Use of cannabinoids in the treatment of epilepsy

Abstract

The present invention relates to the use of cannabidiol (CBD) in the treatment of patients with childhood-onset epilepsy who are concurrently taking one or more antiepileptic drugs that function via GABA receptor agonism. The AED is preferably stiripentol. The CBD used is preferably in the form of a highly purified extract of cannabis, in which CBD is present at greater than 98% (w / w) of the total extract, and the other components of the extract are characterized. Specifically, the cannabinoid tetrahydrocannabinol (THC) is substantially removed to a level of 0.15% (w / w) or less, and cannabidivarin (CBDV), a propyl analog of CBD, is present in an amount up to 1%. Alternatively, the CBD may be synthetically produced CBD.

Description

Technical Field

[0001] The present invention relates to the use of cannabidiol (CBD) in the treatment of patients with childhood-onset epilepsy who are taking one or more anti-epileptic drugs that function via GABA receptor activation. The AED is preferably stiripentol.

[0002] The CBD used is preferably in the form of a highly purified extract of cannabis such that the CBD is present in an amount greater than 98% (w / w) of the total extract, and the other components of the extract are characterized. Specifically, the cannabinoid tetrahydrocannabinol (THC) is substantially removed to a level of 0.15% (w / w) or less, and cannabidivarin (CBDV), which is a propyl analogue of CBD, is present in an amount up to 1%. Alternatively, the CBD may be synthetically produced CBD.

Background Art

[0003] Epilepsy occurs in approximately 1% of the world's population (Thurman et al., 2011), and 70% of them can adequately control their symptoms using available existing anti-epileptic drugs (AEDs). However, 30% of this patient group (Eadie et al., 2012) cannot obtain relief from seizures with available AEDs and are thus said to suffer from refractory or "treatment-resistant epilepsy" (TRE).

[0004] Refractory or treatment-resistant epilepsy was defined in 2009 by the International League Against Epilepsy (ILAE) as "the failure of adequate trials of two appropriately chosen and used AED schedules (either as monotherapy or in combination), whether as adjunctive or as monotherapy" (Kwan et al., 2009).

[0005] Individuals who develop epilepsy during the first few years of life are often difficult to treat and are therefore often referred to as treatment-resistant. Children who experience frequent seizures during childhood often have neurological damage that can cause delays in cognition, behavior, and motor skills.

[0006] Childhood-onset epilepsy is a relatively common neurological disorder in children and young adults, with a prevalence of approximately 700 per 100,000 people. This is twice the number of adult epilepsy patients per capita.

[0007] When a child or young adult presents with seizures, an investigation is usually carried out to determine the cause. Childhood epilepsy can be caused by many different syndromes and genetic mutations, and therefore the diagnosis of these children can sometimes be time-consuming.

[0008] The main symptom of epilepsy is frequent seizures. To determine the type of epilepsy or epilepsy syndrome a patient is suffering from, an investigation is carried out into the types of seizures the patient is experiencing. Clinical observations and electroencephalogram (EEG) tests are performed, and the type of seizure is classified based on the ILAE classification described below.

[0009] The International Classification of Seizure Types proposed by the ILAE was adopted in 1981, and a revision was published by the ILAE in 2010 and has not yet replaced the 1981 classification. The 2010 proposal regarding revised terminology includes a proposed change to replace the term "partial" with the term "focal". In addition, the term "simple partial seizure" has been replaced by the term "focal seizure without impairment of awareness / responsiveness", and the term "complex partial seizure" has been replaced by the term "focal seizure with impairment of awareness / consciousness".

[0010] A generalized seizure can be divided into six subtypes: tonic-clonic (grand mal) seizure; absence (petit mal) seizure; clonic seizure; tonic seizure; atonic seizure and myoclonic seizure when the seizure occurs within a bilaterally distributed network and rapidly involves the network.

[0011] Focal (partial) seizures, whose origin lies within a network limited to only one hemisphere, can also be further classified. Here, the seizure is characterized based on one or more features of the seizure, including aura, motor, autonomic, and awareness / responsiveness. When a seizure begins as a local seizure and rapidly progresses to be distributed within a bilateral network, this seizure is known as a bilateral convulsive seizure, which is a specialized term proposed to replace a secondary generalized seizure (a generalized seizure that progresses from a focal seizure and is no longer local).

[0012] The epilepsy syndrome often presents many different types of seizures. Since many standard AEDs aim to treat a given seizure type / subtype or are only effective against a given seizure type / subtype, it is important to identify the type of seizure the patient is suffering from.

[0013] One such childhood epilepsy syndrome is Lennox-Gastaut syndrome (LGS). LGS is a severe form of epilepsy, and typically, seizures begin before the age of 4. Seizure types vary among patients and include tonic (rigidity of the body, upward deviation of the eyes, dilation of the pupils, and changes in the breathing pattern), atonic (causing an unexpected fall, short-term loss of muscle tone and consciousness), atypical absence (staring spells), and myoclonic (sudden single muscle contractions). There can be periods of frequent seizures interspersed with relatively seizure-free short periods.

[0014] Seizures in LGS are often referred to as "drop seizures." Such drop seizures are defined as attacks or seizures (weakness, stiffness, or atonic) related to the whole body, trunk, or head that caused or could have caused a fall, injury, collapse onto a chair, or striking of the patient's head against the ground.

[0015] Most patients with LGS experience some degree of impairment of intellectual function or information processing, along with developmental delay and behavioral disorders.

[0016] LGS can be caused by brain malformations, perinatal asphyxia, severe head injury, central nervous system infections, and hereditary or metabolic conditions. In 30 - 35% of cases, no cause can be found.

[0017] The first - line treatment for drop seizures, including treatment of drop seizures in patients with LGS, usually includes broad - spectrum AEDs such as sodium valproate, which is often combined with rufinamide or lamotrigine. Other AEDs that may be considered include felbamate, clobazam, and topiramate.

[0018] Another childhood epilepsy syndrome is the Dravet syndrome. The onset of Dravet syndrome almost always occurs in previously healthy and developmentally normal infants during the first year of life, with myoclonic and tonic - clonic seizures (Dravet, 2011). The symptoms peak at about 5 months of age. Other seizures, such as prolonged focal cognitive impairment seizures and brief absence seizures, occur between 1 and 4 years of age.

[0019] In the diagnosis of Dravet syndrome, both focal and generalized seizures are considered essential, and Dravet patients may also experience atypical absence seizures, myoclonic absence seizures, atonic seizures, and non - convulsive status epilepticus.

[0020] Seizures are frequent and progress to treatment resistance, meaning that the seizures do not respond well to treatment. The seizures are also prolonged and tend to last longer than 5 minutes. Prolonged seizures can lead to status epilepticus, which is a seizure that lasts longer than 30 minutes or a series of seizures that cluster together.

[0021] The prognosis is poor, and approximately 14% of children die during a seizure, due to infection or suddenly for unknown reasons, often due to severe neurological decline. Patients develop intellectual disabilities and seizures that progress throughout their lives. Intellectual dysfunction varies from severe in 50% of patients to moderate and mild intellectual disabilities, each accounting for 25% of cases.

[0022] Currently, there are no FDA-approved treatments, especially for Dravet syndrome. Typically, standard care includes combinations of the following anticonvulsants: clobazam, clonazepam, levetiracetam, topiramate, and valproic acid.

[0023] Stiripentol is approved in Europe for the treatment of Dravet syndrome in combination with clobazam and valproic acid. In the United States, stiripentol received Orphan Designation for the treatment of Dravet syndrome in 2008, but the drug is not FDA-approved.

[0024] Powerful sodium channel blockers used to treat epilepsy actually increase the seizure frequency in patients with Dravet syndrome. The most common ones are phenytoin, carbamazepine, lamotrigine, and rufinamide.

[0025] Management may include the ketogenic diet, as well as physical and vagus nerve stimulation. In addition to anticonvulsants, many patients with Dravet syndrome are treated with antipsychotics, stimulants, and medications to treat insomnia.

[0026] Common AEDs defined by their mechanism of action are listed in the following table.

[0027]

Table 1

[0028]

Table 2A

[0029]

Table 2B

[0030]

Table 3

[0031] The present invention demonstrates that patients with treatment - resistant childhood - onset epilepsy have a poor response rate of seizure reduction when treated with the antiepileptic drug stiripentol. Furthermore, the efficacy of treatment with stiripentol has been found to be further reduced when combined with the antiepileptic drug clobazam. However, surprisingly, when cannabidiol (CBD) is provided in combination with either stiripentol or both stiripentol and clobazam, there is a significant and beneficial increase in the response rate in the ability of the drug to reduce seizures.

[0032] Such an increase in efficacy by adding CBD is unexpected, especially considering the data demonstrating a decrease in efficacy when stiripentol is combined with clobazam.

Summary of the Invention

Means for Solving the Problems

[0033] According to a first aspect of the present invention, there is provided cannabidiol (CBD) for use in reducing seizures of treatment - resistant epilepsy, administered in combination with an antiepileptic drug (AED) that functions via GABA receptor activation.

[0034] The AED that functions through GABA receptor activation is preferably stiglentine.

[0035] In a further embodiment, CBD is administered in combination with stiglentine and clobazam.

[0036] CBD is preferably in the form of a highly purified extract of cannabis that contains at least 98% (w / w) CBD and less than 0.15% THC and up to 1% CBDV.

[0037] Alternatively, CBD exists as a synthetic compound.

[0038] The dose of CBD is preferably less than 50 mg / kg / day. More preferably, the dose of CBD is more than 10 mg / kg / day, and even more preferably, the dose of CBD is more than 20 mg / kg / day.

[0039] The treatment-resistant epilepsy is preferably Lennox-Gastaut syndrome or Dravet syndrome.

[0040] According to a second aspect of the present invention, there is provided a method of treating treatment-resistant epilepsy, wherein CBD is administered to an individual in need thereof in combination with stiglentine (STP).

[0041] The individual is preferably a human.

[0042] Definitions The definitions of some terms used to describe the present invention are described in detail below.

[0043] The cannabinoids described in this application are listed below together with their standard abbreviations.

[0044] [Table 4]

[0045] The table above is not exhaustive and is provided for reference only, simply listing in detail the cannabinoids identified in the present application. To date, over 60 different cannabinoids have been identified, and these cannabinoids can be divided into the following different groups: plant cannabinoids; endogenous cannabinoids and synthetic cannabinoids (which can be novel cannabinoids or plant or endogenous cannabinoids produced by synthesis).

[0046] "Plant cannabinoids" are cannabinoids of natural origin and can be found in cannabis plants. Plant cannabinoids can produce extracts that are isolated from plants and highly purified, or can be reproduced synthetically.

[0047] "Highly purified cannabinoid extract" is defined as a cannabinoid that is extracted from a cannabis plant and substantially free of other cannabinoid and non-cannabinoid components co-extracted with the cannabinoid, and is purified to such an extent that the highly purified cannabinoid has a purity of 98% (w / w) or more.

[0048] "Synthetic cannabinoids" are compounds that have a cannabinoid or cannabinoid-like structure and are produced using chemical means rather than by plants.

[0049] Plant cannabinoids can be obtained either in neutral (decarboxylated form) or carboxylic acid form, depending on the method used to extract the cannabinoid. For example, it is known that by heating the carboxylic acid form, most of the carboxylic acid form is decarboxylated to the neutral form.

[0050] "Treatment-resistant epilepsy" (TRE) or "intractable epilepsy" is defined, according to the 2009 ILAE guidance, as epilepsy that is not adequately controlled by trials of one or more AEDs. Treatment-resistant epilepsy such as Dravet syndrome or Lennox-Gastaut syndrome is a pediatric epilepsy that is difficult to treat. Treatment of seizures in patients with these syndromes often involves the use of adjunctive therapies such as, for example, treatment with two or more antiepileptic drugs simultaneously.

[0051] "Pediatric epilepsy" refers to many different syndromes and genetic mutations that can cause epilepsy during childhood. Some of these examples are as follows: Dravet syndrome; myoclonic-astatic epilepsy; Lennox-Gastaut syndrome; generalized epilepsy with unknown etiology; CDKL5 mutations; Aicardi syndrome; tuberous sclerosis; bilateral polymicrogyria; Dup15q; SNAP25; and febrile infection-related epilepsy syndrome (FIRES); benign Rolandic epilepsy; juvenile myoclonic epilepsy; infantile spasms (West syndrome); and Landau-Kleffner syndrome. The above list is non-exhaustive as there are many different pediatric epilepsies.

Mode for Carrying Out the Invention

[0052] Preparation of Highly Purified CBD Extract The production of a highly purified (greater than 98% w / w) cannabidiol extract, known and having a certain composition, was used in the following examples and will be described below.

[0053] In summary, the active ingredient used is a liquid carbon dioxide extract of Cannabis sativa L. of high CBD-containing chemical species, further purified by solvent crystallization to obtain CBD. In the crystallization process, other cannabinoids and plant components are specifically removed to obtain more than 98% CBD. Since CBD is produced from the cannabis plant rather than synthesized, although highly purified, there are a few other cannabinoids produced and co-extracted with CBD. The details of these cannabinoids and the amounts in which they are present in the pharmaceutical are described in Table 5 below.

[0054]

Table 5

Examples

[0055] Drug-drug interaction between cannabidiol (CBD) and stiripentol (STP) in clinical trials The efficacy of CBD for the adjunctive treatment of seizures associated with Dravet syndrome was demonstrated in a single trial in patients aged 2 to 18 years. Following the end of a 4-week baseline period, patients were randomized to receive either 20 mg / kg / day CBD (n = 61) or placebo (n = 59). CBD or placebo was added to the patients' current anti-seizure treatment, which was kept stable throughout the treatment period of the study.

[0056] All patients had received a diagnosis of treatment-resistant Dravet syndrome and had inadequate seizure control with one or more concomitant anti-epileptic drugs (AEDs) with or without vagus nerve stimulation or ketogenic diet.

[0057] The number of seizures was reported daily via an interactive voice response system. Convulsive seizures were defined as all countable atonic, tonic, clonic, and tonic-clonic seizures. The primary efficacy measure was the percent change from baseline in convulsive seizures.

[0058] At baseline, the disease state characteristics were equivalent between groups, 72.5% reported an increase in seizure frequency with previous treatment, and 15% had never experienced a reduction in seizure frequency with previous medications.

[0059] During the 4-week baseline period, patients were required to have at least 4 seizure episodes (tonic-clonic, clonic, tonic, or atonic) during a stable AED treatment period. Patients had not previously had a median of 4 with previous AEDs, and 93% were receiving two or more concomitant AEDs during the trial. The most commonly used concomitant AEDs (more than 25% of patients) were clobazam, valproate, stiripentol, levetiracetam, and topiramate.

[0060] The median percent change from baseline in seizure reduction for the 20 mg / kg / day group of CBD in Dravet syndrome was statistically superior to placebo (p = 0.0123).

[0061] Following the trial, statistical analyses were performed on various patient groups to determine if there were any interactions between any of the concomitant AEDs the patients were receiving. Data regarding the interaction between CBD and stiripentol (STP) are described below.

[0062] Results The following Table 6 lists the percentage of patients who recorded a 50% reduction in seizure episodes over the treatment period.

[0063]

Table 6

[0064] As shown, 14% of patients receiving stiripentol and placebo experienced a greater than 50% reduction in seizure counts from those recorded during the 4-week baseline recording period.

[0065] Surprisingly, there was a reduction in efficacy in patients receiving stiripentol and clobazam, and only 8% of these patients experienced a reduction of more than 50% in seizures from the baseline rate.

[0066] In the group receiving the test compound CBD, there was an increase in efficacy in both groups. It was found that 43% of the patients receiving stiripentol and CBD achieved a reduction in seizure attacks of more than 50%, while 26% of the patients receiving stiripentol, clobazam and CBD achieved a reduction in seizures of more than 50%.

[0067] Conclusion The increase in efficacy brought about by adding CBD to the AED stiripentol provides a useful treatment combination. Such an increase in efficacy was not expected as it was when combined with stiripentol.

[0068] Furthermore, these patients who were already receiving the combination of stiripentol and clobazam were able to benefit from the inclusion of CBD as an adjuvant therapy as it was found that the inclusion reduced the seizure frequency.

[0069] As can be seen from Table 3, both stiripentol and clobazam are AEDs commonly used in childhood epilepsy syndrome, and furthermore, both of them function through enhancing the activation of gamma-aminobutyric acid (GABA) A-receptors.

[0070] Stiripentol is a positive allosteric modulator of the GABA-A receptor in the brain that enhances the duration of channel opening by binding to a site different from the benzodiazepine binding site. Reduced uptake of GABA into synaptosomes and / or inhibition of GABA transaminase may also explain the role of stiripentol in seizure reduction.

[0071] Clobazam binds to postsynaptic GABA receptors at different binding sites. These GABA receptors are located at various positions in the CNS (limbic system, reticular formation), and clobazam increases the duration for which the receptor remains open. As a result, the postsynaptic inhibitory effect of GABA is enhanced, leading to hyperpolarization and stabilization of the membrane.

[0072] The combination of CBD and an AED that functions as a GABA receptor activator can, therefore, be demonstrated to be particularly beneficial in the treatment of childhood epilepsy syndromes.

Example

[0073] Drug-drug interaction between cannabidiol (CBD) and silybin (STP) in healthy volunteers As part of an open-label, fixed-sequence, healthy volunteer study, the first objective was to investigate the effect of CBD (750 mg twice daily) on the steady-state pharmacokinetics of silybin (STP) (750 mg), and the mutual effects on CBD, 7-hydroxy-cannabidiol (7-OH-CBD), and 7-carboxy-cannabidiol (7-COOH-CBD).

[0074] The analytical species plasma concentrations were determined using a validated biochemical analysis method. The second objective was to evaluate the safety and tolerability of CBD when co-administered with STP.

[0075] When CBD was combined with STP (12 subjects), there was a 1.28- to 1.55-fold increase in exposure (Cmax and AUCtau). Co-administration of STP and CBD had no effect on CBD exposure. However, STP reduced the exposure of 7-OH-CBD and 7-COOH-CBD by 29% and 13%, respectively.

[0076] The most common adverse event (AE) was diarrhea, and none of the observed effects on the analytical species exposure were considered to be clinically significant or correlated with the incidence or severity of the AE.

[0077] Conclusion The above data demonstrate that the combination of CBD and STP provides a safe and effective combination treatment option.

Claims

**Claim 1** A pharmaceutical composition for use in reducing spastic seizures of treatment-resistant Dravet syndrome, comprising only cannabidiol (CBD) as an active ingredient, wherein the pharmaceutical composition is administered in combination with an anti-epileptic drug (AED) comprising only stiripentol as an active ingredient. **Claim 2** The pharmaceutical composition according to claim 1, wherein the CBD is in the form of a highly purified extract of cannabis containing at least 98% (w / w) CBD. **Claim 3** The pharmaceutical composition according to claim 2, wherein the highly purified extract contains less than 0.15% tetrahydrocannabinol (THC). **Claim 4** The pharmaceutical composition according to claim 2, wherein the extract further contains up to 1% cannabidivarin (CBDV). **Claim 5** The pharmaceutical composition according to claim 1, wherein the CBD is present as a synthetic compound. **Claim 6** The pharmaceutical composition according to any one of claims 1 to 5, wherein the dose of CBD is less than 50 mg / kg / day. **Claim 7** The pharmaceutical composition according to any one of claims 1 to 6, wherein the dose of CBD is more than 10 mg / kg / day. **Claim 8** The pharmaceutical composition according to any one of claims 1 to 7, wherein the dose of CBD is more than 20 mg / kg / day.

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