Use of cannabidivarin in the treatment of seizures associated with rare epilepsy syndromes linked to genetic abnormalities

Abstract

The present invention relates to the use of cannabidivarin (CBDV) for the treatment of seizures associated with rare epilepsy syndromes. In particular, the seizures associated with rare epilepsy syndromes to be treated are those experienced by patients diagnosed with Rett syndrome. In a further embodiment, the types of seizures include focal motor seizures with functional impairment, focal non-motor seizures with functional impairment, generalized motor seizures, generalized non-motor seizures, motor seizures of unknown onset, and non-motor seizures. Preferably, the dose of CBDV is between 2.5 mg / kg / day and 10 mg / kg / day.

Description

[Technical Field]

[0001] The present invention relates to the use of cannabidivarin (CBDV) for the treatment of seizures associated with rare epilepsy syndromes. In particular, the seizures associated with rare epilepsy syndromes to be treated are those experienced by patients diagnosed with Rett syndrome. In a further embodiment, the types of seizures include focal motor seizures with functional impairment, focal non-motor seizures with functional impairment, generalized motor seizures, generalized non-motor seizures, motor seizures of unknown onset, and non-motor seizures. Preferably, the dose of CBDV is between 2.5 mg / kg / day and 10 mg / kg / day.

[0002] In a further embodiment, the CBDV used is in the form of a highly purified cannabis extract, such that CBDV is present at greater than 95% (w / w) of the total extract and the cannabinoid tetrahydrocannabinol (THC) has been substantially removed to levels of 1.5% (w / w) or less.

[0003] Preferably, the CBDV used is in the form of purified CBDV derived from plants containing at least 95% (w / w) CBDV and up to 5% (w / w) other cannabinoids, including the cannabinoids tetrahydrocannabinol (THC), tetrahydrocannabivarin (THCV), cannabidiol-C1 (CBD-C1), cannabidiol (CBD), cannabidivarinic acid (CBDVA), and cannabidiol-C4 (CBD-C4). Alternatively, synthetically produced CBDV is used.

[0004] When CBDV is administered concomitantly with one or more other antiepileptic drugs (AEDs), the CBDV may be formulated for separate, sequential, or simultaneous administration with the one or more AEDs, or the combination may be provided in a single dosage form. [Background technology]

[0005] Epilepsy affects approximately 1% of the population worldwide (Thurman et al., 2011), of whom 70% can achieve adequate symptom control with currently available antiepileptic drugs (AEDs). However, 30% of this patient population (Eadie et al., 2012) are unable to achieve seizure freedom with available AEDs and are therefore said to suffer from intractable or "treatment-resistant epilepsy" (TRE).

[0006] In 2009, the International League Against Epilepsy (ILAE) defined refractory or treatment-resistant epilepsy as “the failure of an adequate trial of two tolerated, appropriately selected and used AED schedules (monotherapy or combination therapy) to achieve sustained seizure freedom” ( Kwan et al., 2009 ).

[0007] Individuals who develop epilepsy in 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 are often left with neurological damage that can cause cognitive, behavioral, and motor delays.

[0008] Childhood epilepsy is a relatively common neurological disorder in children and young adults, with a prevalence of approximately 700 per 100,000. Childhood epilepsy is twice as prevalent per capita as adult epilepsy.

[0009] When a child or young adult presents with seizures, an investigation is usually carried out to determine the cause. Because childhood epilepsy can be caused by many different syndromes and genetic mutations, diagnosing these children can take time.

[0010] The main symptom of epilepsy is recurrent seizures. To determine the type of epilepsy or epilepsy syndrome a patient suffers from, an investigation is conducted into the type of seizures the patient is experiencing. Clinical observations and electroencephalogram (EEG) tests are performed, and the type of seizure is classified according to the ILEA classification.

[0011] Generalized seizures, in which seizures occur in bilaterally distributed networks with rapid involvement, can be divided into six subtypes: tonic-clonic (grand mal), absence (petit mal), clonic, tonic, atonic, and myoclonic.

[0012] Focal (partial) seizures, in which the seizures occur within a network limited to only one hemisphere, are also divided into subcategories, where the seizures are characterized according to one or more seizure characteristics, including aura, motor, autonomic, and consciousness / responsiveness. When a seizure begins as a focal seizure and rapidly progresses to become distributed within a bilateral network, it is known as a bilateral convulsive seizure, a term proposed to replace secondarily generalized seizures (generalized seizures that progress from focal seizures and are not localized).

[0013] Focal seizures in which the subject's awareness / responsiveness is altered are called focal seizures with impairment, and focal seizures in which the subject's awareness or responsiveness is not impaired are called focal seizures without impairment.

[0014] Rett syndrome is a brain disorder that affects almost exclusively girls. Girls with Rett syndrome develop seemingly normally for the first six to eight months of life, before developing severe problems with language, communication, learning, coordination, and other brain functions.

[0015] Early in childhood, affected girls are unable to use their hands purposefully and begin to make repetitive wringing, washing, or clapping movements. Affected girls tend to grow more slowly than other children, and about three-quarters have small head size (microcephaly).

[0016] Other signs and symptoms that may occur include breathing problems, spitting or drooling, abnormal eye movements such as intense staring or excessive blinking, cold hands and feet, irritability, sleep problems, seizures, and an abnormal curvature of the spine from side to side (scoliosis).

[0017] Nearly all cases of Rett syndrome are caused by mutations in the methyl-CpG-binding protein 2, or MECP2, gene. The MECP2 gene contains instructions for the synthesis of a protein called methylcytosine-binding protein 2 (MeCP2), which is necessary for brain development and acts as one of many biochemical switches that can either increase gene expression or tell other genes when to switch off and stop producing their own proteins. Because the MECP2 gene does not function properly in individuals with Rett syndrome, insufficient amounts of the protein or a structurally abnormal form of the protein is produced, which can lead to the abnormal expression of other genes.

[0018] Not everyone with an MECP2 mutation has Rett syndrome. Mutations in the CDKL5 and FOXG1 genes have also been linked to Rett syndrome.

[0019] Cannabidiol (CBD), a non-psychoactive derivative derived from the cannabis plant, has shown anticonvulsant properties in several case reports, preclinical and clinical studies in both animal models and humans. Three randomized controlled trials have demonstrated the efficacy of a purified pharmaceutical preparation of CBD in patients with Dravet syndrome and Lennox-Gastaut syndrome.

[0020] Based on these three studies, a plant-derived purified CBD preparation was approved by the FDA in June 2018 for the treatment of seizures associated with Dravet syndrome and Lennox-Gastaut syndrome.

[0021] Clinical trials are currently underway to test the ability of purified plant-derived CBD to treat behavioral symptoms associated with Rett syndrome. 1 .

[0022] Cannabidivarin (CBDV) has been shown to reverse behavioral changes in a mouse model of Rett syndrome 2 In another study, CBDV reversed memory deficits and delayed the onset of neurological and motor deficits in a mouse model of Rett syndrome. 3 .

[0023] UK Patent No. 2487183 discloses the use of CBDV in a hippocampal brain slice model, a rat pentylenetetrazole (PTZ) seizure model, and a rat pilocarpine epilepsy model, but makes no mention of Rett syndrome and provides no data demonstrating efficacy in patients with Rett syndrome.

[0024] Amada et al. (2013) 4 further described the use of CBDV in the PTZ model, but did not mention Rett syndrome. 5 disclose a study investigating the anticonvulsant properties of cannabis-derived botanical drug substances (BDS). The BDS used contained 47 to 58% CBDV. Again, there is no mention of Rett syndrome. In a previous paper, Hill et al., 2012 6 showed that CBDV alone in fact had no effect on pilocarpine-induced seizures.

[0025] Huizenga et al. (2019) 7 conducted a systematic evaluation of CBDV in multiple seizure models in postnatal day (P) 10 and 20 animals. They found that CBDV did not suppress seizures in the methyl-6,7-dimethoxy-4-ethyl-beta-carboline-3-carboxylate (DMCM) and maximal electroshock models in P10 animals.

[0026] British Patent No. 2569961 discloses non-oily oral pharmaceutical formulations containing cannabinoids, which may be CBDV formulations, but there is no data demonstrating the efficacy of such formulations in treating patients with Rett syndrome.

[0027] WO 2017 / 178807 relates to the use of CBDV in the treatment of autism spectrum disorder (ASD) and ASD-related disorders, such as Rett syndrome. Using a MeCP2 KO mouse model of Rett syndrome, the effects on motor changes and cognitive impairment were evaluated. CBDV was found to reduce weight loss and reduced survival, as well as improve general condition and motor and respiratory symptoms. The effect on seizures associated with Rett syndrome was not studied.

[0028] Public summary of the 2018 European Medicines Agency opinion 8 mentions the use of CBDV to potentially reduce seizures in individuals with Rett syndrome, but no data have been provided, let alone the specific types of seizures reduced with CBDV treatment.

[0029] Applicants discovered through an open-label Phase 1 study that treatment with CBDV resulted in a significant reduction in specific seizure types, including focal motor seizures with functional impairment, focal non-motor seizures with functional impairment, generalized motor seizures, generalized non-motor seizures, motor seizures of unknown onset, and non-motor seizures, in patients diagnosed with Rett syndrome. [Prior art documents] [Patent documents]

[0030] [Patent Document 1] British Patent No. 2487183 [Patent Document 2] British Patent No. 2569961 [Patent Document 3] International Publication No. 2017 / 178807 Brochure [Non-patent literature]

[0031] [Non-Patent Document 1] Handbook of Cannabis, Roger Pertwee, Chapter 1, pp. 3-15 Summary of the Invention [Means for solving the problem]

[0032] According to a first aspect of the present invention there is provided a cannabidivarin (CBDV) preparation for use in the treatment of seizures associated with Rett Syndrome.

[0033] In further embodiments, the seizures associated with Rett Syndrome are focal motor seizures with functional impairment, focal non-motor seizures with functional impairment, generalized motor seizures, generalized non-motor seizures, motor seizures of unknown onset, and non-motor seizures.

[0034] In a further embodiment, the CBDV preparation comprises greater than 95% (w / w) CBDV and less than or equal to 1.5% (w / w) tetrahydrocannabinol (THC).

[0035] Preferably, the CBDV preparation comprises 95% (w / w) or more CBDV and 5% (w / w) or less other cannabinoids, including the cannabinoids tetrahydrocannabinol (THC), tetrahydrocannabivarin (THCV), cannabidiol-C1 (CBD-C1), cannabidiol (CBD), cannabidivarinic acid (CBDVA), and cannabidiol-C4 (CBD-C4).

[0036] Preferably, the CBDV preparation is used in combination with one or more concomitant antiepileptic drugs (AEDs).

[0037] Preferably, the one or more AEDs are selected from the group consisting of primidone, carbamazepine, zonegran, phenobarbitone, lamotrigine, levetiracetam, sodium valproate, and clobazam.

[0038] In one embodiment, the CBDV is present in and isolated from cannabis plant material. Preferably, at least a portion of at least one of the cannabinoids present in the CBDV preparation is isolated from cannabis plant material.

[0039] In a further embodiment, the CBDV is present as a synthetic preparation. Preferably, at least a portion of at least one of the cannabinoids present in the CBDV preparation is synthetically prepared.

[0040] Preferably, the CBDV dose is greater than 2.5 mg / kg / day. More preferably, the CBDV dose is 10 mg / kg / day. More preferably, the CBDV dose is 20 mg / kg / day. More preferably, the CBDV dose is 25 mg / kg / day. More preferably, the CBDV dose is 50 mg / kg / day.

[0041] According to a second aspect of the present invention, there is provided a method of treating seizures associated with Rett Syndrome, the method comprising administering a cannabidivarin (CBDV) preparation to a subject in need thereof.

[0042] definition Definitions of some of the terms used to describe this invention are detailed below:

[0043] Over 100 different cannabinoids have been identified, see for example Handbook of Cannabis, Roger Pertwee, Chapter 1, pages 3-15. These cannabinoids can be divided into various groups as follows: phytocannabinoids, endocannabinoids, and synthetic cannabinoids (which may be novel cannabinoids or synthetically produced phytocannabinoids or endocannabinoids).

[0044] "Phytocannabinoids" are cannabinoids that occur naturally and can be found in the cannabis plant. Phytocannabinoids can be isolated from the plant to produce highly purified extracts, or they can be reproduced synthetically.

[0045] "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 cannabinoid have been removed; therefore, highly purified cannabinoids are 95% (w / w) or greater in purity.

[0046] "Synthetic cannabinoids" are compounds that have cannabinoid or cannabinoid-like structures and are produced using chemical means rather than from plants.

[0047] Phytocannabinoids can be obtained as either the neutral (decarboxylated) or carboxylic acid form depending on the method used to extract the cannabinoids. For example, it is known that heating the carboxylic acid form will decarboxylate most of the carboxylic acid form to the neutral form.

[0048] "Treatment-resistant epilepsy" (TRE) or "refractory epilepsy" is defined according to the 2009 ILAE guidelines as epilepsy that is not adequately controlled by a trial of one or more AEDs.

[0049] "Tonic seizures" may be generalized, affecting both sides of the brain, or focal, starting on only one side of the brain. When a tonic seizure starts on both sides of the brain, all muscles tense and the subject's body becomes rigid. If standing, the subject may fall to the floor, their neck may be stretched, their eyes may be wide and rolled upward, their arms may be raised overhead, and their legs may be extended and retracted. When a tonic seizure starts on one side of the brain, muscles in only one area of ​​the body tense. A tonic seizure usually lasts less than one minute.

[0050] "Clonic seizures" are characterized by sustained rhythmic jerks. During clonic seizures, spasms of the body or parts of the body are the main symptom. They may start in one area of ​​the brain or affect both sides of the brain. These seizures are rare, but cannot be stopped by restraining the person.

[0051] A "tonic-clonic seizure" consists of two phases: a tonic phase and a clonic phase. During the tonic phase, the entire body stiffens, and during the clonic phase, uncontrollable convulsions occur. Tonic-clonic seizures may or may not be preceded by an aura and are often followed by headache, confusion, and sleep. They may last from just a few seconds to several minutes. These seizures are also known as grand mal seizures.

[0052] "Cataplexy" occurs when a person suddenly loses muscle tone, causing the head or body to go limp. This is also known as a drop attack. In some children, just the head suddenly drops. They can start in one area or side of the brain (focal onset seizures) or both sides of the brain (generalized onset seizures).

[0053] "Myoclonic seizures" are characterized by "muscle spasms." Myoclonic seizures are brief but can occur in clusters (many seizures occurring close together in time), often occurring shortly after waking. During a myoclonic seizure, the person is conscious, but is classified as a generalized seizure.

[0054] "Absence seizures" are sometimes called "petit mal" seizures. These types of seizures cause a brief loss of consciousness. They can occur at any age, but primarily affect children. During an absence seizure, the person may stare blankly into space, appear to be "daydreaming," have shaking eyes, or slight jerking of the body or limbs. Seizures usually last only a maximum of 15 seconds and can occur several times a day.

[0055] "Focal seizures" are defined as seizures that occur within a network limited to only one hemisphere. What happens during a seizure depends on where in the brain the seizure occurs and what that part of the brain normally does.

[0056] "Focal seizures without functional impairment" are seizures occurring within a network restricted to only one hemisphere, without impairing the subject's awareness or responsiveness.

[0057] "Focal seizures with impaired function" usually begin in a small area of ​​the temporal or frontal lobe of the brain and involve other areas of the brain within the same hemisphere, affecting alertness and consciousness. Most subjects experience automatisms during focal seizures with impaired consciousness.

[0058] "Focal seizures with secondary generalization" begin in a limited area on one side of the brain and spread to involve both sides. This differs from generalized-onset seizures, which begin on both sides of the brain.

[0059] "Epileptic spasms," "spasms," "infantile spasms," "juvenile spasms," or "West syndrome" are defined as sudden flexion, extension, or mixed flexion-extension of proximal and trunk muscles, lasting 1 to 2 seconds. Spasms typically occur one after the other, usually during awakening. Subtle forms may occur, involving only jaw movement, grimacing, or head nodding. Spasms may be symmetric, asymmetric, or unilateral, depending on whether they are generalized or focal in origin.

[0060] A "generalized seizure" affects both sides of the brain or groups of cells on both sides of the brain simultaneously. This term includes types of seizures such as tonic-clonic, absence, or atonic.

[0061] A "seizure of unknown onset" occurs when the start of a seizure is unknown. For example, if a seizure occurs at night or in a person living alone and is not witnessed or observed by anyone, the seizure may be called of unknown onset.

[0062] Seizures can also be described by whether they cause motor symptoms, i.e., movements during the seizure, known as a "motor seizure." If no motor symptoms occur, they may be called a "non-motor seizure."

[0063] For focal-onset seizures, motor seizures may include clonic, atonic, tonic, myoclonic, or epileptic spasms. There may also be automatisms or repetitive automatic movements, such as clapping or rubbing the hands, lip smacking or biting, or running. Non-motor symptoms may include changes in sensation, emotion, thought or cognition, autonomic function, or lack of movement (behavioral arrest).

[0064] For generalized-onset seizures, motor seizures usually consist of tonic-clonic seizures. Other types include clonic, atonic, tonic, myoclonic, or epileptic spasms. Non-motor symptoms are usually absence seizures. Absence seizures may also have myoclonus, which may affect only certain parts of the body or the eyelids.

[0065] For seizures of unknown onset, motor seizures are described as either tonic-clonic or epileptic spasms. Non-motor seizures usually involve the arrest of behavior. DETAILED DESCRIPTION OF THE INVENTION

[0066] Preparation of highly purified CBDV extract Method overview The following describes the production of purified CBDV (>95% w / w) from plants of known, consistent composition that was used in the following examples.

[0067] Plant material harvested from cannabis (Cannabis sativa L.) plants was subjected to liquid carbon dioxide extraction to produce a plant extract containing CBDV in addition to other cannabinoids and non-cannabinoid components. This extract was then further purified by solvent crystallization to obtain purified plant-derived CBDV. The crystallization process specifically removed other cannabinoids and plant components, yielding greater than 95% (w / w) CBDV.

[0068] Both the plant starting material and the plant extract may be controlled by specifications.

[0069] Examples of plant-derived purified CBDV preparations are set forth below in Table 1.1. In some embodiments, the isomeric content of each cannabinoid may also be specified.

[0070] [Table 1]

[0071] The plant-derived purified CBDV preparation was greater than 95% pure and contained THC and other cannabinoids, such as CBD, CBDVA, THCV, CBD-C1, and CBD-C4.

[0072] Distinct chemical varieties of the cannabis plant have been developed to maximize the production of specific chemical constituents, or cannabinoids. Certain chemical varieties produce primarily CBDV. Only the (-)-trans isomer of CBDV is believed to occur naturally. During purification, the stereochemistry of CBDV is unaffected.

[0073] CBDV botanical drug substance production The process for producing plant extracts and intermediates is outlined below. a. Cultivation b. Direct drying c. Decarboxylation d. Extraction - using liquid CO2 e. Dewaxing with ethanol f.Filtration g. Evaporation

[0074] The high-CBDV chemovariety was grown, harvested, dried, packaged, and stored in a dry room until needed. The raw plant material (BRM) was finely ground using an Apex mill fitted with a 1 mm screen. The ground BRM was stored in a freezer prior to extraction.

[0075] Decarboxylation of CBDVA to CBDV was carried out using heat: BRM was decarboxylated at 115°C for 60 minutes.

[0076] Extraction was performed using liquid CO2 to produce the botanical drug substance (BDS), which was then crystallized to produce the test substance. The crude CBDV BDS was winterized under standard conditions (2 volumes of ethanol at -20°C for approximately 50 hours) to purify the extract. The precipitated wax was removed by filtration, and the solvent was removed to yield the BDS.

[0077] Production of purified plant-derived CBDV preparations The manufacturing process for producing a purified plant-derived CBDV preparation from BDS is as follows: a.C5~C 12 Crystallization using linear or branched alkanes b.Filtration c. Vacuum drying

[0078] The BDS generated using the above methodology is C5-C 12 The crystals were dispersed in a linear or branched alkane. The mixture was manually stirred to break up clumps, and the sealed container was then placed in a freezer for approximately 48 hours. The crystals were isolated by vacuum filtration and added to a small amount of cold C5-C 12 The purified plant-derived CBDV preparations were stored in pharmaceutical-grade stainless steel containers with FDA food-grade approved silicone stoppers and fasteners in a -20°C freezer.

[0079] Apparently, CBDV preparations could be produced synthetically by creating compositions with overlapping components.

[0080] Example 1 below describes the use of purified plant-derived cannabidivarin (CBDV) in an open-label Phase I study to investigate the clinical efficacy and safety of purified pharmaceutical cannabidivarin (CBDV) in treating patients diagnosed with Rett Syndrome. [Example]

[0081] Clinical efficacy and safety of purified pharmaceutical cannabidivarin (CBDV) in the treatment of patients diagnosed with Rett syndrome research design Subjects were required to have been on stable doses of one or more AEDs for at least 4 weeks prior to baseline. Subjects had to have a diagnosis of refractory epilepsy: failed an adequate trial of two or more standard anticonvulsants, had four or more quantifiable seizures within the eight weeks prior to screening, and had two or more quantifiable seizures during the prospective baseline phase.

[0082] Patients received a 50 mg / mL sesame oil-based solution of purified plant-derived CBDV, adjusted to an initial dose of 2.5 milligrams per kilogram per day (mg / kg / day), with the dose subsequently increased to a target of 10 mg / kg / day.

[0083] The study included five patients who received CBDV for various durations. Concomitant AEDs were modified according to clinical indications.

[0084] Seizure frequency, intensity, and duration were recorded in diaries by caregivers 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 time points during treatment.

[0085] statistical methods Patients may be defined as responders if they experience a greater than 50% reduction in seizure frequency compared to baseline. The percentage increase or decrease in seizure frequency at the end of the treatment period was calculated as follows:

[0086]

number

[0087] result Patient description Five patients enrolled in the open-label Phase 1 trial were diagnosed with Rett syndrome. These patients experienced a range of seizure types, including disabling focal seizures, generalized seizures, seizures of unknown onset, non-motor seizures, and other seizure types.

[0088] The patients' ages ranged from 6 to 13 years, and all five were female, as detailed in Table 1 below.

[0089] [Table 2]

[0090] Test drug and concomitant drug Patients participating in this study were titrated to various doses of CBDV.

[0091] Patients were taking an average of three AEDs.

[0092] Clinical changes Tables 2A-2E (Tables 3-7) show the frequency of attacks for each patient.

[0093] [Table 3]

[0094] Patient 1 was treated for 14 months and experienced a 52.5% reduction in seizures during treatment.

[0095] [Table 4]

[0096] Patient 2 was treated for 11 months and experienced a 79.4% reduction in seizures during treatment.

[0097] [Table 5]

[0098] Patient 3 was treated for 12 months and experienced a 90.0% reduction in seizures during treatment.

[0099] [Table 6]

[0100] Patient 4 was treated for 12.5 months and experienced a 5.7% reduction in seizures during treatment.

[0101] [Table 7]

[0102] Patient 5 was treated for 11 months and experienced a 98.1% reduction in seizures during treatment.

[0103] Overall, patients reported a 5.7-98.1% reduction in seizures during treatment with CBDV.

[0104] CBDV was effective in reducing the frequency of all types of seizures: focal motor seizures with functional impairment, focal non-motor seizures with functional impairment, generalized motor seizures, generalized non-motor seizures, motor seizures of unknown onset, non-motor seizures, and other types of seizures.

[0105] Importantly, three patients (patients 3–5) suffered from generalized seizures, and all three experienced a reduction in these seizures. Four patients (patients 1–4) suffered from focal seizures with functional impairment, and three of these patients (patients 1–3) experienced a reduction in these seizures.

[0106] conclusion These data indicate that CBDV was able to significantly reduce the number of seizures associated with Rett syndrome. Given that four out of five patients experienced a high responder rate, it is clear that this treatment represents a significant benefit for this difficult-to-treat epilepsy syndrome.

[0107] Importantly, four of the five patients were found to have a greater than 50% reduction in seizure frequency compared to baseline after treatment with CBDV, with three experiencing a reduction of greater than 75%.

[0108] In conclusion, this study demonstrates that the use of CBDV for the treatment of seizures associated with Rett syndrome, including focal motor seizures with functional impairment, focal non-motor seizures with functional impairment, generalized motor seizures, generalized non-motor seizures, motor seizures of unknown onset, and non-motor seizures, significantly reduced seizure frequency by up to 98%. References 1. https: / / www.clinicaltrials.gov / ct2 / show / NCT03848832?term=cannabidiol&cond=Rett+Syndrome Accessed: 10 July 2020. 2.Vigli et al. (2018) “Chronic Treatment With the Phytocannabinoid Cannabidivarin (CBDV) Rescues Behavioural Alterations and Brain Atrophy in a Mouse Model of Rett Syndrome” Neuropharmacology 3.Zamberletti et al. (2019) “Cannabidivarin completely rescues cognitive deficits and delays neurological and motor defects in male Mecp2 mutant mice” Journal of Psychopharmacology 4.Amada et al. (2013) "Cannabidivarin (CBDV) suppresses pentylenetetrazole (PTZ)-induced increases in epilepsy-related gene expression", pages 1-18, PeerJ, vol. 1. 5.Hill et al. (2013) "Cannabidivarin-rich cannabis extracts are anticonvulsant in mouse and rat via a CB1 receptor-independent mechanism", pages 679-692. British Journal of Pharmacology, vol. 170 6.Hill et al. (2012) "Cannabidivarin is anticonvulsant in mouse and rat", pages 1629-1642, British Journal of Pharmacology, vol. 167 7.Huizenga et al. (2019) "Preclinical safety and efficacy of cannabidivarin for early life seizures", pages 189-198, Neuropharmacology, vol. 148. 8.European Medicines Agency (2018) “Public summary of opinion on orphan designation: Cannabidivarin for the treatment of Rett syndrome.”

Claims

1. A pharmaceutical composition for use in treating seizures associated with Rett syndrome, comprising a cannabidivarin (CBDV) preparation, wherein the CBDV preparation comprises greater than 95% (w / w) CBDV and less than or equal to 1.5% (w / w) tetrahydrocannabinol (THC), and wherein the dose of CBDV is between 2.5 mg / kg / day and 10 mg / kg / day.

2. 2. The pharmaceutical composition of claim 1, wherein the seizures associated with Rett syndrome are focal motor seizures with functional impairment, focal non-motor seizures with functional impairment, generalized motor seizures, generalized non-motor seizures, motor seizures of unknown onset, and non-motor seizures.

3. A pharmaceutical composition described in claim 1 or 2, wherein the CBDV preparation contains 95% (w / w) or more CBDV and 5% (w / w) or less other cannabinoids, and the 5% (w / w) or less other cannabinoids include the cannabinoids tetrahydrocannabinol (THC), tetrahydrocannabivarin (THCV), cannabidiol-C1 (CBD-C1), cannabidiol (CBD), cannabidivarinic acid (CBDVA), and cannabidiol-C4 (CBD-C4).

4. A pharmaceutical composition described in any one of claims 1 to 3, wherein the CBDV preparation is used in combination with one or more concomitant antiepileptic drugs (AEDs).

5. 5. The pharmaceutical composition of claim 4, wherein the one or more AEDs are selected from the group consisting of primidone, carbamazepine, zonegran, phenobarbitone, lamotrigine, levetiracetam, sodium valproate, and clobazam.

6. 6. A pharmaceutical composition according to any one of claims 1 to 5, wherein the CBDV is present in and isolated from cannabis plant material.

7. 7. A pharmaceutical composition according to any one of claims 1 to 6, wherein at least a portion of at least one of the cannabinoids present in the CBDV preparation is isolated from cannabis plant material.

8. 6. A pharmaceutical composition according to any one of claims 1 to 5, wherein the CBDV is present as a synthetic preparation.

9. 9. The pharmaceutical composition of claim 8, wherein at least a portion of at least one of the cannabinoids present in the CBDV preparation is synthetically prepared.

10. 10. The pharmaceutical composition of any one of claims 1 to 9, wherein the dose of CBDV is 10 mg / kg / day.

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