WO2022017936A1 - Use of cannabidiol in the treatment of seizures associated with rare epilepsy syndromes related to structural abnormalities of the brain - Google Patents

Use of cannabidiol in the treatment of seizures associated with rare epilepsy syndromes related to structural abnormalities of the brain Download PDF

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WO2022017936A1
WO2022017936A1 PCT/EP2021/069868 EP2021069868W WO2022017936A1 WO 2022017936 A1 WO2022017936 A1 WO 2022017936A1 EP 2021069868 W EP2021069868 W EP 2021069868W WO 2022017936 A1 WO2022017936 A1 WO 2022017936A1
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cbd
preparation
seizures
use according
heterotopia
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PCT/EP2021/069868
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French (fr)
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Daniel Adam CHECKETTS
Kevin James CRAIG
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GW Research Limited
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Priority claimed from GB2011119.1A external-priority patent/GB2597278A/en
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Publication of WO2022017936A1 publication Critical patent/WO2022017936A1/en

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    • A61K31/19—Carboxylic acids, e.g. valproic acid
    • A61K31/195—Carboxylic acids, e.g. valproic acid having an amino group
    • A61K31/197—Carboxylic acids, e.g. valproic acid having an amino group the amino and the carboxyl groups being attached to the same acyclic carbon chain, e.g. gamma-aminobutyric acid [GABA], beta-alanine, epsilon-aminocaproic acid or pantothenic acid
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    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
    • A61K31/4015—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil having oxo groups directly attached to the heterocyclic ring, e.g. piracetam, ethosuximide
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    • A61K31/33—Heterocyclic compounds
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    • A61K31/55—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole
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    • A61P25/08—Antiepileptics; Anticonvulsants
    • A61P25/12—Antiepileptics; Anticonvulsants for grand-mal

Definitions

  • the present invention relates to the use of cannabidiol (CBD) for the treatment of seizures associated with rare epilepsy syndromes.
  • CBD cannabidiol
  • the seizures associated with rare epilepsy syndromes that are treated are those which are experienced in patients diagnosed with Heterotopia.
  • the types of seizures include tonic, tonic-clonic, atonic, absence and focal seizures without impairment.
  • the dose of CBD is between 5 mg/kg/day to 50 mg/kg/day.
  • the CBD used is in the form of a highly purified extract of cannabis such that the CBD is present at greater than 95% of the total extract (w/w) and the cannabinoid tetrahydrocannabinol (THC) has been substantially removed, to a level of not more than 0.15% (w/w).
  • the CBD used is in the form of a botanically derived purified CBD which comprises greater than or equal to 98% (w/w) CBD and less than or equal to 2% (w/w) of other cannabinoids. More preferably the other cannabinoids present are THC at a concentration of less than or equal to 0.1% (w/w); CBD-C1 at a concentration of less than or equal to 0.15% (w/w); CBDV at a concentration of less than or equal to 0.8% (w/w); and CBD-C4 at a concentration of less than or equal to 0.4% (w/w).
  • the botanically derived purified CBD preferably also comprises a mixture of both trans-THC and cis-THC. Alternatively, a synthetically produced CBD is used.
  • the other cannabinoids present are THC at a concentration of about 0.01% to about 0.1% (w/w); CBD-C1 at a concentration of about 0.1% to about 0.15% (w/w); CBDV at a concentration of about 0.2% to about 0.8% (w/w); and CBD-C4 at a concentration of about 0.3% to about 0.4% (w/w).
  • THC is present at a concentration of about 0.02% to about 0.05% (w/w).
  • the CBD may be formulated for administration separately, sequentially or simultaneously with one or more AED or the combination may be provided in a single dosage form.
  • Epilepsy occurs in approximately 1% of the population worldwide, (Thurman et al., 2011) of which 70% are able to adequately control their symptoms with the available existing anti-epileptic drugs (AED). However, 30% of this patient group, (Eadie etal., 2012), are unable to obtain seizure freedom from the AED that are available and as such are termed as suffering from intractable or “treatment-resistant epilepsy” (TRE).
  • TRE treatment-resistant epilepsy
  • Intractable or treatment-resistant epilepsy was defined in 2009 by the International League against Epilepsy (I LAE) as “failure of adequate trials of two tolerated and appropriately chosen and used AED schedules (whether as monotherapies or in combination) to achieve sustained seizure freedom ” (Kwan et al., 2009).
  • Childhood epilepsy is a relatively common neurological disorder in children and young adults with a prevalence of approximately 700 per 100,000. This is twice the number of epileptic adults per population.
  • the main symptom of epilepsy is repeated seizures.
  • Clinical observations and electroencephalography (EEG) tests are conducted and the type(s) of seizures are classified according to the ILEA classification.
  • Generalized seizures where the seizure arises within and rapidly engages bilaterally distributed networks, can be split into six subtypes: tonic-clonic (grand mal) seizures; absence (petit mal) seizures; clonic seizures; tonic seizures; atonic seizures and myoclonic seizures.
  • Focal (partial) seizures where the seizure originates within networks limited to only one hemisphere, are also split into sub-categories.
  • the seizure is characterized according to one or more features of the seizure, including aura, motor, autonomic and awareness / responsiveness.
  • a seizure begins as a localized seizure and rapidly evolves to be distributed within bilateral networks this seizure is known as a bilateral convulsive seizure, which is the proposed terminology to replace secondary generalized seizures (generalized seizures that have evolved from focal seizures and are no longer remain localized).
  • focal seizures where the subject’s awareness / responsiveness is altered are referred to as focal seizures with impairment and focal seizures where the awareness or responsiveness of the subject is not impaired are referred to as focal seizures without impairment.
  • Heterotopia is defined as a cluster of normal neurons in abnormal locations and is divided into three main groups: periventricular nodular heterotopia, subcortical heterotopia, and band heterotopia.
  • the condition results from the nerve cells not migrating properly during early development of the foetal brain and is caused by one of several mutations in genes that code for proteins involved in neuronal migration.
  • Treatment of Heterotopia is generally focused on managing recurrent seizures with medications.
  • Subcortical band heterotopia is a condition in which neurons do not migrate to their proper locations in the fetal brain during early development. Normally, the neurons that make up the cerebral cortex are distributed in a well-organized and multi-layered way. In people with subcortical band heterotopia, some neurons that should be part of the cerebral cortex do not reach it. These neurons stop their migration process in areas of the brain where they are not supposed to be and form band-like clusters of tissue.
  • these bands are located beneath the cerebral cortex, they are said to be subcortical. In most cases, the bands are symmetric, which means they occur in the same places on the right and left sides of the brain.
  • the abnormal brain development causes neurological problems in people with subcortical band heterotopia.
  • the signs and symptoms of the condition depend on the size of the bands and the lack of development of the cerebral cortex.
  • the signs and symptoms can vary from severe intellectual disability and seizures that begin early in life and affect both sides of the brain (generalized seizures) to normal intelligence with seizures occurring later in life and affecting only one side of the brain (focal seizures).
  • Some affected individuals also have weak muscle tone (hypotonia), loss of fine motor skills such as using utensils, or behavioral problems.
  • Subcortical band heterotopia is typically found when brain imaging is done following the onset of seizures, usually in adolescence or early adulthood.
  • CBD Cannabidiol
  • One anecdotal report describes using CBD oil to treat a child with Heterotopia. 1
  • the oil which as well as comprising CBD, is unpurified and therefore comprises all the cannabinoid and non-cannabinoid components of a cannabis plant extract.
  • Gedde (2014) discloses an observational study carried out on a cohort of patients diagnosed with epilepsies of multiple etiologies. Amongst a wide range of diagnoses, structural causes of epilepsy were included, one of which listed is Heterotopia. It is stated that a wide range of cannabinoid products was used, from high ratio CBD:THC products to tetrahydrocannabinolic acid (THCA), low ratio CBD:THC, or a combination, without any further indication of the ratios. Despite stating seizure types were recorded, there is no actual disclosure of any types of seizures experienced by the patients.
  • WO 2019/245639 relates to the delivery of lipophilic drugs across the blood-brain barrier using an edible substrate to treat numerous central nervous system conditions, of which Heterotopia is listed as one.
  • An example given of a lipophilic drug is CBD, which may be given in the form of a CBD infused tea bag.
  • CBD cannabidiol
  • the seizures associated with Heterotopia are tonic, tonic- clonic, atonic, absence and focal seizures without impairment.
  • the CBD preparation comprises greater than 95% (w/w) CBD and not more than 0.15% (w/w) tetrahydrocannabinol (THC).
  • the CBD preparation comprises greater than or equal to 98% (w/w) CBD and less than or equal to 2% (w/w) other cannabinoids, wherein the less than or equal to 2% (w/w) other cannabinoids comprise the cannabinoids tetrahydrocannabinol (THC); cannabidiol- C1 (CBD-C1); cannabidivarin (CBDV); and cannabidiol-C4 (CBD-C4), and wherein the THC is present as a mixture of trans-THC and cis-THC.
  • THC cannabinoids tetrahydrocannabinol
  • CBD-C1 cannabidiol- C1
  • CBDDV cannabidivarin
  • CBD-C4 cannabidiol-C4
  • the CBD preparation is used in combination with one or more concomitant anti-epileptic drugs (AED).
  • AED concomitant anti-epileptic drugs
  • the one or more AED is selected from the group consisting of: valproic acid, levetiracetam, clobazam, vigabatrin, rufinamide, lacosamide, topiramate, lamotrigine, eslicarbazepine and felbamate.
  • the CBD is present is isolated from cannabis plant material.
  • the CBD is present as a synthetic preparation.
  • the dose of CBD is greater than 5 mg/kg/day. More preferably the dose of CBD is 20 mg/kg/day. More preferably the dose of CBD is 25 mg/kg/day. More preferably the dose of CBD is 50 mg/kg/day.
  • a method of treating seizures associated with Heterotopia comprising administering a cannabidiol (CBD) preparation to the subject in need thereof.
  • CBD cannabidiol
  • cannabinoids Over 100 different cannabinoids have been identified, see for example, Handbook of Cannabis, Roger Pertwee, Chapter 1, pages 3 to 15. These cannabinoids can be split into different groups as follows: Phytocannabinoids; Endocannabinoids and Synthetic cannabinoids (which may be novel cannabinoids or synthetically produced phytocannabinoids or endocannabinoids).
  • phytocannabinoids are cannabinoids that originate from nature and can be found in the cannabis plant.
  • the phytocannabinoids can be isolated from plants to produce a highly purified extract or can be reproduced synthetically.
  • “Highly purified cannabinoids” are defined as cannabinoids that have been extracted from the cannabis plant and purified to the extent that other cannabinoids and non-cannabinoid components that are co-extracted with the cannabinoids have been removed, such that the highly purified cannabinoid is greater than or equal to 95% (w/w) pure.
  • Synthetic cannabinoids are compounds that have a cannabinoid or cannabinoid-like structure and are manufactured using chemical means rather than by the plant.
  • Phytocannabinoids can be obtained as either the neutral (decarboxylated form) or the carboxylic acid form depending on the method used to extract the cannabinoids. For example, it is known that heating the carboxylic acid form will cause most of the carboxylic acid form to decarboxylate into the neutral form.
  • Treatment-resistant epilepsy (TRE) or “intractable epilepsy” is defined as per the I LAE guidance of 2009 as epilepsy that is not adequately controlled by trials of one or more AED.
  • Tonic seizures can be generalised onset, affecting both sides of the brain, or they can be focal onset, starting in just one side of the brain. If a tonic seizure starts in both sides of the brain, all muscles tighten and the subject’s body goes stiff. If standing, they may fall to the floor, their neck may extend, eyes open wide and roll upwards, whilst their arms may raise upwards and legs stretch or contract. If a tonic seizure starts in one side of the brain muscles tighten in just one area of the body. Tonic seizures usually last less than one minute.
  • Tonic-clonic seizures consist of two phases: the tonic phase and the clonic phase. In the tonic phase the body becomes entire rigid, and in the clonic phase there is uncontrolled jerking. Tonic-clonic seizures may or may not be preceded by an aura, and are often followed by headache, confusion, and sleep. They may last mere seconds or continue for several minutes. These seizures are also known as a grand mal seizure.
  • Atonic seizures occur when a person suddenly loses muscle tone so their head or body may go limp. They are also known as drop attacks. In some children, only their head drops suddenly. They can begin in one area or side of the brain (focal onset) or both sides of the brain (generalized onset).
  • “Absence seizures” are also called “petit mal” seizures. These types of seizure cause a loss of awareness for a short time. They mainly affect children although can happen at any age. During an absence seizure, a person may: stare blankly into space; look like they are "daydreaming”; flutter their eyes; make slight jerking movements of their body or limbs. The seizures usually only last up to 15 seconds and may occur several times a day.
  • “Focal Seizures” are defined as seizures which originate within networks limited to only one hemisphere. What happens during the seizure depends on where in the brain the seizure happens and what that part of the brain normally does.
  • “Focal seizures without impairment” are seizures which originate within networks limited to only one hemisphere where the awareness or responsiveness of the subject is not impaired.
  • the drug substance used is a liquid carbon dioxide extract of high-CBD containing chemotypes of Cannabis sativa L. which had been further purified by a solvent crystallization method to yield CBD.
  • the crystallisation process specifically removes other cannabinoids and plant components to yield greater than 95% CBD.
  • CBD is highly purified because it is produced from a cannabis plant rather than synthetically there is a small number of other cannabinoids which are co-produced and co-extracted with the CBD. Details of these cannabinoids and the quantities in which they are present in the medication are as described in Table A below.
  • the drug substance used in the trials is a liquid carbon dioxide extract of high-CBD containing chemotypes of Cannabis sativa L. which had been further purified by a solvent crystallization method to yield CBD.
  • the crystallisation process specifically removes other cannabinoids and plant components to yield greater than 95% CBD w/w, typically greater than 98% w/w.
  • the Cannabis sativa L. plants are grown, harvested, and processed to produce a botanical extract (intermediate) and then purified by crystallization to yield the CBD (botanically derived purified CBD).
  • the plant starting material is referred to as Botanical Raw Material (BRM); the botanical extract is the intermediate; and the active pharmaceutical ingredient (API) is CBD, the drug substance.
  • BRM Botanical Raw Material
  • API active pharmaceutical ingredient
  • the purity of the botanically derived purified CBD preparation was greater than or equal to 98%.
  • the botanically derived purified CBD includes THC and other cannabinoids, e.g., CBDA, CBDV, CBD-C1 , and CBD-C4.
  • the CBD preparation comprises not more than 0.15% THC based on total amount of cannabinoid in the preparation. In some embodiments, the CBD preparation comprises about 0.01% to about 0.1% THC based on total amount of cannabinoid in the preparation. In some embodiments, the CBD preparation comprises about 0.02% to about 0.05% THC based on total amount of cannabinoid in the preparation.
  • the CBD preparation comprises about 0.2% to about 1.0% CBDV based on total amount of cannabinoid in the preparation. In some embodiments, the CBD preparation comprises about 0.2% to about 0.8% CBDV based on total amount of cannabinoid in the preparation. [0063] In some embodiments, the CBD preparation comprises about 0.3% to about 0.5%
  • CBD-C4 based on total amount of cannabinoid in the preparation.
  • the CBD preparation comprises about 0.3% to about 0.4% CBD-C4 based on total amount of cannabinoid in the preparation.
  • the CBD preparation comprises about 0.1% to about 0.15% CBD-C1 based on total amount of cannabinoid in the preparation.
  • Distinct chemotypes of the Cannabis sativa L. plant have been produced to maximize the output of the specific chemical constituents, the cannabinoids. Certain chemovars produce predominantly CBD. Only the (-)-trans isomer of CBD is believed to occur naturally. During purification, the stereochemistry of CBD is not affected.
  • High CBD chemovars were grown, harvested, dried, baled and stored in a dry room until required.
  • the botanical raw material (BRM) was finely chopped using an Apex mill fitted with a 1 mm screen. The milled BRM was stored in a freezer prior to extraction.
  • the BDS produced using the methodology above was dispersed in C5-C12 straight chain or branched alkane.
  • the mixture was manually agitated to break up any lumps and the sealed container then placed in a freezer for approximately 48 hours.
  • the crystals were isolated via vacuum filtration, washed with aliquots of cold C5-C12 straight chain or branched alkane, and dried under a vacuum of ⁇ 10mb at a temperature of 60°C until dry.
  • the botanically derived purified CBD preparation was stored in a freezer at -20°C in a pharmaceutical grade stainless steel container, with FDA food grade approved silicone seal and clamps.
  • the botanically derived purified CBD used in the clinical trial described in the invention comprises greater than or equal to 98% (w/w) CBD and less than or equal to 2% (w/w) of other cannabinoids.
  • the other cannabinoids present are THC at a concentration of less than or equal to 0.1% (w/w); CBD-C1 at a concentration of less than or equal to 0.15% (w/w); CBDV at a concentration of less than or equal to 0.8% (w/w); and CBD-C4 at a concentration of less than or equal to 0.4% (w/w).
  • the botanically derived purified CBD used additionally comprises a mixture of both trans-THC and cis-THC. It was found that the ratio of the trans-THC to cis-THC is altered and can be controlled by the processing and purification process, ranging from 3.3:1 (trans-THC:cis- THC) in its unrefined decarboxylated state to 0.8:1 (trans-THC:cis-THC) when highly purified. [0074] Furthermore, the cis-THC found in botanically derived purified CBD is present as a mixture of both the (+)-cis-THC and the (-)-cis-THC isoforms.
  • CBD preparation could be produced synthetically by producing a composition with duplicate components.
  • Example 1 describes the use of a botanically derived purified CBD in an open label, expanded-access program to investigate the clinical efficacy and safety of purified pharmaceutical cannabidiol formulation (CBD) in the treatment of Heterotopia.
  • CBD cannabidiol formulation
  • EXAMPLE 1 CLINICAL EFFICACY AND SAFETY OF PURIFIED PHARMACEUTICAL CANNABIDIOL (CBD) IN THE TREATMENT OF PATIENTS DIAGNOSED WITH HETEROTOPIA
  • Subjects were required to be on one or more AEDs at stable doses for a minimum of two weeks prior to baseline and to have stable vagus nerve stimulation (VNS) settings and ketogenic diet ratios for a minimum of four weeks prior to baseline.
  • VNS vagus nerve stimulation
  • Patients were administered botanically derived purified CBD in a 100 mg/ml_ sesame oil- based solution at an initial dose of between 1.5 and 10 milligrams per kilogram per day (mg/kg/day) in two divided doses. Dose was then increased weekly by 5mg/kg/day to a goal of 20 to 25 mg/kg/day.
  • a maximum dose of 50 mg/kg/day could be utilised for patients who were tolerating the medication but had not achieved seizure control; these patients had further weekly titration by 5mg/kg/day.
  • Seizure frequency, intensity, and duration were recorded by caregivers in a diary during a baseline period of at least 28 days. Changes in seizure frequency relative to baseline were calculated after at least 2 weeks and at defined timepoints of treatment.
  • Patients may be defined as responders if they had more than 50% reduction in seizure frequency compared to baseline.
  • the percent change in seizure frequency was calculated as follows:
  • % change ((weekly seizure frequency time interval)- (weekly seizure frequency Baseline)) x100 seizure (weekly seizure frequency Baseline) frequency
  • the percent change of seizure frequency may be calculated for any time interval where seizure number has been recorded.
  • the percent change of seizure frequency for the end of the treatment period was calculated as follows:
  • % reduction ((weekly seizure frequency Baseline) - (weekly seizure frequency End)) x100 seizure frequency (weekly seizure frequency Baseline)
  • Table 1 Patient demographics, seizure type and concomitant medication
  • VPA valproic acid
  • LEV levetiracetam
  • CLB clobazam
  • VGB vigabatrin
  • RFN rufinamide
  • LCS lacosamide
  • TPM topiramate
  • LTG lamotrigine
  • ECB eslicarbazepine
  • FLB felbamate
  • the average number of concomitant AEDs at the time of starting CBD was three per patient (range: 2-4, median: 3).
  • Tables 2A-D illustrate the seizure frequency for each patient as well as the dose of CBD given.
  • Table 2A Seizure frequency data for Patient 1
  • Patient 1 was treated for 24 weeks and experienced a 11.3% reduction in tonic seizures and a 10.4% reduction in focal seizures without impairment over the treatment period.
  • Table 2B Seizure frequency data for Patient 2 [0090] Patient 2 was treated for 132 weeks and experienced a 83.7% reduction in absence seizures over the treatment period.
  • Patient 3 was treated for 132 weeks and experienced a 38.9% reduction in tonic seizures, a 80% reduction in tonic-clonic seizures, a 93.1% reduction in atonic seizures and a 100% reduction in focal seizures without impairment over the treatment period.
  • Patient 4 was treated for 108 weeks and experienced a 100% reduction in tonic- clonic seizures over the treatment period.
  • CBD was effective in reducing the frequency of the following seizure types: tonic, tonic-clonic, atonic, absence and focal seizures without impairment.
  • the subject was required to be on one or more AEDs at stable doses for a minimum of two weeks prior to baseline and to have stable vagus nerve stimulation (VNS) settings and ketogenic diet ratios for a minimum of four weeks prior to baseline.
  • VNS vagus nerve stimulation
  • the patient was administered botanically derived purified CBD in a 100 mg/mL sesame oil-based solution at an initial dose of 10 milligrams per kilogram per day (mg/kg/day) in two divided doses. Dose was then increased weekly by 5mg/kg/day to a goal of 25 mg/kg/day.
  • a maximum dose of 50 mg/kg/day could be utilised for the patient if they were tolerating the medication but had not achieved seizure control; the patient had further weekly titration by 5mg/kg/day.
  • Seizure frequency, intensity, and duration were recorded by caregivers in a diary during a baseline period of at least 28 days. Changes in seizure frequency relative to baseline were calculated after at least 2 weeks and at defined timepoints of treatment.
  • Patients may be defined as responders if they had more than 50% reduction in seizure frequency compared to baseline.
  • the percent change in seizure frequency was calculated as follows:
  • % change ((weekly seizure frequency time interval)- (weekly seizure frequency Baseline)) x100 seizure (weekly seizure frequency Baseline) frequency
  • the percent change of seizure frequency may be calculated for any time interval where seizure number has been recorded.
  • Table 3 Patient demographics, seizure type and concomitant medication
  • VPA valproic acid
  • LTG lamotrigine
  • the patient was on two concomitant AEDs at the time of starting CBD.
  • T able 4 illustrates the seizure frequency for the patient as well as the dose of CBD given.
  • Patient 1 was treated for 84 weeks and experienced a 71.7% reduction in tonic seizures over the treatment period.
  • CBD was effective in reducing the frequency of tonic seizures.
  • this study signifies the use of CBD for treatment of seizures associated with subcortical band heterotopia.
  • Seizure types include tonic seizures for which seizure frequency rates decreased by significant rates, by up to 72%.

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Abstract

The present invention relates to the use of cannabidiol (CBD) for the treatment of seizures associated with rare epilepsy syndromes. In particular the seizures associated with rare epilepsy syndromes that are treated are those which are experienced in patients diagnosed with Heterotopia. In a further embodiment the types of seizures include tonic, tonic-clonic, atonic, absence and focal seizures without impairment. Preferably the dose of CBD is between 5 mg/kg/day to 50 mg/kg/day.

Description

USE OF CANNABIDIOL IN THE TREATMENT OF SEIZURES ASSOCIATED WITH RARE EPILEPSY SYNDROMES RELATED TO STRUCTURAL ABNORMALITIES OF THE BRAIN
FIELD OF THE INVENTION
[0001] The present invention relates to the use of cannabidiol (CBD) for the treatment of seizures associated with rare epilepsy syndromes. In particular the seizures associated with rare epilepsy syndromes that are treated are those which are experienced in patients diagnosed with Heterotopia. In a further embodiment the types of seizures include tonic, tonic-clonic, atonic, absence and focal seizures without impairment. Preferably the dose of CBD is between 5 mg/kg/day to 50 mg/kg/day.
[0002] In a further embodiment the CBD used is in the form of a highly purified extract of cannabis such that the CBD is present at greater than 95% of the total extract (w/w) and the cannabinoid tetrahydrocannabinol (THC) has been substantially removed, to a level of not more than 0.15% (w/w).
[0003] Preferably the CBD used is in the form of a botanically derived purified CBD which comprises greater than or equal to 98% (w/w) CBD and less than or equal to 2% (w/w) of other cannabinoids. More preferably the other cannabinoids present are THC at a concentration of less than or equal to 0.1% (w/w); CBD-C1 at a concentration of less than or equal to 0.15% (w/w); CBDV at a concentration of less than or equal to 0.8% (w/w); and CBD-C4 at a concentration of less than or equal to 0.4% (w/w). The botanically derived purified CBD preferably also comprises a mixture of both trans-THC and cis-THC. Alternatively, a synthetically produced CBD is used.
[0004] Most preferably the other cannabinoids present are THC at a concentration of about 0.01% to about 0.1% (w/w); CBD-C1 at a concentration of about 0.1% to about 0.15% (w/w); CBDV at a concentration of about 0.2% to about 0.8% (w/w); and CBD-C4 at a concentration of about 0.3% to about 0.4% (w/w). Most preferably still the THC is present at a concentration of about 0.02% to about 0.05% (w/w).
[0005] Where the CBD is given concomitantly with one or more other anti-epileptic drugs (AED), the CBD may be formulated for administration separately, sequentially or simultaneously with one or more AED or the combination may be provided in a single dosage form.
BACKGROUND TO THE INVENTION
[0006] Epilepsy occurs in approximately 1% of the population worldwide, (Thurman et al., 2011) of which 70% are able to adequately control their symptoms with the available existing anti-epileptic drugs (AED). However, 30% of this patient group, (Eadie etal., 2012), are unable to obtain seizure freedom from the AED that are available and as such are termed as suffering from intractable or “treatment-resistant epilepsy” (TRE).
[0007] Intractable or treatment-resistant epilepsy was defined in 2009 by the International League Against Epilepsy (I LAE) as “failure of adequate trials of two tolerated and appropriately chosen and used AED schedules (whether as monotherapies or in combination) to achieve sustained seizure freedom ” (Kwan et al., 2009).
[0008] Individuals who develop epilepsy during the first few years of life are often difficult to treat and as such are often termed treatment resistant. Children who undergo frequent seizures in childhood are often left with neurological damage which can cause cognitive, behavioral and motor delays.
[0009] Childhood epilepsy is a relatively common neurological disorder in children and young adults with a prevalence of approximately 700 per 100,000. This is twice the number of epileptic adults per population.
[0010] When a child or young adult presents with a seizure, investigations are normally undertaken in order to investigate the cause. Childhood epilepsy can be caused by many different syndromes and genetic mutations and as such diagnosis for these children may take some time.
[0011] The main symptom of epilepsy is repeated seizures. In order to determine the type of epilepsy or the epileptic syndrome that a patient is suffering from an investigation into the type of seizures that the patient is experiencing is undertaken. Clinical observations and electroencephalography (EEG) tests are conducted and the type(s) of seizures are classified according to the ILEA classification.
[0012] Generalized seizures, where the seizure arises within and rapidly engages bilaterally distributed networks, can be split into six subtypes: tonic-clonic (grand mal) seizures; absence (petit mal) seizures; clonic seizures; tonic seizures; atonic seizures and myoclonic seizures.
[0013] Focal (partial) seizures where the seizure originates within networks limited to only one hemisphere, are also split into sub-categories. Here the seizure is characterized according to one or more features of the seizure, including aura, motor, autonomic and awareness / responsiveness. Where a seizure begins as a localized seizure and rapidly evolves to be distributed within bilateral networks this seizure is known as a bilateral convulsive seizure, which is the proposed terminology to replace secondary generalized seizures (generalized seizures that have evolved from focal seizures and are no longer remain localized).
[0014] Focal seizures where the subject’s awareness / responsiveness is altered are referred to as focal seizures with impairment and focal seizures where the awareness or responsiveness of the subject is not impaired are referred to as focal seizures without impairment. [0015] Heterotopia is defined as a cluster of normal neurons in abnormal locations and is divided into three main groups: periventricular nodular heterotopia, subcortical heterotopia, and band heterotopia.
[0016] People with this condition typically develop recurrent seizures beginning in mid adolescence. Intelligence is usually normal, but some people may have mild intellectual disability, including difficulty with reading or spelling. Less common features include microcephaly, developmental delay, recurrent infections, and blood vessel abnormalities.
[0017] The condition results from the nerve cells not migrating properly during early development of the foetal brain and is caused by one of several mutations in genes that code for proteins involved in neuronal migration.
[0018] Treatment of Heterotopia is generally focused on managing recurrent seizures with medications.
[0019] Subcortical band heterotopia is a condition in which neurons do not migrate to their proper locations in the fetal brain during early development. Normally, the neurons that make up the cerebral cortex are distributed in a well-organized and multi-layered way. In people with subcortical band heterotopia, some neurons that should be part of the cerebral cortex do not reach it. These neurons stop their migration process in areas of the brain where they are not supposed to be and form band-like clusters of tissue.
[0020] Since these bands are located beneath the cerebral cortex, they are said to be subcortical. In most cases, the bands are symmetric, which means they occur in the same places on the right and left sides of the brain.
[0021] The abnormal brain development causes neurological problems in people with subcortical band heterotopia. The signs and symptoms of the condition depend on the size of the bands and the lack of development of the cerebral cortex. The signs and symptoms can vary from severe intellectual disability and seizures that begin early in life and affect both sides of the brain (generalized seizures) to normal intelligence with seizures occurring later in life and affecting only one side of the brain (focal seizures). Some affected individuals also have weak muscle tone (hypotonia), loss of fine motor skills such as using utensils, or behavioral problems. Subcortical band heterotopia is typically found when brain imaging is done following the onset of seizures, usually in adolescence or early adulthood.
[0022] Mutations in the DCX or PAFAH1B1 gene cause subcortical band heterotopia. Both genes provide instructions for making proteins that are involved in neuronal migration which is essential for normal brain development and function.
[0023] Most individuals with subcortical band heterotopia have DCX gene mutations. These mutations impair the protein's function or alter the protein's structure or stability. PAFAH1B1 gene mutations are less common. Mutations in this gene reduce the protein's function. [0024] Cannabidiol (CBD), a non-psychoactive derivative from the cannabis plant, has demonstrated anti-convulsant properties in several anecdotal reports, pre-clinical and clinical studies both in animal models and humans. Three randomized control trials showed efficacy of the purified pharmaceutical formulation of CBD in patients with Dravet and Lennox-Gastaut syndrome.
[0025] Based on these three trials, a botanically derived purified CBD preparation was approved by FDA in June 2018 for the treatment of seizures associated with Dravet and Lennox-Gastaut syndromes.
[0026] One anecdotal report describes using CBD oil to treat a child with Heterotopia.1 The oil, which as well as comprising CBD, is unpurified and therefore comprises all the cannabinoid and non-cannabinoid components of a cannabis plant extract.
[0027] Gedde (2014) discloses an observational study carried out on a cohort of patients diagnosed with epilepsies of multiple etiologies. Amongst a wide range of diagnoses, structural causes of epilepsy were included, one of which listed is Heterotopia. It is stated that a wide range of cannabinoid products was used, from high ratio CBD:THC products to tetrahydrocannabinolic acid (THCA), low ratio CBD:THC, or a combination, without any further indication of the ratios. Despite stating seizure types were recorded, there is no actual disclosure of any types of seizures experienced by the patients.
[0028] WO 2019/245639 relates to the delivery of lipophilic drugs across the blood-brain barrier using an edible substrate to treat numerous central nervous system conditions, of which Heterotopia is listed as one. An example given of a lipophilic drug is CBD, which may be given in the form of a CBD infused tea bag.
[0029] The applicant has found by way of an open label, expanded-access program that treatment with CBD resulted in a significant reduction in tonic, tonic-clonic, atonic, absence and focal seizures without impairment in patients with Heterotopia.
BRIEF SUMMARY OF THE DISCLOSURE
[0030] In accordance with a first aspect of the present invention there is provided a cannabidiol (CBD) preparation for use in the treatment of Heterotopia.
[0031] In a further embodiment, the seizures associated with Heterotopia are tonic, tonic- clonic, atonic, absence and focal seizures without impairment.
[0032] In a further embodiment, the CBD preparation comprises greater than 95% (w/w) CBD and not more than 0.15% (w/w) tetrahydrocannabinol (THC).
[0033] Preferably the CBD preparation comprises greater than or equal to 98% (w/w) CBD and less than or equal to 2% (w/w) other cannabinoids, wherein the less than or equal to 2% (w/w) other cannabinoids comprise the cannabinoids tetrahydrocannabinol (THC); cannabidiol- C1 (CBD-C1); cannabidivarin (CBDV); and cannabidiol-C4 (CBD-C4), and wherein the THC is present as a mixture of trans-THC and cis-THC.
[0034] Preferably the CBD preparation is used in combination with one or more concomitant anti-epileptic drugs (AED).
[0035] Preferably the one or more AED is selected from the group consisting of: valproic acid, levetiracetam, clobazam, vigabatrin, rufinamide, lacosamide, topiramate, lamotrigine, eslicarbazepine and felbamate.
[0036] In one embodiment the CBD is present is isolated from cannabis plant material. Preferably at least a portion of at least one of the cannabinoids present in the CBD preparation is isolated from cannabis plant material.
[0037] In a further embodiment the CBD is present as a synthetic preparation. Preferably at least a portion of at least one of the cannabinoids present in the CBD preparation is prepared synthetically.
[0038] Preferably the dose of CBD is greater than 5 mg/kg/day. More preferably the dose of CBD is 20 mg/kg/day. More preferably the dose of CBD is 25 mg/kg/day. More preferably the dose of CBD is 50 mg/kg/day.
[0039] In accordance with a second aspect of the present invention there is provided a method of treating seizures associated with Heterotopia comprising administering a cannabidiol (CBD) preparation to the subject in need thereof.
DEFINITIONS
[0040] Definitions of some of the terms used to describe the invention are detailed below:
[0041] Over 100 different cannabinoids have been identified, see for example, Handbook of Cannabis, Roger Pertwee, Chapter 1, pages 3 to 15. These cannabinoids can be split into different groups as follows: Phytocannabinoids; Endocannabinoids and Synthetic cannabinoids (which may be novel cannabinoids or synthetically produced phytocannabinoids or endocannabinoids).
[0042] “Phytocannabinoids” are cannabinoids that originate from nature and can be found in the cannabis plant. The phytocannabinoids can be isolated from plants to produce a highly purified extract or can be reproduced synthetically.
[0043] “Highly purified cannabinoids” are defined as cannabinoids that have been extracted from the cannabis plant and purified to the extent that other cannabinoids and non-cannabinoid components that are co-extracted with the cannabinoids have been removed, such that the highly purified cannabinoid is greater than or equal to 95% (w/w) pure.
[0044] “Synthetic cannabinoids” are compounds that have a cannabinoid or cannabinoid-like structure and are manufactured using chemical means rather than by the plant.
[0045] Phytocannabinoids can be obtained as either the neutral (decarboxylated form) or the carboxylic acid form depending on the method used to extract the cannabinoids. For example, it is known that heating the carboxylic acid form will cause most of the carboxylic acid form to decarboxylate into the neutral form.
[0046] “Treatment-resistant epilepsy” (TRE) or “intractable epilepsy” is defined as per the I LAE guidance of 2009 as epilepsy that is not adequately controlled by trials of one or more AED.
[0047] “Tonic seizures” can be generalised onset, affecting both sides of the brain, or they can be focal onset, starting in just one side of the brain. If a tonic seizure starts in both sides of the brain, all muscles tighten and the subject’s body goes stiff. If standing, they may fall to the floor, their neck may extend, eyes open wide and roll upwards, whilst their arms may raise upwards and legs stretch or contract. If a tonic seizure starts in one side of the brain muscles tighten in just one area of the body. Tonic seizures usually last less than one minute.
[0048] “Tonic-clonic seizures” consist of two phases: the tonic phase and the clonic phase. In the tonic phase the body becomes entire rigid, and in the clonic phase there is uncontrolled jerking. Tonic-clonic seizures may or may not be preceded by an aura, and are often followed by headache, confusion, and sleep. They may last mere seconds or continue for several minutes. These seizures are also known as a grand mal seizure.
[0049] “Atonic seizures” occur when a person suddenly loses muscle tone so their head or body may go limp. They are also known as drop attacks. In some children, only their head drops suddenly. They can begin in one area or side of the brain (focal onset) or both sides of the brain (generalized onset).
[0050] “Absence seizures” are also called "petit mal" seizures. These types of seizure cause a loss of awareness for a short time. They mainly affect children although can happen at any age. During an absence seizure, a person may: stare blankly into space; look like they are "daydreaming"; flutter their eyes; make slight jerking movements of their body or limbs. The seizures usually only last up to 15 seconds and may occur several times a day.
[0051] “Focal Seizures” are defined as seizures which originate within networks limited to only one hemisphere. What happens during the seizure depends on where in the brain the seizure happens and what that part of the brain normally does.
[0052] “Focal seizures without impairment” are seizures which originate within networks limited to only one hemisphere where the awareness or responsiveness of the subject is not impaired.
DETAILED DESCRIPTION
PREPARATION OF HIGHLY PURIFIED CBD EXTRACT
[0053] The following describes the production of the highly-purified (>95% w/w) cannabidiol extract which has a known and constant composition.
[0054] In summary the drug substance used is a liquid carbon dioxide extract of high-CBD containing chemotypes of Cannabis sativa L. which had been further purified by a solvent crystallization method to yield CBD. The crystallisation process specifically removes other cannabinoids and plant components to yield greater than 95% CBD. Although the CBD is highly purified because it is produced from a cannabis plant rather than synthetically there is a small number of other cannabinoids which are co-produced and co-extracted with the CBD. Details of these cannabinoids and the quantities in which they are present in the medication are as described in Table A below.
Table A: Composition of highly purified CBD extract
Figure imgf000008_0001
> - greater than NMT - not more than
PREPARATION OF BOTANICALLY DERIVED PURIFIED CBD
[0055] The following describes the production of the botanically derived purified CBD which comprises greater than or equal to 98% w/w CBD and less than or equal to other cannabinoids was used in the open label, expanded-access program described in Example 1 below.
[0056] In summary the drug substance used in the trials is a liquid carbon dioxide extract of high-CBD containing chemotypes of Cannabis sativa L. which had been further purified by a solvent crystallization method to yield CBD. The crystallisation process specifically removes other cannabinoids and plant components to yield greater than 95% CBD w/w, typically greater than 98% w/w. [0057] The Cannabis sativa L. plants are grown, harvested, and processed to produce a botanical extract (intermediate) and then purified by crystallization to yield the CBD (botanically derived purified CBD).
[0058] The plant starting material is referred to as Botanical Raw Material (BRM); the botanical extract is the intermediate; and the active pharmaceutical ingredient (API) is CBD, the drug substance.
[0059] All parts of the process are controlled by specifications. The botanical raw material specification is described in Table B and the CBD API is described in Table C. Table B: CBD botanical raw material specification
Figure imgf000009_0001
Table C: Specification of an exemplary botanically derived purified CBD preparation
Figure imgf000010_0001
[0060] The purity of the botanically derived purified CBD preparation was greater than or equal to 98%. The botanically derived purified CBD includes THC and other cannabinoids, e.g., CBDA, CBDV, CBD-C1 , and CBD-C4.
[0061] In some embodiments, the CBD preparation comprises not more than 0.15% THC based on total amount of cannabinoid in the preparation. In some embodiments, the CBD preparation comprises about 0.01% to about 0.1% THC based on total amount of cannabinoid in the preparation. In some embodiments, the CBD preparation comprises about 0.02% to about 0.05% THC based on total amount of cannabinoid in the preparation.
[0062] In some embodiments, the CBD preparation comprises about 0.2% to about 1.0% CBDV based on total amount of cannabinoid in the preparation. In some embodiments, the CBD preparation comprises about 0.2% to about 0.8% CBDV based on total amount of cannabinoid in the preparation. [0063] In some embodiments, the CBD preparation comprises about 0.3% to about 0.5%
CBD-C4 based on total amount of cannabinoid in the preparation. In some embodiments, the CBD preparation comprises about 0.3% to about 0.4% CBD-C4 based on total amount of cannabinoid in the preparation.
[0064] In some embodiments, the CBD preparation comprises about 0.1% to about 0.15% CBD-C1 based on total amount of cannabinoid in the preparation.
[0065] Distinct chemotypes of the Cannabis sativa L. plant have been produced to maximize the output of the specific chemical constituents, the cannabinoids. Certain chemovars produce predominantly CBD. Only the (-)-trans isomer of CBD is believed to occur naturally. During purification, the stereochemistry of CBD is not affected.
Production of CBD botanical drug substance
[0066] An overview of the steps to produce a botanical extract, the intermediate, are as follows: a) Growing b) Direct drying c) Decarboxylation d) Extraction - using liquid CO2 e) Winterization using ethanol f) Filtration g) Evaporation
[0067] High CBD chemovars were grown, harvested, dried, baled and stored in a dry room until required. The botanical raw material (BRM) was finely chopped using an Apex mill fitted with a 1 mm screen. The milled BRM was stored in a freezer prior to extraction.
[0068] Decarboxylation of CBDA to CBD was carried out using heat. BRM was decarboxylated at 115°C for 60 minutes.
[0069] Extraction was performed using liquid CO2 to produce botanical drug substance (BDS), which was then crystalized to produce the test material. The crude CBD BDS was winterized to refine the extract under standard conditions (2 volumes of ethanol at -20°C for approximately 50 hours). The precipitated waxes were removed by filtration and the solvent was removed to yield the BDS.
Production of botanically derived purified CBD preparation
[0070] The manufacturing steps to produce the botanically derived purified CBD preparation from BDS were as follows: a) Crystallization using C5-C12 straight chain or branched alkane b) Filtration c) Vacuum drying
[0071] The BDS produced using the methodology above was dispersed in C5-C12 straight chain or branched alkane. The mixture was manually agitated to break up any lumps and the sealed container then placed in a freezer for approximately 48 hours. The crystals were isolated via vacuum filtration, washed with aliquots of cold C5-C12 straight chain or branched alkane, and dried under a vacuum of <10mb at a temperature of 60°C until dry. The botanically derived purified CBD preparation was stored in a freezer at -20°C in a pharmaceutical grade stainless steel container, with FDA food grade approved silicone seal and clamps.
Physicochemical properties of the botanically derived purified CBD [0072] The botanically derived purified CBD used in the clinical trial described in the invention comprises greater than or equal to 98% (w/w) CBD and less than or equal to 2% (w/w) of other cannabinoids. The other cannabinoids present are THC at a concentration of less than or equal to 0.1% (w/w); CBD-C1 at a concentration of less than or equal to 0.15% (w/w); CBDV at a concentration of less than or equal to 0.8% (w/w); and CBD-C4 at a concentration of less than or equal to 0.4% (w/w).
[0073] The botanically derived purified CBD used additionally comprises a mixture of both trans-THC and cis-THC. It was found that the ratio of the trans-THC to cis-THC is altered and can be controlled by the processing and purification process, ranging from 3.3:1 (trans-THC:cis- THC) in its unrefined decarboxylated state to 0.8:1 (trans-THC:cis-THC) when highly purified. [0074] Furthermore, the cis-THC found in botanically derived purified CBD is present as a mixture of both the (+)-cis-THC and the (-)-cis-THC isoforms.
[0075] Clearly a CBD preparation could be produced synthetically by producing a composition with duplicate components.
[0076] Example 1 below describes the use of a botanically derived purified CBD in an open label, expanded-access program to investigate the clinical efficacy and safety of purified pharmaceutical cannabidiol formulation (CBD) in the treatment of Heterotopia.
EXAMPLE 1: CLINICAL EFFICACY AND SAFETY OF PURIFIED PHARMACEUTICAL CANNABIDIOL (CBD) IN THE TREATMENT OF PATIENTS DIAGNOSED WITH HETEROTOPIA
Study design [0077] Subjects were required to be on one or more AEDs at stable doses for a minimum of two weeks prior to baseline and to have stable vagus nerve stimulation (VNS) settings and ketogenic diet ratios for a minimum of four weeks prior to baseline.
[0078] Patients were administered botanically derived purified CBD in a 100 mg/ml_ sesame oil- based solution at an initial dose of between 1.5 and 10 milligrams per kilogram per day (mg/kg/day) in two divided doses. Dose was then increased weekly by 5mg/kg/day to a goal of 20 to 25 mg/kg/day.
[0079] A maximum dose of 50 mg/kg/day could be utilised for patients who were tolerating the medication but had not achieved seizure control; these patients had further weekly titration by 5mg/kg/day.
[0080] There were four patients in this study, and each received CBD for various durations of time. Modifications were made to concomitant AEDs as per clinical indication.
[0081] Seizure frequency, intensity, and duration were recorded by caregivers in a diary during a baseline period of at least 28 days. Changes in seizure frequency relative to baseline were calculated after at least 2 weeks and at defined timepoints of treatment.
Statistical Methods:
[0082] Patients may be defined as responders if they had more than 50% reduction in seizure frequency compared to baseline. The percent change in seizure frequency was calculated as follows:
% change= ((weekly seizure frequency time interval)- (weekly seizure frequency Baseline)) x100 seizure (weekly seizure frequency Baseline) frequency
[0083] The percent change of seizure frequency may be calculated for any time interval where seizure number has been recorded. For the purpose of this example the percent change of seizure frequency for the end of the treatment period was calculated as follows:
% reduction = ((weekly seizure frequency Baseline) - (weekly seizure frequency End)) x100 seizure frequency (weekly seizure frequency Baseline)
Results Patient description
[0084] The four patients enrolled in the open label, expanded-access program were diagnosed with Heterotopia. These patients experienced several different seizure types including tonic, tonic-clonic, atonic, absence and focal seizures without impairment and were taking several concomitant AEDs.
[0085] The age of patients ranged from 6-17 years, one was male and three were female as detailed in Table 1 below.
Table 1: Patient demographics, seizure type and concomitant medication
Figure imgf000014_0001
VPA = valproic acid, LEV = levetiracetam, CLB = clobazam, VGB = vigabatrin, RFN = rufinamide, LCS = lacosamide, TPM = topiramate, LTG = lamotrigine, ECB = eslicarbazepine, FLB = felbamate
Study medication and concomitant medications
[0086] All four patients were titrated up to at least 25 mg/kg/day of CBD.
[0087] The average number of concomitant AEDs at the time of starting CBD was three per patient (range: 2-4, median: 3).
Clinical changes
[0088] Tables 2A-D illustrate the seizure frequency for each patient as well as the dose of CBD given.
Table 2A: Seizure frequency data for Patient 1
Figure imgf000014_0002
Figure imgf000015_0001
[0089] Patient 1 was treated for 24 weeks and experienced a 11.3% reduction in tonic seizures and a 10.4% reduction in focal seizures without impairment over the treatment period. Table 2B: Seizure frequency data for Patient 2
Figure imgf000015_0002
[0090] Patient 2 was treated for 132 weeks and experienced a 83.7% reduction in absence seizures over the treatment period.
Table 2C: Seizure frequency data for Patient 3
Figure imgf000016_0001
[0091] Patient 3 was treated for 132 weeks and experienced a 38.9% reduction in tonic seizures, a 80% reduction in tonic-clonic seizures, a 93.1% reduction in atonic seizures and a 100% reduction in focal seizures without impairment over the treatment period.
Table 2D: Seizure frequency data for Patient 4
Figure imgf000016_0002
Figure imgf000017_0001
[0092] Patient 4 was treated for 108 weeks and experienced a 100% reduction in tonic- clonic seizures over the treatment period.
[0093] Overall, patients reported reductions of 10.4-100.0% in seizures over period of treatment with CBD.
[0094] Significantly, one patient (#3) became seizure-free in their focal seizures without impairment after 132 weeks of treatment with CBD. Another patient (#4) also became seizure- free in their tonic-clonic seizures after 72 weeks of treatment.
[0095] CBD was effective in reducing the frequency of the following seizure types: tonic, tonic-clonic, atonic, absence and focal seizures without impairment.
Conclusions [0096] These data indicate that CBD was able to significantly reduce the number of seizures associated with Heterotopia. Clearly the treatment is of significant benefit in this difficult to treat epilepsy syndrome given the high response rate experienced in all patients.
[0097] Of interest is that patients with tonic-clonic seizures (patients 3 and 4) obtained significant benefit after treatment with CBD. [0098] In conclusion, this study signifies the use of CBD for treatment of seizures associated with Heterotopia. Seizure types include: tonic, tonic-clonic, atonic, absence and focal seizures without impairment for which seizure frequency rates decreased by significant rates, by 10.4-100.0%. EXAMPLE 2: CLINICAL EFFICACY AND SAFETY OF PURIFIED PHARMACEUTICAL CANNABIDIOL (CBD) IN THE TREATMENT OF PATIENTS DIAGNOSED WITH SUBCORTICAL BAND HETEROTOPIA
Study design
[0099] The subject was required to be on one or more AEDs at stable doses for a minimum of two weeks prior to baseline and to have stable vagus nerve stimulation (VNS) settings and ketogenic diet ratios for a minimum of four weeks prior to baseline.
[00100] The patient was administered botanically derived purified CBD in a 100 mg/mL sesame oil-based solution at an initial dose of 10 milligrams per kilogram per day (mg/kg/day) in two divided doses. Dose was then increased weekly by 5mg/kg/day to a goal of 25 mg/kg/day.
[00101] A maximum dose of 50 mg/kg/day could be utilised for the patient if they were tolerating the medication but had not achieved seizure control; the patient had further weekly titration by 5mg/kg/day.
[00102] There was one patient in this study, and they received CBD for 84 weeks. Modifications were made to concomitant AEDs as per clinical indication.
[00103] Seizure frequency, intensity, and duration were recorded by caregivers in a diary during a baseline period of at least 28 days. Changes in seizure frequency relative to baseline were calculated after at least 2 weeks and at defined timepoints of treatment.
Statistical Methods:
[00104] Patients may be defined as responders if they had more than 50% reduction in seizure frequency compared to baseline. The percent change in seizure frequency was calculated as follows:
% change= ((weekly seizure frequency time interval)- (weekly seizure frequency Baseline)) x100 seizure (weekly seizure frequency Baseline) frequency
[00105] The percent change of seizure frequency may be calculated for any time interval where seizure number has been recorded. For the purpose of this example the percent change of seizure frequency for the end of the treatment period was calculated as follows: % reduction = ((weekly seizure frequency Baseline) - (weekly seizure frequency End)) x100 seizure frequency (weekly seizure frequency Baseline)
Results
Patient description
[00106] One patient enrolled in the open label, expanded-access program was diagnosed with subcortical band heterotopia caused by a OCX mutation. The patient experienced tonic seizures was taking two concomitant AEDs.
[00107] The patient was 15 years old and she was female as detailed in Table 3 below.
Table 3: Patient demographics, seizure type and concomitant medication
Figure imgf000019_0001
VPA = valproic acid, LTG = lamotrigine
Study medication and concomitant medications
[00108] The patient on the study was titrated up to 20 mg/kg/day of CBD.
[00109] The patient was on two concomitant AEDs at the time of starting CBD.
Clinical changes
[00110] T able 4 illustrates the seizure frequency for the patient as well as the dose of CBD given.
Table : Seizure frequency data for Patient 1
Figure imgf000019_0002
Figure imgf000020_0001
[00111] Patient 1 was treated for 84 weeks and experienced a 71.7% reduction in tonic seizures over the treatment period.
[00112] Overall, the patient reported reductions of 71.7% in seizures over period of treatment with CBD. CBD was effective in reducing the frequency of tonic seizures.
Conclusions [00113] These data indicate that CBD was able to significantly reduce the number of seizures associated with subcortical band heterotopia. Clearly the treatment is of significant benefit in this difficult to treat epilepsy syndrome given the high response rate experienced in the patient.
[00114] In conclusion, this study signifies the use of CBD for treatment of seizures associated with subcortical band heterotopia. Seizure types include tonic seizures for which seizure frequency rates decreased by significant rates, by up to 72%.
References
1. https://ourabrammavhem.weebly.com/abes beginning.html
2. Gedde (2014) "Clinical Experience with Cannabis in Treatment-Resistant Pediatric Epilepsy" Marijuana for Medical Professionals Conference. http://www.theme.us/images/gedde presentation.pdf

Claims

1. A cannabidiol (CBD) preparation for use in the treatment of seizures associated with Heterotopia, wherein the CBD preparation comprises greater than 95% (w/w) CBD and not more than 0.15% (w/w) tetrahydrocannabinol (THC).
2. A CBD preparation for use according to claim 1, wherein the seizures associated with Heterotopia are tonic, tonic-clonic, atonic, absence and focal seizures without impairment.
3. A CBD preparation for use according to claim 1, wherein the seizures associated with Heterotopia are seizures associated with subcortical band heterotopia.
4. A CBD preparation for use according to claim 3, wherein the seizures associated with subcortical band heterotopia are tonic seizures.
5. A CBD preparation for use according to any of the preceding claims, wherein the CBD preparation comprises greater than or equal to 98% (w/w) CBD and less than or equal to 2% (w/w) other cannabinoids, wherein the less than or equal to 2% (w/w) other cannabinoids comprise the cannabinoids tetrahydrocannabinol (THC); cannabidiol-C1 (CBD-C1); cannabidivarin (CBDV); and cannabidiol-C4 (CBD-C4), and wherein the THC is present as a mixture of trans-THC and cis-THC.
6. A CBD preparation to any of the preceding claims, wherein the CBD preparation is used in combination with one or more concomitant anti-epileptic drugs (AED).
7. A CBD preparation for use according to claim 6, wherein the one or more AED is selected from the group consisting of: valproic acid, levetiracetam, clobazam, vigabatrin, rufinamide, lacosamide, topiramate, lamotrigine, eslicarbazepine and felbamate.
8. A CBD preparation for use according to any of the preceding claims, wherein the CBD is present is isolated from cannabis plant material.
9. A CBD preparation for use according to any of the preceding claims, wherein at least a portion of at least one of the cannabinoids present in the CBD preparation is isolated from cannabis plant material.
10. A CBD preparation for use according to claims 1 to 7, wherein the CBD is present as a synthetic preparation.
11. A CBD preparation for use according to claim 10, wherein at least a portion of at least one of the cannabinoids present in the CBD preparation is prepared synthetically.
12. A CBD preparation for use according to any of the preceding claims, wherein the dose of CBD is greater than 5 mg/kg/day.
13. A CBD preparation for use according to any of the preceding claims, wherein the dose of CBD is 20 mg/kg/day.
14. A CBD preparation for use according to any of the preceding claims, wherein the dose of CBD is 25 mg/kg/day.
15. A CBD preparation for use according to any of the preceding claims, wherein the dose of CBD is 50 mg/kg/day.
16. A method of treating seizures associated with Heterotopia comprising administering a cannabidiol (CBD) preparation to the subject in need thereof.
17. A method of treating seizures associated with subcortical band heterotopia comprising administering a cannabidiol (CBD) preparation to the subject in need thereof.
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