Use of cannabinoids in the treatment of epilepsy and related comorbidities

Abstract

The present invention relates to the use of certain compositions of cannabidiol (CBD) in the treatment of epilepsy and associated comorbidities. In one embodiment, the comorbidities are surprisingly found to improve in patients with unreduced seizures. The CBD used is in the form of a highly purified cannabis extract in which CBD is present at greater than 98% (w / w) of the total extract, and the other components of the extract are characterized. In particular, the cannabinoid tetrahydrocannabinol (THC) is present in an amount of 0.02-0.1% (w / w).

Description

[Technical field]

[0001] The present invention relates to the use of certain compositions of cannabidiol (CBD) in the treatment of comorbidities associated with epilepsy. In one embodiment, the comorbidities are surprisingly found to improve in patients whose seizures do not decrease.

[0002] The CBD used is in the form of a highly purified cannabis extract in which CBD is present at more than 98% (w / w) of the total extract and the other components of the extract have been characterized. In particular, the cannabinoid tetrahydrocannabinol (THC) is present in an amount of 0.02-0.1% (w / w). [Background technology]

[0003] Epilepsy occurs in approximately 1% of the population worldwide (Thurman et al., 2011), of which 70% are able to adequately control their epileptic symptoms with available antiepileptic drugs (AEDs). However, 30% of this patient population (Eadie et al., 2012) are unable to achieve seizure freedom from available AEDs and are therefore considered 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 "failure to adequately trial two well-tolerated AED schedules (whether as monotherapy or in combination) appropriately selected and used to achieve sustained seizure freedom" (Kwan et al., 2009).

[0005] 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.

[0006] Childhood epilepsy is a relatively common neurological disorder in children and young adults, with a prevalence of approximately 700 per 100,000 people, which is twice the number of adults with epilepsy per population.

[0007] When a child or young adult exhibits seizures, an investigation is usually carried out to determine the cause. Childhood epilepsy can be caused by many different syndromes and genetic mutations, so a diagnosis may sometimes be made for such children.

[0008] The main symptom of epilepsy is repeated seizures. A study of the type of seizures a patient is experiencing is performed to determine the type of epilepsy or epilepsy syndrome the patient suffers from. Clinical observations and electroencephalography (EEG) tests are performed and the seizure type is classified according to the ILAE classification below.

[0009] In 1981, the International Classification of Seizure Types proposed by the ILAE was adopted, and in 2010, a revised proposal was published by the ILAE, which has not yet replaced the 1981 classification. Figure 1 is an adaptation of the revised terminology from the 2010 proposal, including the proposed change to replace the term partial with focal. In addition, the term "simple partial seizures" has been replaced by the term "focal seizures with unimpaired awareness / responsiveness" and the term "complex partial seizures" has been replaced by the term "focal seizures with impaired awareness / consciousness".

[0010] Generalized seizures, which occur in bilaterally distributed networks and involve rapidly, can be divided into six subtypes: tonic-clonic (grand mal); absence (petit mal); clonic; tonic; atonic; and myoclonic.

[0011] Also, focal (partial) seizures originating from networks confined to only one hemisphere are divided into subclassifications, where the seizures are characterized according to one or more features of a seizure, including aura, motor, autonomic, and awareness / reactivity. When a seizure begins as a focal seizure and rapidly progresses to distribute to bilateral networks, it is known as a bilateral convulsive seizure, a term proposed to replace secondary generalized seizures (generalized seizures that have progressed from focal seizures and are no longer focal).

[0012] It is important to identify the seizure type that a patient suffers from because epilepsy syndromes often present with many different seizure types and many of the standard AEDs are targeted to or only effective against a given seizure type / subtype.

[0013] One such childhood epilepsy is Dravet syndrome. Onset of Dravet syndrome almost always occurs within the first year of life in previously healthy, developmentally normal infants with clonic and tonic-clonic seizures (Dravet, 2011). Symptoms peak at approximately 5 months of age. Other seizures, including long-lasting focal dyscognitive seizures and brief absence seizures, occur between 1 and 4 years of age.

[0014] Both focal and generalized seizures are considered essential for the diagnosis of Dravet syndrome, and Dravet patients may also experience atypical absence seizures, myoclonic absence seizures, atonic seizures, and non-convulsive status epilepticus.

[0015] Seizures are frequent and progress to being treatment-resistant, meaning that they do not respond adequately to treatment. Seizures also tend to be prolonged, lasting more than 5 minutes. Prolonged seizures may lead to status epilepticus, which is a seizure lasting more than 30 minutes or a cluster of seizures one after the other.

[0016] The prognosis is poor, with approximately 14% of children dying during attacks due to sudden, often unrelenting neurological decline caused by infection or of unknown origin. Patients develop intellectual disability and lifelong seizures. Intellectual impairment ranges from severe in 50% of patients to moderate and mild intellectual disability, each accounting for 25% of cases.

[0017] Currently, there are no FDA-approved treatments specifically indicated for Dravet syndrome. Standard of care usually includes a combination of the following anticonvulsants: clobazam, clonazepam, levetiracetam, topiramate, and valproic acid.

[0018] Stiripentol, in combination with clobazam and valproic acid, is approved in Europe for the treatment of Dravet syndrome. In the United States, Stiripentol received Orphan Designation for the treatment of Dravet syndrome in 2008, but the drug is not approved by the FDA.

[0019] Potent sodium channel blockers used to treat epilepsy actually increase seizure frequency in patients with Dravet syndrome, the most common of which are phenytoin, carbamazepine, lamotrigine and rufinamide.

[0020] Management may also include a ketogenic diet, and physical and vagus nerve stimulation. Many patients with Dravet syndrome are treated with anticonvulsant medications, as well as antipsychotic medications, stimulants, and medications to treat insomnia.

[0021] Another such childhood epilepsy syndrome is Lennox-Gastaut syndrome (LGS). LGS is a severe form of epilepsy in which seizures usually begin before age 4. Seizure types vary from patient to patient and include tonic (stiffening of the body, upward deviation of the eyes, dilated pupils, and changes in breathing patterns), atonic (brief loss of muscle tone and consciousness causing a sudden fall), atypical absence (staring spells), and myoclonia (sudden muscle twitching). There may be frequent periods of seizures combined with relatively short seizure-free periods.

[0022] Seizures in LGS are often described as "astatic seizures", defined as attacks or spells (atonic, tonic or tonic-clonic) involving the whole body, trunk or head that have resulted or threatened to result in a fall, injury, collapse into a chair or striking the patient's head on a surface.

[0023] Most patients with LGS experience some degree of impairment in intellectual functioning or information processing, along with developmental delay and behavioral disorders.

[0024] LGS can be caused by brain malformations, perinatal asphyxia, severe head injuries, neurological infections, and inherited degenerative or metabolic conditions. In 30-35% of cases, no cause can be found.

[0025] First-line treatment for astatic seizures, including treatment of astatic seizures in patients with LGS, usually involves a broad-spectrum AED such as sodium valproate, often combined with rufinamide or lamotrigine. Other AEDs that may be considered include felbamate, clobazam, and topiramate.

[0026] Comorbidities occur in many patients diagnosed with epilepsy or epilepsy syndromes.

[0027] Comorbidity is defined as the presence of one or more additional disorders occurring simultaneously with a primary condition. There are multiple comorbid conditions associated with epilepsy. The 2007 NINDS Epilepsy Research Criteria included comorbidity as one of the criteria (Criteria Domain III: Preventing, Limiting, and Reversing Comorbidities Associated with Epilepsy and Its Treatment), and the Institute of Medicine also identified epilepsy comorbidity in the IOM report on epilepsy.

[0028] Although many conditions can coexist with epilepsy, commonly occurring comorbidities in epilepsy include psychiatric disorders, cognitive impairment, migraine headaches, sleep disorders; cardiovascular, respiratory, inflammatory disorders, and sudden death in epilepsy (SUDEP).

[0029] Some antiepileptic medicines may have adverse effects on cognitive dysfunction, mood or behavior and should be used with caution in patients with pre-existing comorbidities in these areas. AEDs may also cause adverse behavioral effects, and these effects may be more commonly seen in people with coexisting behavioral comorbidities.

[0030] A paper published in 2009 listed the following comorbid conditions as having rates significantly higher in the population with epilepsy than in the general population (Seidenberg et al., 2009):

[0031] Medical: musculoskeletal disorders; gastrointestinal and digestive disorders; respiratory disorders; chronic pain disorders; cerebrovascular accidents; migraines; tumors; arthritis; rheumatism; obesity; diabetes; infections; fractures and allergies.

[0032] Psychiatric: depression; anxiety; autism spectrum disorders; interictal dysphoric disorders; interictal behavioural syndromes and psychosis in epilepsy.

[0033] Cognitive: Attention Deficit Hyperactivity Disorder; Learning Disabilities; Mental Retardation; Alzheimer's Disease and Dementia.

[0034] Rosenberg et al. 2017 described a study in which quality of life (QOL) was measured with the Caregiver-Reported Quality of Life in Childhood Epilepsy (QOLCE) questionnaire. Pediatric patients with epilepsy were enrolled in a 12-week prospective open-label study of CBD. Improvements were seen in the domains of energy / fatigue; memory; other cognitive functions; control / helplessness; social interaction; behavior, and overall quality of life. The group reported that changes in QOL did not correlate with changes in seizure frequency or adverse effects. The group also acknowledged the inherent bias associated with such questionnaires, as well as limitations associated with open-label studies without a control group.

[0035] The applicant has shown that administration of certain compositions of CBD in patients with epilepsy has a significant effect on the treatment of certain comorbidities associated with epilepsy. Surprisingly, it was found that certain comorbidities improved in patients regardless of the improvement in seizure burden.

[0036] The areas found to be improved were attention and concentration; stigma items; general well-being; language and social activities. These improvements were seen in both open-label and randomized controlled trials, thus providing solid evidence of such improvements in quality of life.

[0037] The CBD used was in the form of a highly purified cannabis extract in which CBD was present at >98% (w / w) of the total extract and the other components of the extract were characterized. In particular, the cannabinoid tetrahydrocannabinol (THC) was present in amounts between 0.02 and 0.1% (w / w).

[0038] Co-pending International Patent Application No. 2019 / 207319 describes the surprising finding that purified CBD preparations derived from plants, containing minor amounts of the cannabinoids CBD-C1, CBDV, CBD-C4 and THC, have greater efficacy than synthetic CBD that does not contain the minor cannabinoids.

[0039] These data are particularly surprising given that the concentrations of CBD in the plant-derived purified CBD preparations and the synthetic preparations were the same. [Prior art documents] [Patent documents]

[0040] [Patent Document 1] International Patent Application No. 2019 / 207319 Summary of the Invention [Problem to be solved by the invention]

[0041] The present invention demonstrates the ability of purified CBD derived from the same plant to ameliorate certain comorbidities associated with epilepsy. [Means for solving the problem]

[0042] According to a first aspect of the present invention there is provided a cannabidiol (CBD) preparation for use in the treatment of epilepsy and associated comorbidities, the CBD preparation comprising at least 98% (w / w) CBD and not more than 2% (w / w) other cannabinoids, the 2% (w / w) or less other cannabinoids comprising 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.

[0043] Preferably, the CBD preparation contains no more than 1.5% (w / w) THC relative to the total amount of cannabinoids in the preparation.

[0044] More preferably, the CBD preparation contains about 0.01% to about 0.1% (w / w) THC relative to the total amount of cannabinoids in the preparation.

[0045] Even more preferably, the CBD contains about 0.02% to about 0.05% (w / w) THC relative to the total amount of cannabinoids in the preparation.

[0046] In a further embodiment, the mixture of trans-THC and cis-THC is present in a ratio of about 3.6:1 trans-THC:cis-THC.

[0047] More preferably, the mixture of trans-THC and cis-THC is present in a ratio of about 0.8:1 trans-THC:cis-THC.

[0048] In a further embodiment, the CBD preparation comprises from about 0.1% to about 0.15% (w / w) CBD-C1 relative to the total amount of cannabinoids in the preparation.

[0049] In a further embodiment, the CBD preparation contains from about 0.2% to about 0.8% (w / w) CBDV relative to the total amount of cannabinoids in the preparation.

[0050] In a further embodiment, the CBD preparation comprises about 0.3% to about 0.4% (w / w) CBD-C4 relative to the total amount of cannabinoids in the preparation.

[0051] Preferably, the comorbidities associated with epilepsy to be treated are one or more of: attention / concentration; stigma items; overall health status; language and social activities.

[0052] More preferably, comorbidities associated with epilepsy are improved independently of seizure reduction.

[0053] In a further embodiment, the epilepsy is treatment-resistant epilepsy (TRE).

[0054] Preferably, the treatment-resistant epilepsy is one of Dravet syndrome; myoclonic absence epilepsy; Lennox-Gastaut syndrome; generalized epilepsy of unknown etiology; CDKL5 mutation; 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.

[0055] Preferably, the dose of CBD is 5-50 mg / kg / day.

[0056] According to a second aspect of the present invention there is provided a method of treating quality of life associated with epilepsy comprising administering to a subject in need thereof a cannabidiol (CBD) preparation for use in the treatment of quality of life domains associated with epilepsy, wherein the CBD preparation comprises at least 98% (w / w) CBD and not more than 2% (w / w) other cannabinoids, wherein the 2% (w / w) or less 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.

[0057] Preferably, the subject is a human. Alternatively, the subject is an animal. Preferably, the animal is a dog.

[0058] Embodiments of the present invention are further described below with reference to the accompanying drawings. [Brief description of the drawings]

[0059] [Figure 1] FIG. 1 shows a principal component analysis of symptom domains in an open-label seizure study. [Diagram 2] FIG. 1 is a graph showing principal component analysis of symptom domains in a randomized controlled trial. [Diagram 3] 1 is a graph showing the correlation between seizure index ratio and cognitive performance in a rat model of epilepsy. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0060] definition Definitions of some of the terms used to describe this specification are set forth below.

[0061] The cannabinoids described in this application are listed below with their standard abbreviations.

[0062] [Table 1]

[0063] The above table is not comprehensive, but merely details the cannabinoids identified in this application for reference. More than 60 different cannabinoids have been identified so far, and these cannabinoids can be divided into different groups as follows: phytocannabinoids; endocannabinoids and synthetic cannabinoids (which may be novel cannabinoids or synthetically produced phytocannabinoids or endocannabinoids).

[0064] "Phytocannabinoids" are cannabinoids that are naturally derived and can be found in the cannabis plant. Phytocannabinoids can be isolated from the plant to produce highly purified extracts, or can be synthetically reproduced.

[0065] A "highly purified cannabinoid extract" is 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 cannabinoids are at least 98% (w / w) pure.

[0066] "Synthetic cannabinoids" are compounds that have a cannabinoid or cannabinoid-like structure and are produced using chemical means rather than by the plant.

[0067] Plant cannabinoids can be obtained either in neutral (decarboxylated) or carboxylated form depending on the method used to extract the cannabinoids. For example, heating the carboxylated form is known to decarboxylate most of the carboxylated form to the neutral form.

[0068] "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.

[0069] "Childhood epilepsy" refers to many different syndromes and genetic mutations that can occur in childhood to cause epilepsy. Some examples of these are: Dravet syndrome; myoclonic absence epilepsy; Lennox-Gastaut syndrome; generalized epilepsy of 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. There are many different childhood epilepsies, so the above list is not comprehensive.

[0070] "Comorbidities in epilepsy" refers to diseases or conditions occurring in addition to epilepsy. These include: Medical diseases or conditions: musculoskeletal disorders; gastrointestinal and digestive disorders; respiratory disorders; chronic pain disorders; cerebrovascular accidents; migraines; tumors; arthritis; rheumatism; obesity; diabetes; infections; fractures and allergies. Psychiatric diseases or conditions: depression; anxiety; autism spectrum disorders; interictal dysphoric disorders; interictal behavioral syndromes and psychoses in epilepsy. Cognitive diseases or conditions: attention deficit hyperactivity disorder; learning disabilities; mental retardation; Alzheimer's disease and dementia.

[0071] "Quality of Life (QOL) scales" are questionnaires or surveys administered to a patient or the patient's caregiver that ask questions regarding how the patient's condition affects the patient's quality of life. They are used to monitor the impact of the disease on the patient's life and to determine whether treatment allows for improvement in such areas.

[0072] Detailed Description Preparation of highly purified CBD extracts The following describes the production of purified plant-derived CBD with a known, consistent composition that is used in the following examples.

[0073] Briefly, the drug substance used was a CBD-rich liquid carbon dioxide extract containing the Cannabis sativa L species, which was further purified by solvent crystallization to obtain CBD. The crystallization process removes other cannabinoids and plant components, specifically to obtain greater than 98% CBD. CBD is produced from the cannabis plant and not synthetically, so is highly purified, however there are small amounts of other cannabinoids that are produced and co-extracted with CBD. Details of these cannabinoids and the amounts in which they are present in the pharmaceutical product are as follows:

[0074] [Table 2]

[0075] In some embodiments, the CBD preparation comprises tetrahydrocannabinol (THC). In some embodiments, the CBD preparation comprises up to about 1%, about 2%, about 3%, about 4%, or about 5% THC relative to the total amount of cannabinoids in the preparation. In some embodiments, the CBD preparation comprises 0.15% or less THC relative to the total amount of cannabinoids in the preparation. In some embodiments, the CBD preparation comprises about 0.01% to about 0.1% THC relative to the total amount of cannabinoids in the preparation. In some embodiments, the CBD preparation comprises about 0.02% to about 0.05% THC relative to the total amount of cannabinoids in the preparation. In some embodiments, the CBD preparation comprises at least about 0.1% THC relative to the total amount of cannabinoids in the preparation. In some embodiments, the CBD preparation comprises at least about 0.02% THC relative to the total amount of cannabinoids in the preparation. In some embodiments, the THC comprises Δ9-THC.

[0076] In some embodiments, THC is present as a mixture of different isomers. In some embodiments, THC includes trans-THC and cis-THC. In some embodiments, trans-THC and cis-THC are present in a ratio of about 5:1 (trans-THC:cis-THC). In some embodiments, trans-THC and cis-THC are present in a ratio of about 3.5:1 (trans-THC:cis-THC). In some embodiments, trans-THC and cis-THC are present in a ratio of about 2:1 (trans-THC:cis-THC). In some embodiments, trans-THC and cis-THC are present in a ratio of about 1:1 (trans-THC:cis-THC). In some embodiments, trans-THC and cis-THC are present in a ratio of about 0.8:1 (trans-THC:cis-THC).

[0077] In some embodiments, cis-THC is present as a mixture of (-)-cis-THC and (+)-cis-THC. In some embodiments, (-)-cis-THC and (+)-cis-THC are present in a ratio of about 20:1 to 1:20 ((-)-cis-THC:(+)-cis-THC). In some embodiments, (-)-cis-THC and (+)-cis-THC are present in a ratio of about 15:1 to 1:15 ((-)-cis-THC:(+)-cis-THC). In some embodiments, (-)-cis-THC and (+)-cis-THC are present in a ratio of about 10:1 to 1:10 ((-)-cis-THC:(+)-cis-THC). In some embodiments, (-)-cis-THC and (+)-cis-THC are present in a ratio of about 9:1 to 1:9 ((-)-cis-THC:(+)-cis-THC). In some embodiments, (-)-cis-THC and (+)-cis-THC are present in a ratio of about 5:1 to 1:5 ((-)-cis-THC:(+)-cis-THC). In some embodiments, (-)-cis-THC and (+)-cis-THC are present in a ratio of about 3:1 to 1:3 ((-)-cis-THC:(+)-cis-THC). In some embodiments, (-)-cis-THC and (+)-cis-THC are present in a ratio of about 2:1 to 1:2 ((-)-cis-THC:(+)-cis-THC). In some embodiments, (-)-cis-THC and (+)-cis-THC are present in a ratio of about 1:1 ((-)-cis-THC:(+)-cis-THC). In some embodiments, (-)-cis-THC and (+)-cis-THC are present in a ratio of about 9:1 ((-)-cis-THC:(+)-cis-THC).

[0078] In some embodiments, the CBD preparation comprises one or more cannabinoids other than THC, In some embodiments, the CBD preparation comprises 2% or less cannabinoids other than CBD relative to the total amount of cannabinoids in the preparation.

[0079] In some embodiments, the CBD preparation comprises cannabidivarin (CBDV). In some embodiments, the CBDV comprises the (-)-trans-CBDV isoform. In some embodiments, the CBD preparation comprises about 0.2% to about 0.8% CBDV relative to the total amount of cannabinoids in the preparation.

[0080] In some embodiments, the CBD preparation comprises CBD-C4 (CBD-C4). In some embodiments, the CBD-C4 comprises the (-)-trans-CBD-C4 isoform. In some embodiments, the CBD preparation comprises about 0.3% to about 0.4% CBD-C4 relative to the total amount of cannabinoids in the preparation.

[0081] In some embodiments, the CBD preparation comprises CBD-C1 (CBD-C1). In some embodiments, the CBD-C1 comprises the (-)-trans-CBD-C1 isoform. In some embodiments, the CBD preparation comprises about 0.1% to about 0.15% CBD-C1 relative to the total amount of cannabinoids in the preparation.

[0082] In some embodiments, at least a portion of at least one of the cannabinoids present in the CBD preparation is isolated from a cannabis plant material. In some embodiments, at least a portion of the CBD present in the CBD preparation is isolated from a cannabis plant material. In some embodiments, at least a portion of the THC present in the CBD preparation is isolated from a cannabis plant material. In some embodiments, substantially all of at least one of the cannabinoids present in the CBD preparation is isolated from a cannabis plant material. In some embodiments, substantially all of the CBD present in the CBD preparation is isolated from a cannabis plant material. In some embodiments, substantially all of the THC present in the CBD preparation is isolated from a cannabis plant material. In some embodiments, substantially all of the cannabinoids present in the CBD preparation are isolated from a cannabis plant material. In some embodiments, the cannabis plant material is derived from a Cannabis sativa, Cannabis indica, or Cannabis ruderalis plant. In some embodiments, the cannabis plant is a cannabis chemotype that contains high CBD. In some embodiments, the cannabis plant is a cannabis chemotype of Cannabis sativa L. that contains high CBD. In some embodiments, the cannabis plant material comprises about 5% to about 20% CBD relative to the total amount of cannabinoids in the preparation. In some embodiments, the cannabis plant material comprises about 10% to about 15% CBD relative to the total amount of cannabinoids in the preparation. In some embodiments, the cannabis plant material comprises trans-THC and cis-THC present in a ratio of about 3.5:1 (trans-THC:cis-THC). In some embodiments, the cannabis plant material comprises trans-THC and cis-THC present in a ratio of about 0.8:1 (trans-THC:cis-THC). EXAMPLES

[0083] Principal component analysis (PCA) of open-label study data Principal component analysis (PCA) is a statistical procedure that uses an orthogonal transformation to convert a set of observed values ​​of possibly correlated variables into a set of values ​​of linearly uncorrelated variables called principal components.

[0084] This transformation is defined in such a way that the first principal component has the maximum possible variance (accounting for as much of the variability in the data as possible) and each subsequent component in turn has the maximum possible variance under the constraint that it is orthogonal to the preceding component.

[0085] PCA is a useful tool for visualizing associations between data populations and was used in the present examples to determine symptom domains that were improved during an open-label study of cannabidiol (CBD) in patients with treatment-resistant epilepsy.

[0086] Materials and Methods Children and young adults with severe childhood-onset treatment-resistant epilepsy (TRE) were tested with a highly purified extract of cannabidiol (CBD) obtained from the cannabis plant. Participation in the study was part of an expanded access compassionate use program for CBD.

[0087] All patients enrolled in a 4-week baseline period during which parents / caregivers completed a prospective seizure diary, describing all countable motor seizure types.

[0088] Patients then received a highly purified CBD extract of known, constant composition (>98% w / w CBD) in sesame oil at a dose of 5 mg / kg / day in addition to their baseline antiepileptic drug (AED) regimen.

[0089] The daily dose was gradually increased in increments of 2 to 5 mg / kg until intolerance occurred or a maximum dose of 50 mg / kg / day was achieved.

[0090] Patients were seen at regular intervals over 2 to 4 weeks. Laboratory tests for blood, liver, renal function, and concomitant AED levels were performed at baseline and at regular intervals throughout the 12-week study.

[0091] Multiple QOL domains were measured using the Quality of Life in Childhood Epilepsy (QOLCE) survey. Caregivers completed surveys at baseline and after the 12-week study. The QOLCE questionnaire assessed 91 items divided into five subdomains: physical function; cognitive function; emotional well-being; social function and behavior. Overall health status was also recorded.

[0092] PCA was performed on the collected QOLCE data and seizure reduction to determine whether participants experienced a reduction in certain QOL domains as a result of seizure reduction, or whether there was a reduction in QOL domains that was independent of response to study drug as seizure reduction.

[0093] result Figure 1 details the principal components analysis of the data obtained from the QOLCE survey.

[0094] QOL domains plotted to the right of the zero point on the F1 axis are domains that showed improvement over baseline, and conversely, QOL domains plotted to the left of the zero point on the F1 axis are domains that showed no improvement over the baseline measure.

[0095] QOL domains plotted above the zero point on the F2 axis are domains that were improved in participants who experienced a reduction in seizures, and QOL domains plotted below the zero point on the F2 axis are areas that were improved despite the reduction in seizures.

[0096] Table 2 below details the percentage contribution of the observations in more detail, and Table 3 provides the cosine squared of the observations.

[0097] [Table 3]

[0098] [Table 4]

[0099] These data demonstrate that there was improvement (to the right of zero on the F1 axis) in several domains associated with quality of life. These domains were attention and concentration; QOL items; energy / fatigue; mastery / helplessness, and stigma items.

[0100] In the domains of dominance / helplessness and stigma items, improvements were surprisingly observed without improvement in seizures (lower right region of the biplot).

[0101] conclusion Several areas of improvement were found that were related to quality of life. Improvement in these very important areas would allow patients to enjoy a better quality of life. Improvements in some of these areas were seen regardless of seizure reduction, meaning that patients enjoy improved quality of life even though pharmaceutical drugs are ineffective in reducing seizures in these patients. This is particularly surprising considering that these patients were treatment resistant and had tried and failed at least three antiepileptic drugs prior to the study. EXAMPLES

[0102] Principal component analysis (PCA) of pooled study data from randomized controlled trials As described in Example 1, the above PCA is a useful tool for examining data with several variables. Similar analyses were performed on data generated using pooled data from three randomized controlled clinical trials in children and young adults with treatment-resistant epilepsy associated with Dravet syndrome (one study) and Lennox-Gastaut syndrome (LGS) (two studies).

[0103] Materials and Methods In two placebo-controlled studies of CBD as a treatment for seizures associated with LGS, cannabidiol (CBD) was used as add-on treatment in patients defined as treatment-resistant. Patients had already tried and stopped a median of 6 AEDs and were maintained on a median of 3 AEDs.

[0104] The first study was a 1:1 randomized, double-blind, 14-week comparison of cannabidiol oral solution (CBD-OS) versus placebo. The treatment period consisted of a 2-week titration period followed by a 12-week maintenance period. The treatment period was followed by a 10-day taper period and a 4-week follow-up period. The study aimed to determine the efficacy, safety, and tolerability of cannabidiol at 20 mg / kg / day compared to placebo.

[0105] The second study was a 1:1:1 randomized, double-blind, 14-week comparison of two dose levels of cannabidiol (10 mg / kg / day and 20 mg / kg / day) versus placebo. The treatment period consisted of a 2-week titration period followed by a 12-week maintenance period. The treatment period was followed by a 10-day taper period and a 4-week follow-up period. The study aimed to determine the efficacy, safety and tolerability of two dose levels of CBD-OS compared to placebo. Patients in the placebo group were divided into two equal dose cohorts, half of which received a dose volume of 10 mg / kg / day and half of which received a dose volume of 20 mg / kg / day.

[0106] In a placebo-controlled study of CBD as a treatment for seizures associated with Dravet syndrome, CBD was used as add-on treatment in patients defined as treatment-resistant. The study was a 1:1 randomized, double-blind, 14-week comparison of cannabidiol oral solution (CBD-OS) versus placebo. The treatment period consisted of a 2-week titration period followed by a 12-week maintenance period. The treatment period was followed by a 10-day taper period and a 4-week follow-up period. The study aimed to determine the efficacy, safety, and tolerability of cannabidiol at 20 mg / kg / day compared to placebo.

[0107] The Quality of Life in Childhood Epilepsy (QOLCE) survey was used to measure multiple QOL domains. Caregivers completed surveys at baseline and after 12 weeks of treatment. The QOLCE questionnaire assessed 91 items divided into five subdomains: physical function; cognitive function; emotional well-being; social function and behavior. Overall health status was also recorded.

[0108] result Figure 2 details the principal components analysis of the data obtained from the QOLCE survey.

[0109] As described in Example 1, areas that showed improvement in the QOL domains are plotted to the right of zero on the F1 axis, and areas where there was also a reduction in seizures are found above the zero point on the F2 axis.

[0110] Table 4 below details the percentage contribution of the observations in more detail, and Table 5 provides the cosine squared of the observations.

[0111] [Table 5]

[0112] [Table 6]

[0113] As can be seen, improvements associated with quality of life were seen in additional domains compared to Example 1. These domains were quality of life items; overall health status; social interactions; social activities; attention / concentration; overall quality of life; memory; language; feelings of dominance / helplessness; stigma items and cognition.

[0114] Again surprisingly, although patients did not experience any improvement in seizure burden, some quality of life domains improved. Such improvements were observed in the following areas: memory; language; feelings of control / helplessness; stigma items; and cognition.

[0115] conclusion As suggested by the expanded access data described in Example 1, in these data from a randomized controlled clinical trial of CBD in patients with Dravet Syndrome and Lennox-Gastaut Syndrome, there were improvements in certain quality of life domains, with the exception of seizure reduction.

[0116] In patients with epilepsy, seizure burden is often not the most devastating part of the disease. Reductions in certain quality of life domains, such as language and memory, can distress patients with epilepsy syndromes and their caregivers. Improvements in these domains allow patients and their caregivers to lead more normal lives, despite still experiencing seizures. EXAMPLES

[0117] Biostatistical analysis of data from the Lennox-Gastaut study, a randomized controlled trial Biostatistical analysis is the application of statistics to the broader discussion of biology, especially medical biostatistics, exclusively as it relates to medicine and health.

[0118] The following example uses biostatistical analysis to explore trends in quality of life data collected in a randomized controlled trial of cannabidiol in patients with Lennox-Gastaut syndrome.

[0119] method The study was a 1:1 randomized, double-blind, 14-week comparison of cannabidiol oral solution (CBD-OS) versus placebo. The treatment period consisted of a 2-week titration period followed by a 12-week maintenance period. The treatment period was followed by a 10-day taper period and a 4-week follow-up period. The study aimed to determine the efficacy, safety, and tolerability of cannabidiol at 20 mg / kg / day compared to placebo.

[0120] The Quality of Life in Childhood Epilepsy (QOLCE) survey was used to measure multiple QOL domains. Caregivers completed surveys at baseline and after 12 weeks of treatment. The QOLCE questionnaire assessed 91 items divided into five subdomains: physical function; cognitive function; emotional well-being; social function and behavior. Overall health status was also recorded.

[0121] result Table 6 below details areas where there was no change (indicated by ⇔) or where there was a difference of more than 10 points between the medians (indicated by ↑), and whether this change was statistically significant (indicated by *).

[0122] [Table 7]

[0123] As can be seen, there were significant increases over baseline in the memory and language quality of life domains, which is consistent with the areas found to be improved in the analysis of the pooled data in Example 2.

[0124] Interestingly, there was no domain in which quality of life declined.

[0125] conclusion The data presented in this example support improvements in the quality of life domains of language and memory. This analysis of a smaller set of data strongly supports evidence of improvements in specific quality of life domains in patients with Lennox-Gastaut syndrome. EXAMPLES

[0126] Case study analysis of open-label study data Examples 1-3 provide details of improvements in specific quality of life domains in patients with Dravet Syndrome and Lennox-Gastaut Syndrome.

[0127] The present examples provide further data on additional epilepsy syndromes that were studied as part of the expanded access program described in Example 1.

[0128] method Children and young adults with severe childhood-onset treatment-resistant epilepsy (TRE) were tested with a highly purified extract of cannabidiol (CBD) obtained from the cannabis plant. Participation in the study was part of an Expanded Access Compassionate Use Program for CBD.

[0129] All patients will enroll in a 4-week baseline period during which parents / caregivers will complete a prospective seizure diary, describing all countable motor seizure types.

[0130] Patients then received a highly purified CBD extract of known, constant composition (>98% w / w CBD) in sesame oil at a dose of 5 mg / kg / day in addition to their baseline antiepileptic drug (AED) regimen.

[0131] The daily dose was gradually increased in increments of 2 to 5 mg / kg until intolerance occurred or a maximum dose of 50 mg / kg / day was achieved.

[0132] Patients were seen at regular intervals over 2 to 4 weeks. Laboratory tests for blood, liver, renal function, and concomitant AED levels were performed at baseline and at regular intervals throughout the 12-week study.

[0133] Quality of life was recorded by either the physician, the patient / caregiver, or both at each visit and was indicated by a scale of: much worse; much worse; worse; no change; slightly improved; much improved, or very improved.

[0134] result Table 7 below details the results obtained at the end of the study period (after 12 to 108 weeks) from patients suffering from epilepsy syndromes in the open-label study.

[0135] [Table 8A]

[0136] [Table 8B]

[0137] As observed in Table 7, there was an observable improvement in quality of life in patients diagnosed with tuberous sclerosis complex; CDKL5; Sturge-Weber; Dawes syndrome; Angelman syndrome; SNAP25; Febrile Infection-Related Epilepsy Syndrome (FIRES); DUP15Q, and Aicardi syndrome.

[0138] Thirty-four of the 39 patients for whom data were recorded responded positively (slightly improved; much improved or very improved). Although such data were collected via an open-label procedure and therefore subject to potential bias, they provide evidence that quality of life is improved in additional epilepsy syndromes, excluding the better studied Dravet and Lennox-Gastaut syndromes.

[0139] conclusion The data presented in the Examples suggest that improvements in quality of life measures are not restricted to a specific epilepsy syndrome, but are seen in patient populations suffering from a variety of different childhood-onset treatment-resistant epilepsy syndromes. EXAMPLES

[0140] Efficacy of cannabidiol on cognitive performance in rats CBD has already been shown to be able to reverse cognitive deterioration in rats exhibiting spontaneous recurrent seizures, but it also improved the seizure rate in these animals.

[0141] To understand whether the improvement in cognitive performance was simply a result of the reduction in seizure severity by CBD, the correlation between seizure scores and behavioral performance was evaluated in the present examples by Pearson's correlation coefficient.

[0142] method Induction of epilepsy A lithium-pilocarpine induced low intensity status epilepticus (RISE) form of epilepsy was used in male Wistar rats (Harlan Envigo, UK; age: P21-28; body weight >70 g).

[0143] Animals were maintained on a 12:12 h dark:light cycle, at a room temperature of 21° C. and humidity of 50±10%, with food and water available ad libitum throughout the study. Only animals classified as epileptic within 4-8 weeks from the date of induction were used in the present study to minimize any age-related variability.

[0144] research design To understand whether a correlation exists between seizure burden and cognitive performance and the effect of CBD on this relationship, 20 epileptic rats were divided into two groups: 10 animals were treated with 200 mg / kg CBD in drinking water for 6 weeks, and 10 animals received only the vehicle (3.5% Kolliphor® HS, Sigma-Aldrich, Poole, UK) for the entire study period.

[0145] An additional group of 10 vehicle-treated healthy rats was also included. Drug / vehicle treatment was continued throughout the behavioral experiments (7 and 8 weeks of drug treatment).

[0146] Drugs and Chemicals Highly purified CBD (>98% w / w) of plant origin was used in the experiments.

[0147] Video monitoring of seizures and behavioral assessment All animals were video monitored 24 hours per day for the entire 6-week study period. Twenty CCTV cameras (TP-101BK, Topica, Taiwan) were established and connected to a PC, and video footage was recorded using Zoneminder (v1.2.3; Triornis Ltd., Bristol, UK) software.

[0148] Video footage obtained during the light phase (07:00–19:00) from the first 4 days (at the start of treatment) and the last 4 days (before the start of behavioral experiments) was coded offline to analyze the rats' behavior.

[0149] Blinded independent investigators were trained to identify and code convulsive behavior using a modified Racine scale. Scores ≥ 3 reflected clearly identifiable motor convulsions, and these scores were recorded and included in the results.

[0150] The seizure index of the animals was then calculated by multiplying each severity score (Racine scale) by its corresponding frequency (number of occurrences) during the observation period.

[0151] The seizure index ratio was calculated from the seizure index by using the formula: Seizure ratio = (average seizure index of the last bin) / (average seizure index of the first bin). Thus, a higher seizure ratio indicates worsening of the disease.

[0152] Cognitive assessment The animals' cognitive function was assessed using a Plexiglas hole-board apparatus (70 x 70 x 45 cm) placed on a table 72 cm above floor level. The apparatus consisted of 16 equally spaced holes, each 2.5 cm in diameter, on the floor of the apparatus. Each rat was placed in the center of the hole-board and allowed to freely explore the apparatus for 10 min.

[0153] The four reachable pellets were kept in four holes, randomly selected for each animal, and kept constant across all test days. Olfactory cues were abolished by placing inaccessible pellets in all other holes.

[0154] Before the start of the test, the animals were habituated to the holeboard for 4 days (2 days in which the animals were allowed to use the test arena without food, followed by 2 days in which the animals were habituated to the rules of the task with food). On the day of the test, food was deprived from the animals 4-5 hours before the start of the test to increase their motivation to complete the task.

[0155] Tests were performed on three consecutive days, with the animals undergoing five tests each day. Head dips were recorded by a video camera for later analysis. Head dips were scored if the head looked into the hole at least to the level of the rodent's eyes.

[0156] Errors consisted of head-dips into holes that had never contained food (reference memory errors) or re-dips into holes where food had been removed (working memory errors). The total number of reference and working memory errors made by the test animals over the 3 days was used as a measure of cognitive performance. The mean number of reference and working memory errors over the 15 trials was calculated for each animal.

[0157] statistical analysis Linear correlations between the seizure index and the number of reference and working memory errors were assessed for each animal using the Pearson correlation coefficient with values ​​between +1 and -1 (+1 being an overall positive correlation and -1 being an overall negative correlation).

[0158] Note that correlations reflect nonlinearity and the direction of the linear relationship, but not the slope of the relationship, nor many aspects of the nonlinear relationship. In all cases, p<0.05 was considered significant.

[0159] result FIG. 3 details the correlation between seizure index ratio and cognitive performance in the hole-board test.

[0160] In graph A, no significant correlation was found between the seizure index ratio and the number of reference memory errors in vehicle-treated rats (R2=0.05533, p=0.05749, n=8).

[0161] In graph B, in vehicle-treated rats, the seizure index ratio was not significantly correlated with the number of working memory errors (R2=0.03884, p=0.6399, n=8).

[0162] In graph C, the number of reference memory errors was not significantly correlated with the seizure index ratio in rats treated with CBD (R2=0.2486, p=0.2085, n=8).

[0163] In graph D, there was no significant correlation between working memory error and seizure index ratio in animals treated with CBD (R2=0.04755, p=0.6039, n=8).

[0164] conclusion Correlation analysis showed that both vehicle and CBD treated RISE-SRS rats did not demonstrate a linear relationship between seizure burden and cognitive performance.

[0165] This suggests that the beneficial effects of CBD on seizure burden and cognitive performance are independent of each other.

[0166] overall conclusion Taken together, the data from the five examples presented herein provide evidence of the effectiveness of highly purified CBD of plant origin in improving quality of life.

[0167] In particular, improvements were seen in specific quality of life domains including attention / concentration; stigma items; general health status; and language and social activities.

[0168] It was found that such improvements were observed independently of seizure reduction, suggesting that the benefit was an actual improvement in these specific areas, rather than an improvement resulting from a reduction in the number of seizures the patient was suffering from.

Claims

1. 1. A pharmaceutical composition comprising cannabidiol (CBD) for use in improving speech in patients with Dravet syndrome or Lennox-Gastaut syndrome, the pharmaceutical composition comprising at least 98% (w / w) CBD and not more than 2% (w / w) other cannabinoids, wherein the 2% (w / w) or less other cannabinoids comprise the cannabinoids tetrahydrocannabinol (THC); cannabidiol-C1 (CBD-C1); cannabidivarin (CBDV); and cannabidiol-C4 (CBD-C4), wherein the THC is present as a mixture of trans-THC and cis-THC, and wherein the pharmaceutical composition comprises 0.01% to 0.1% (w / w) THC relative to the total amount of cannabinoids.

2. 2. A pharmaceutical composition for use according to claim 1, comprising no more than 1.5% (w / w) THC relative to the total amount of cannabinoids.

3. 2. The pharmaceutical composition for use according to claim 1, comprising 0.02% to 0.05% (w / w) THC relative to the total amount of cannabinoids.

4. 4. The pharmaceutical composition for use according to any one of claims 1 to 3, wherein the mixture of trans-THC and cis-THC is present in a ratio of trans-THC:cis-THC of 3.6:

1.

5. 4. The pharmaceutical composition for use according to any one of claims 1 to 3, wherein the mixture of trans-THC and cis-THC is present in a ratio of trans-THC:cis-THC of 0.8:

1.

6. 6. A pharmaceutical composition for use according to any one of claims 1 to 5, comprising 0.1% to 0.15% (w / w) of CBD-C1 relative to the total amount of cannabinoids.

7. A CBD preparation for use according to any one of claims 1 to 6, comprising 0.2% to 0.8% (w / w) CBDV relative to the total amount of cannabinoids.

8. 8. A pharmaceutical composition for use according to any one of claims 1 to 7, comprising 0.3% to 0.4% (w / w) of CBD-C4 relative to the total amount of cannabinoids.

9. 9. The pharmaceutical composition for use according to any one of claims 1 to 8, wherein language is improved independently of a reduction in seizures.

10. 10. The pharmaceutical composition for use according to any one of claims 1 to 9, wherein the epilepsy is treatment-resistant epilepsy (TRE).

11. The pharmaceutical composition for use according to any one of claims 1 to 10, wherein the dose of CBD is 5 to 50 mg / kg / day.

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