USE OF CANNABINOLIDS IN THE TREATMENT OF EPILEPSY

Abstract

The present invention relates to the use of cannabidiol (CBD) in the treatment of epilepsy which results from mutation of the GRIN2A gene. The CBD used is in the form of a highly purified extract of cannabis such that the CBD is present at greater than 98% of the total extract (w/w) and the other components of the extract are characterised. In particular the cannabinoid tetrahydrocannabinol (THC) is present in an amount of from 0.02 to 0.1% (w/w). In an alternative embodiment the CBD may be in a synthetic form. In use the CBD may also be used 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. Where the CBD is formulated for administration separately, sequentially or simultaneously it may be provided as a kit or together with instructions to administer the one or more components in the manner indicated. It may also be used as the sole medication, i.e. as a monotherapy.

Claims

1. Cannabidiol (CBD) for use in the treatment of epilepsy associated with GRIN2A mutation.

2. Cannabidiol (CBD) for use according to claim 1, for the treatment of non-seizure symptoms in epilepsy associated with GRIN2A mutation.

3. CBD for use according to any of the preceding claims, wherein the epilepsy is a treatment resistant epilepsy (TRE).

4. CBD for use according to any of the preceding claims, wherein the CBD is for use in combination with one or more concomitant anti-epileptic drugs (AED).

5. CBD for use according to any of the preceding claims, wherein the CBD is present as a highly purified extract of cannabis which comprises at least 98% (w/w) CBD.

6. CBD for use according to claim 5, wherein the extract comprises up to 0.1% (w/w) THC.

7. CBD for use according to claim 6, wherein the THC is present at a concentration of between 0.02 and 0.1% (w/w).

8. CBD for use according to claim 5 or 6, wherein the extract further comprises up to 1% (w/w) CBDV.

9. CBD for use according to claims 1 to 4, wherein the CBD is present as a synthetic compound

10. CBD for use according to any of the preceding claims, wherein the dose of CBD is between 5 and 50 mg/kg/day.

11. A method of treating epilepsy associated with GRIN2A mutation comprising administering cannabidiol (CBD) to a subject.

Description

BRIEF DESCRIPTION OF THE DRAWINGS

[0047] Embodiments of the invention are further described hereinafter with reference to the accompanying drawings, in which:

[0048] FIG. 1 shows an EEG of the patient before treatment; and

[0049] FIG. 2 shows an EEG of the patient after treatment.

DEFINITIONS

[0050] Definitions of some of the terms used to describe the invention are detailed below:

[0051] The cannabinoids described in the present application are listed below along with their standard abbreviations.

Cannabinoids and their Abbreviations

TABLE-US-00001 CBD Cannabidiol [00001] THC Tetrahydrocannabinol [00002] CBDV Cannabidivarin [00003] CBD-C4 Cannabidiol-C4 [00004] CBD-C4 Cannabidiol-C1 [00005]

[0052] The table above is not exhaustive and merely details the cannabinoids which are identified in the present application for reference. So far over 60 different cannabinoids have been identified and 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).

[0053] “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.

[0054] “Highly purified cannabinoid extracts” 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 substantially removed, such that the highly purified cannabinoid is greater than or equal to 98% (w/w) pure.

[0055] “Synthetic cannabinoids” are compounds that have a cannabinoid or cannabinoid-like structure and are manufactured using chemical means rather than by the plant.

[0056] 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.

[0057] “Treatment-resistant epilepsy” (TRE) “refractory epilepsy” or “intractable epilepsy” is defined as per the ILAE guidance of 2009 as epilepsy that is not adequately controlled by trials of one or more AED.

[0058] “Childhood epilepsy” refers to the many different syndromes and genetic mutations that can occur to cause epilepsy in childhood. Examples of some of these are as follows: Dravet Syndrome; Myoclonic-Absence Epilepsy; Lennox-Gastaut syndrome; Generalized Epilepsy of unknown origin; CDKL5 mutation; Aicardi syndrome; bilateral polymicrogyria; Dup15q; SNAP25; and febrile infection related epilepsy syndrome (FIRES); benign rolandic epilepsy; juvenile myoclonic epilepsy; Sturge Weber Syndrome (SWS); infantile spasm (West syndrome); and Landau-Kleffner syndrome. The list above is non-exhaustive as many different childhood epilepsies exist.

[0059] “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.

[0060] “Focal seizure where awareness/consciousness are impaired” has replaced the term “complex partial seizure”. These seizures usually start in a small area of the temporal lobe or frontal lobe of the brain and involve other areas of the brain within the same hemisphere that affect alertness and awareness. Most subjects experience automatisms during a focal seizure with impaired consciousness.

[0061] “Percentage decrease in seizure frequency” is defined as the number of seizures at week 14 minus the number of seizures at baseline divided by the number of seizures at baseline multiplied by 100. In patients who are poor responders to existing AED any improvement in response particularly where the improvement is without side effects such as motor side effects on the central nervous system is highly desirable.

DETAILED DESCRIPTION

Preparation of Highly Purified CBD Extract

[0062] The following describes the production of the highly-purified (>98% w/w) cannabidiol extract of botanical origin which has a known and constant composition was used in the Examples below.

[0063] 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 98% CBD. Although the CBD is highly purified because it is produced from a cannabis plant rather than synthetically there is a small amount 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 follows:

TABLE-US-00002 Cannabinoid Concentration CBDV 0.2-0.8% (w/w) CBD-C4 0.3-0.4% (w/w) CBD-C1 0.1-0.15% (w/w)  Δ.sup.9 THC 0.02-0.1% (w/w) 

Production of the Drug Product

[0064] The drug product is presented as an oral solution. The oral solution presentation contains 25 mg/ml or 100 mg/ml CBD, with the excipients sesame oil, ethanol, sucralose and flavouring. Two product strengths are available to allow dose titration across a wide dose range.

[0065] The 25 mg/ml solution is appropriate at lower doses and the 100 mg/ml solution at higher doses.

[0066] The drug product formulation is as described below:

TABLE-US-00003 Qualitative Reference to Component Composition Function Quality Standard Cannabidiol (CBD) 25 mg/ml or Active In-house 100 mg/ml Anhydrous ethanol 79.0 mg/ml* Excipient Ph. Eur. Sucralose 0.5 mg/ml Sweetener In-house Strawberry 0.2 mg/ml Flavouring In-house flavouring Sesame oil q.s to 1.0 ml Excipient Ph. Eur.

[0067] The drug substance, CBD is insoluble in water. Sesame oil was selected as an excipient to solubilize the drug substance.

[0068] A sweetener and fruit flavouring are required to improve palatability of the sesame oil solution.

[0069] Ethanol was required to solubilize the sweetener and the flavouring.

[0070] The composition can be substantially equivalent, by which is meant the functional ingredients can vary from the qualitative composition specified above by an amount of up to 10%.

[0071] Example 1 below describes the use of a highly purified cannabis extract comprising cannabidiol (CBD). Cannabidiol is the most abundant non-psychoactive cannabinoid in the selected chemovar. Previous studies in animals have demonstrated that CBD has anticonvulsant efficacy in multiple species and models.

[0072] Example 1 describes a case study of a child with a GRIN2A mutation that was provided highly purified cannabidiol as part of an expanded access treatment program of children with refractory epilepsy.

Example 1: Efficacy of Cannabidiol in Reducing Seizures and Other Symptoms in Children and Young Adults with Epilepsy Associated with GRIAN2A Mutation

Materials and Methods

[0073] A child aged fourteen years of age was enrolled in an expanded access compassionate use program for CBD. This subject was treated with a highly purified extract of cannabidiol (CBD) obtained from a cannabis plant. Frequency of seizures was recorded at each visit, as were reported quality of life changes, including mood, behaviour, and cognitive function.

[0074] The patient first presented with seizures at the age of four. He experienced status epilepticus with myoclonic jerks and atypical absence seizures which lasted between 30 seconds to 15 minutes.

[0075] The patient had tried and failed 10 different anti-epileptic drugs, the ketogenic diet, vitamin B6 and vagus nerve stimulation however his seizures remained refractory.

[0076] The patient had initial typical development, however this significantly declined after the age of four when seizures started.

[0077] Treatment with a highly purified CBD extract (greater than 98% CBD w/w) in sesame oil, of known and constant composition, at a dose of 5 mg/kg/day in addition to their baseline anti-epileptic drug (AED) regimen was commenced in September 2014 and has been ongoing for four years.

[0078] The daily dose was gradually increased by 2 to 5 mg/kg increments up to a maximum dose of 25 mg/kg/day.

[0079] The patient was seen at regular intervals of 2-4 weeks. Laboratory testing for hematologic, liver, kidney function and concomitant AED levels was performed at baseline, and after every 4 weeks of CBD therapy.

Results

[0080] FIG. 1 shows an EEG recorded at baseline. There are generalized 2-2.5 Hz slow spike waves, left frontotemporal discharges and electrical status epilepticus of sleep.

[0081] FIG. 2 shows a repeat EEG after treatment with CBD. The EEG shows posterior dominate rhythm of 9 Hz alpha activity, reactivity with eye opening and closure, rare epileptiform discharges in the left frontal head region, and no electrical status epilepticus during sleep as previously recorded.

[0082] The patient has been seizure free for the four years since the start of treatment.

[0083] All AEDs have been stopped with the exception of clobazam and the VNS.

[0084] In addition to the improvement of seizures the patient's cognitive function has significantly improved. The patient is now able to attend regular school and undertake sports activities something that they were unable to do prior to treatment.

CONCLUSIONS

[0085] These data indicate that CBD is effective in the treatment of epilepsy associated with GRIN2A mutations.

[0086] It is surprising that in this very refractory patient there has been a complete resolution of seizures which has been accompanied by an improvement in cognition.

REFERENCES

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