improvements in: seizure severity, behavior, and emotion; sleep onset and maintenance sleep, arousal/nightmare disorders, sleep-wake transitions, and general sleep; as well as vitality, cognition/attention, and social avoidance behavior.

ZYN002 is well tolerated in 18 months of treatment in medically fragile pediatric and adolescent patients with DEE. ZYN002 has positive benefit/risk profile as demonstrated in the belie clinical trial of patients with DEE and FIAS and TCS.

Claims (28)

1. A method of treating refractory seizures in a human subject having an Autism Spectrum Disorder (ASD), the method comprising:

administering to a human subject in need thereof an effective amount of Cannabidiol (CBD) to treat refractory seizures.

2. The method of claim 1, wherein the human subject is between 3-18 years of age and is diagnosed with ASD.

3. The method of claim 1 or 2, wherein the subject has refractory epilepsy.

4. The method of any one of the preceding claims, wherein the refractory seizure to be treated is selected from the group consisting of focal perception impaired seizure (FIAS), generalized tonic-clonic seizure (GTCS), or focal progression to bilateral tonic-clonic seizure (FBTCS).

5. The method of any one of the preceding claims, wherein the CBD is administered transdermally.

6. The method of any one of the preceding claims, wherein the effective amount of CBD is a total of about 250mg to about 1000mg per day.

7. The method of claim 6, wherein the effective amount of CBD is 250mg total daily.

8. The method of claim 6, wherein the effective amount of CBD is a total of 500mg per day.

9. The method of claim 6, wherein the effective amount of CBD is 750mg total daily.

10. The method of claim 6, wherein the effective amount of CBD is a total of 1000mg per day.

11. The method of any one of the preceding claims, wherein the CBD is administered in a single daily dose.

12. The method of any one of claims 1-10, wherein the CBD is administered in two doses per day.

13. The method of any of the preceding claims, wherein the treatment comprises ameliorating sleep-related impairment.

14. The method of claim 13, wherein improving sleep-related impairment comprises improving sleep quality, onset of sleep, overall sleep, falling asleep and maintaining sleep, sleep-wake transitions, or arousal and nightmare disorders.

15. The method of any one of the preceding claims, wherein the CBD is a synthetic CBD.

16. The method of any one of the preceding claims, wherein the CBD is a purified CBD.

17. The method of any one of claims 1-14 or 16, wherein the CBD is a plant-derived CBD.

18. The method of any one of the preceding claims, wherein the cannabidiol is (-) -cannabidiol.

19. The method of any one of the preceding claims, wherein the CBD is formulated as a gel.

20. The method of claim 20, wherein the CBD is formulated as a permeation enhanced gel.

21. The method of any one of the preceding claims, wherein circadian rhythm is maintained or improved upon initiation of administration of an effective amount of CBD.

22. The method of any one of the preceding claims, wherein administering an effective amount of CBD does not cause addiction.

23. The method of any one of the preceding claims, wherein the human subject does not experience excessive sleepiness after the administration of an effective amount of CBD has begun.

24. A method of treating refractory seizures in a human subject suffering from Autism Spectrum Disorder (ASD) and sleep disorders, the method comprising: an effective amount of Cannabidiol (CBD) is administered to a human subject to treat refractory seizures and sleep disorders.

25. The method of claim 25, wherein the human subject is between 3-18 years of age and is diagnosed with ASD.

26. The method of claim 25 or 26, wherein the refractory seizure to be treated is selected from the group consisting of: focal perception damaging seizures (FIAS), generalized tonic-clonic seizures (GTCS), or focal progression to bilateral tonic-clonic seizures (FBTCS).

27. The method of any one of claims 25-27, wherein the human subject further suffers from Developmental and Epileptic Encephalopathy (DEE).

28. A method of treating refractory seizures in children with Developmental and Epileptic Encephalopathy (DEE), the method comprising:

An effective amount of Cannabidiol (CBD) is administered to the child, wherein the refractory seizure is treated after administration of the CBD.