USE OF CANNABINOIDS IN THE TREATMENT OF EPILEPSY

Abstract

The present invention relates to the use of cannabidiol (CBD) in the treatment of focal seizures. In one modality, patients suffering from focal seizures are children and young adults. CBD appears to be particularly effective in reducing focal seizures in patients with etiologies including Lennox-Gastaut syndrome; tuberous sclerosis complex; Dravet syndrome; CDKL5; neuronal ceroid lipofuscinosis (NCL); febrile infection-related epilepsy (FIRES) syndrome; Aicardi syndrome; and brain abnormalities, compared to other types of seizures. Significantly, CBD is also highly effective in reducing a subtype of focal seizures: focal seizures with deterioration.

Description

USE OF CANNABINOIDS IN THE TREATMENT OF EPILEPSY Field of invention [1] The present invention relates to the use of cannabidiol (CBD) in the treatment of focal seizures. In one modality, the patients suffering from focal seizures are children and young adults. CBD appears to be particularly effective in reducing focal seizures in patients suffering from etiologies including: Lennox-Gastaut syndrome; tuberous sclerosis complex; Dravet syndrome; CDKL5; neuronal ceroid lipofuscinosis (NCL); febrile infection-related epilepsy syndrome (FIRES); Aicardi syndrome; and brain abnormalities compared to other types of seizures. [2] Significantly, CBD is also highly effective in reducing a subtype of focal seizures, focal seizures with deterioration. The etiologies of patients experiencing focal seizures with deterioration include: Lennox-Gastaut syndrome; tuberous sclerosis complex; Dravet syndrome; CDKL5; febrile infection-related epilepsy (FIRES) syndrome; Aicardi syndrome; and brain abnormalities. [3] In these patients, CBD treatment reduced the incidence of absence seizures or myoclonic absence seizures by more than 50% in a large proportion of patients, 64% and 75% respectively. This was surprising given that the proportion of patients who benefited from a reduction of more than 50% in total seizures was significantly lower (46%) in all treated subjects. [4] Preferably, the CBD used is in the form of a highly purified cannabis extract such that CBD is present in more than 98% of the total extract (w / w) and the other components of the extract are characterized. In particular, the cannabinoid tetrahydrocannabinol (THC) has been substantially removed, to a level of no more than 0.15% (w / w), and the propyl analogue of CBD, cannabidivarin (CBDV), is present in amounts of up to 1%. Alternatively, the CBD may be synthetically produced. [5] During use, CBD may be used concomitantly with one or more other antiepileptic drugs (AEDs). Alternatively, CBD may be formulated for administration separately, sequentially, or simultaneously with one or more AEDs, or the combination may be provided in a single dosage form. When CBD is formulated for administration separately, sequentially, or simultaneously, it may be provided as a kit or with instructions for administering one or more components as directed. It may also be used as a single medication, i.e., as monotherapy. Background of the invention [6] Epilepsy occurs in approximately 1% of the population worldwide (Thurman et al., 2011), of whom 70% can adequately control their symptoms with existing antiepileptic drugs (AEDs). However, 30% of this group of patients (Eadie et al., 2012) cannot achieve seizure freedom with the available AEDs and, as such, is termed intractable epilepsy or treatment-resistant epilepsy (TRE). [7] Intractable or treatment-resistant epilepsy was defined in 2009 by the International League Against Epilepsy (ILAE) as the failure of adequate trials of two well-tolerated and appropriately chosen and used AED programs (either as monotherapies or in combination) to achieve sustained seizure freedom (Kwan et al, 2009). [8] People who develop epilepsy during the first few years of life are often difficult to treat and, as such, are often referred to as treatment-resistant. Children who experience frequent seizures in infancy often have neurological damage that can cause cognitive, behavioral, and motor delays. [9] Childhood epilepsy is a relatively common neurological disorder in children and young adults with a prevalence of approximately 700 per 100,000. This is twice the number of epileptic adults per population.

[10] When a child or young adult experiences a seizure, investigations are usually carried out to determine the cause. Childhood epilepsy can be caused by many different syndromes and genetic mutations, and as such, diagnosis in these children can take some time.

[11] The main symptom of epilepsy is repeated seizures. To determine the type of epilepsy or epileptic syndrome a patient has, an investigation is carried out on the type of seizures the patient experiences. Clinical observation and electroencephalography (EEG) tests are performed, and the seizure type is classified according to the ILAE classification described below and in Figure 1.

[12] The International Classification of Epilepsy Types proposed by the ILAE was adopted in 1981, and the ILAE published a revised proposal in 2010, which has not yet replaced the 1981 classification. Figure 1 is an adaptation of the 2010 proposal for the revised terminology and includes the proposed changes to replace the term "partial" with "focal." In addition, the term "simple partial seizure" has been replaced by "focal seizure," where consciousness / responsiveness is not impaired, and the term "complex partial seizure" has been replaced by "focal seizure," where consciousness / consciousness is impaired.

[13] From Figure 1, it can be seen that generalized seizures, in which the seizure occurs within bilaterally distributed networks and quickly becomes entangled in them, can be divided into six subtypes: tonic-clonic seizures (grand mal); absence seizures (small mal); clonic seizures; tonic seizures; atonic seizures; and myoclonic seizures.

[14] Focal (partial) seizures, where the seizure originates within networks limited to only one hemisphere, are also divided into subcategories. Here, the seizure is characterized according to one or more seizure features, including aura, motor, autonomic, and consciousness / responsiveness. When a seizure begins as a localized seizure and rapidly evolves to spread within bilateral networks, this seizure is known as a bilateral seizure, which is the proposed terminology to replace secondary generalized seizures (generalized seizures that have evolved from focal seizures and are no longer localized).

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

[16] Focal seizures can occur in epilepsy syndromes including: Lennox-Gastaut syndrome; tuberous sclerosis complex; Dravet syndrome; CDKL5; neuronal ceroid lipofuscinosis (NCL); febrile infection-related epilepsy (FIRES) syndrome; Aicardi syndrome and brain abnormalities.

[17] Epileptic syndromes often present with many different types of seizures, and identifying the types of seizures a patient suffers from is important since many of the standard AEDs are directed at treating, or are only effective against, a given type / subtype of seizure.

[18] One such childhood epilepsy is Dravet syndrome. The onset of Dravet syndrome almost always occurs during the first year of life with clonic and tonic-clonic seizures in otherwise healthy, developmentally normal newborns (Dravet, 2011). Symptoms peak at approximately five months of age. Other seizures develop between one and four years of age, such as prolonged focal disconcerting seizures and brief absence seizures.

[19] When diagnosing Dravet syndrome, both focal and generalized seizures are considered obligatory, Dravet patients may also experience atypical absence seizures, myoclonic absence seizures, atonic seizures and non-convulsive status epilepticus.

[20] The seizures progress to become frequent and resistant to treatment, meaning they do not respond well to treatment. They also tend to be prolonged, lasting more than 5 minutes. Prolonged seizures can lead to status epilepticus, which is a seizure lasting more than 30 minutes or seizures that occur in clusters, one after the other.

[21] The prognosis is poor, and approximately 14% of children die during a seizure, due to infection, or suddenly from uncertain causes, often due to relentless neurological decline. Patients develop intellectual disability and permanent seizures for life. Intellectual impairment ranges from severe intellectual disability in 50% of patients to moderate and mild intellectual disability in 25% of cases.

[22] Currently, there are no EDA-approved treatments specifically indicated for Dravet syndrome. The standard of care generally involves a combination of the following anticonvulsants: clobazam, clonazepam, levetiracetam, topiramate, and valproic acid.

[23] Stiripentol is approved in Europe for the treatment of Dravet syndrome in combination with clobazam and valproic acid. In the United States, stiripentol received orphan drug designation for the treatment of Dravet syndrome in 2008; however, the drug is not approved by the FDA.

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

[25] Treatment may also include a ketogenic diet and physical and vagus nerve stimulation. In addition to anticonvulsant drugs, many patients with Dravet syndrome are treated with antipsychotic medications, stimulants, and medications to treat insomnia.

[26] The first-line treatment for focal seizures is AEDs such as carbamazepine or lamotrigine. Levetiracetam, oxcarbamezapine, or sodium valproate are also considered useful. A combination of these medications may be required to treat focal seizures.

[27] Common AEDs defined by their mechanisms of action are described in the following tables: iviA / a / zuzz / ui ouz;

[28] Table 1. Examples of narrow spectrum AEDs Narrow-Spectrum AEDs Mechanism Indication Phenytoin Sodium channel Complex partial seizures Tonic-clonic Phenobarbital GABA / Calcium channel Partial seizures Tonic-clonic Carbamazepine Sodium channel Partial seizures Tonic-clonic Mixed seizures Oxcarbazepine Sodium channel Partial seizures Tonic-clonic Mixed seizures Gabapentin Calcium channel Partial seizures Mixed seizures Pregabalin Calcium channel Adjunctive therapy for partial seizures with or without secondary generalization Lacosamide Sodium channel Adjunctive therapy for partial seizures Vigabatrin GABA Secondarily generalized tonic-clonic seizures Partial seizures Infantile spasms due to West syndrome

[29] Table 2. Examples of broad spectrum AEDs Broad-spectrum AEDs Mechanism Indication Valproic acid GABA / Sodium channel First-line treatment for tonic-clonic seizures, absence seizures, and myoclonic seizures Second-line treatment for partial seizures and infantile spasms. Intravenous use in status epilepticus Lamotrigine Sodium channel Partial seizures Tonic-clonic Seizures associated with Lennox-Gastaut syndrome Ethosuximide Calcium channel Absence seizures Topiramate GABA / Sodium channel Seizures associated with Lennox-Gastaut syndrome Zonisamide GABA / Calcium / Sodium channel Adjunctive therapy in adults with partial-onset seizures Infantile spasm Mixed seizures Lennox-Gastaut syndrome Myoclonic seizures Generalized tonic-clonic seizures Levetiracetam Calcium channel Partial seizures Adjunctive therapy for partial, myoclonic, and tonic-clonic seizures Clonazepam GABA Typical and atypical absence seizures Infantile myoclonic seizures Akinetic seizures Rufinamide Sodium channel Adjunctive treatment of partial seizures associated with Lennox-Gastaut syndrome

[30] Table 3. Examples of AEDs used specifically in childhood epilepsy AED Mechanism Indication Clobazam GABA Adjunctive therapy in complex partial seizures Status epilepticus Myoclonic Myoclonic-absence Simple partial Complex partial Absence seizures Lennox-Gastaut syndrome Stiripentol GABA Severe myoclonic epilepsy in childhood (Dravet syndrome)

[31] From these tables, it can be seen that there are many AEDs approved for use in focal (partial) seizures that work through different mechanisms. In fact, the only AED approved for use in the treatment of complex partial seizures (focal seizures with deterioration) is phenytoin.

[32] Over the past forty years, several animal studies have been conducted on the use of the non-psychoactive cannabinoid cannabidiol (CBD) to treat seizures. For example, Consroe et al. (1982) determined that CBD was able to prevent seizures in mice after the administration of pro-convulsant drugs or an electric current.

[33] Studies in epileptic adults have also been conducted in the last forty years with CBD. Cunha et al. reported that administration of CBD to eight adult patients with generalized epilepsy produced a marked reduction in seizures in 4 of the patients (Cunha et al., 1980).

[34] A study in 1978 provided 200 mg / day of pure CBD to four adult patients; two of the four patients became seizure-free, while in the rest the seizure frequency did not change (Mechoulam and Carlini, 1978).

[35] Unlike the studies described above, an open-label study reported that 200 mg / day of pure CBD was not effective in controlling seizures in twelve institutionalized adult patients (Ames and Cridland, 1986).

[36] Based on the fact that chronologically the last study to observe the effectiveness of CBD in patients with epilepsy proved that CBD could not control seizures, there would be no expectation that CBD could be useful as an anticonvulsant agent.

[37] In the last forty years of research, more than thirty drugs have been approved for the treatment of epilepsy, none of which are cannabinoids. In fact, there seems to be a bias against cannabinoids, possibly due to the programmed nature of these compounds and / or the fact that THC, which is a known psychoactive substance, has been labeled as pro-convulsant (Consroe et al., 1977).

[38] A recently published paper suggested that cannabidiol-enriched cannabis may be effective in treating epilepsy. Porter and Jacobson (2013) reported on a survey of parents conducted through a Facebook group, which explored the use of CBD-enriched cannabis in children with treatment-resistant epilepsy. Sixteen of the 19 parents surveyed reported an improvement in their child's epilepsy. The children surveyed for this paper were taking cannabis that purportedly contained CBD in a high concentration, although the amount of CBD present and the other constituents, including THC, were unknown in many cases. In fact, while CBD levels ranged from 0.5 to 28.6 mg / kg / day (in the extracts tested), THC levels as high as 0.8 mg / kg / day were reported.

[39] Providing children with TRE with a cannabis extract comprising THC, which has been described as a pro-convulsant (Consroe et al., 1977), at a potentially psychoactive dose of 0.8 mg / kg / day, is a concern and as such, there is a need to determine whether CBD is in fact effective.

[40] In November 2013, GW Pharmaceuticals issued a press release stating their intention to treat Dravet syndrome with CBD, which had received orphan drug designation. A further press release in June 2014 reported promising signs of efficacy in children with treatment-resistant epilepsy, including patients with Dravet syndrome.

[41] International patent application WO 2015 / 193667 describes the use of CBD in treatment-resistant epilepsy. The patients included nine with Dravet syndrome out of 27 others.

[42] International patent application WO 2015 / 193668 describes the use of CBD in the treatment of absence seizures. The patients included those with Dravet syndrome as well as ten other syndromes.

[43] Maa and Figi (2014) discuss the case of medical marijuana in epilepsy and describe the positive treatment of a girl named Charlotte with Dravet syndrome who experienced frequent episodes of febrile and afebrile status epilepticus, as well as tonic, tonic-clonic, and myoclonic seizures (generalized seizures). She was given an extract from a cannabis plant called Charlotte's Web, which, according to the suppliers, CW Botanicals, is described as containing terpenes 10 to 200 times the amount found in other patented plants. In other words, the suggestion is that its efficacy is based on a combination of CBD and the terpenes present in its extracts.

[44] Press et al. (April 3, 2015) provide an in-depth review of reports from parents of pediatric patients with refractory epilepsy who were given oral cannabis extracts (OCE). Despite its thorough nature, it concludes that no study demonstrates clear efficacy.

[45] Significantly, the document acknowledges that the effectiveness of an anticonvulsant drug may depend on: the drug itself, including CBD (see Table 3); the type of epilepsy syndrome (Table 2); and the type of seizure (Table 2).

[46] Significantly, the discussion paper acknowledges that caution should be exercised when reviewing data, particularly from open-label studies, as placebo rates can be high. In fact, it specifically notes that four anticonvulsant drugs recently approved by the EDA had placebo rates of 31.6%, 26.4%, 20%, and 21%, respectively (page 51, left column).

[47] In addition, the analysis observed a surprising finding, namely, that new residents of Colorado (those who moved to receive treatment) were more than three times as likely to report a seizure reduction of more than 50% than families with established care in Colorado, suggesting that studies such as the one published in Porter and Jacobson (2013) may be very flawed.

[48] ​​The expert would therefore deduce from Press et al. that the type of drug CBD plus the presence of other OCEs (such as other cannabinoids, most likely THC and non-cannabinoids such as, for example, terpenes) appears to be a more interesting combination than CBD alone; the responder rate was 63% versus 35%.

[49] Lennox-Gastaut epilepsy syndrome appears to be the most promising target with a response rate of 89% compared to Dravet (response rate of 23%) or Doose (response rate of 0%).

[50] The types of seizures studied ranged from a 44% response rate for atonic seizures to a 17% response rate for tonic seizures, among the seven types of seizures reviewed.

[51] The assessment examined three distinct groups, namely: the type of OCE, Table 3 (four types of OCE); the epilepsy syndrome, see, for example, page 50 right column, line 3 (three types of syndrome); and the type of seizure, see page 51, Table 2 (seven types of seizures).

[52] In all this, the reader is provided with information on 84 different alternative combinations.

[53] The problem faced by the medical expert seeking cannabis medicines in the field of epilepsy, where many patients are refractory to existing medicines, is selecting the appropriate cannabinoid and its form targeted to a given seizure type in a given group of patients.

[54] It is therefore perhaps not surprising that the Cochrane report (Gloss and Vickrey) published in March 2014 carried out a comprehensive review of the effectiveness of cannabinoids in the treatment of epilepsy, concluding that at present no reliable conclusions can be drawn about the effectiveness of cannabinoids as a treatment for epilepsy.

[55] Surprisingly, the applicant has shown that CBD is particularly effective in treating focal seizures in patients with Dravet syndrome, particularly children and more particularly those who are resistant to existing treatments. Brief summary of the description

[56] In accordance with a first aspect of the present invention, Cannabidiol (CBD) is provided for use in the treatment of focal seizures in Dravet syndrome.

[57] In one modality, focal seizures are focal seizures with impairment.

[58] Preferably, Dravet syndrome is resistant to treatment.

[59] In an additional modality, CBD is to be used in combination with one or more concomitant antiepileptic drugs (AEDs).

[60] In an additional embodiment, CBD is present as a highly purified cannabis extract comprising at least 98% (w / w) CBD. Preferably, the extract comprises less than 0.15% THC. Very preferably, the extract further comprises up to 1% CBDV.

[61] In an alternative form, CBD is present as a synthetic compound.

[62] In a further embodiment of the invention, the one or more AEDs are selected from the group consisting of: carbamazepine, clobazam, clonazepam, clonidine, clorazepate, desmethylclobazam, diazepam, ethosuximide, felbamate, ketogenic diet, lacosamide, lamotrigine, levetiracetam, lorazepam, midazolam, N-desmethylclobazam, nordiazepam, oxicarbamezapine, perampanel, phenobarbital, phenytoin, pregabalin, rufinamide, stiripentol, topiramate, trazodone, vagus nerve stimulation, valproic acid, vigabatrin, and zonisamide.

[63] Preferably, the number of different antiepileptic drugs used in combination with CBD is reduced. Alternatively, the dosage of antiepileptic drugs used in combination with CBD is reduced.

[64] There are many side effects associated with commonly used AEDs, including dizziness, blurred vision, nausea, respiratory depression, fatigue, headaches, and other central nervous system motor side effects. These side effects are particularly common with higher doses or combinations of numerous AEDs. Therefore, there is a need for an alternative medication that can reduce the number of seizures while also exhibiting a safe side-effect profile.

[65] Preferably, the CBD dose is greater than 5 mg / kg / day. Therefore, a 15 kg patient would be given a dose of more than 75 mg of CBD per day. Doses greater than 5 mg / kg / day, such as greater than 10 mg / kg / day, greater than 15 mg / kg / day, greater than 20 mg / kg / day, and greater than 25 mg / kg / day, are also considered effective.

[66] In accordance with a second aspect of the present invention, a method is provided for treating focal seizures in Dravet Syndrome comprising administering cannabidiol (CBD) to a subject.

[67] Preferably, the subject is a human being.

[68] Pursuant to a third aspect of the present invention, a composition is provided for use in the treatment of epilepsy characterized by focal seizures in Dravet syndrome, comprising cannabidiol (CBD), a solvent, a co-solvent, a sweetener, and a flavoring.

[69] Preferably, the solvent is sesame oil, the co-solvent is ethanol, the sweetener is sucralose, the flavoring is strawberry flavor, and CBD is present at a concentration of between 25 mg / ml and 100 mg / ml, specifically 50 mg / ml and 75 mg / ml.

[70] Preferably, the composition comprises cannabidiol (CBD) at a concentration of between 25 and 100 mg / ml, ethanol at a concentration of 79 mg / ml, sucralose at a concentration of 0.5 mg / ml, strawberry flavoring at a concentration of 0.2 mg / ml and sesame oil q.s. 1.0 ml.

[71] The composition is intended to be administered as an oral liquid solution. Other routes of administration, including solids, semisolids, gels, aerosols, inhalers, vaporizers, enemas, and suppositories, are alternative forms of administration. Such medications could be administered orally, buccally, sublingually, via the respiratory tract, nasally, and distally. Definitions

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

[73] The cannabinoids described in this application are listed below along with their 10 standard abbreviations. Table 4. Cannabinoids and their abbreviations CBD Cannabidiol (\ OH ftí........... H CEDA Cannabidiolic acid / V) OH O hM / h i. 1 / 'jt -·γ OH CBDV Cannabidiarin A o» H CBDVA Cannabidivarinic acid / v> OH 0 1 H / OH 0ΛΛ^ H THC Tetrahydrocannabinol OH l 1 jT

[74] The table above is not exhaustive and merely details the cannabinoids identified in this application for reference. To date, more than 60 different cannabinoids have been identified, 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).

[75] Phytocannabinoids are cannabinoids that originate from nature and can be found in the cannabis plant. Phytocannabinoids can be isolated from plants to produce a highly purified extract or they can be reproduced synthetically.

[76] Highly purified cannabinoid extracts are defined as cannabinoids that have been extracted from the cannabis plant and purified to the extent that substantially other cannabinoids and non-cannabinoid components co-extracted with the cannabinoids have been removed, such that the highly purified cannabinoid is greater than or equal to 98% (w / w) pure.

[77] Synthetic cannabinoids are compounds that have a cannabinoid or cannabinoid-type structure and are produced using chemical means and not by the plant.

[78] Phytocannabinoids can be obtained either as a neutral (decarboxylated) form or as a carboxylic acid, depending on the method used to extract the cannabinoids. For example, heating the carboxylic acid form is known to cause most of the carboxylic acid form to be decarboxylated into the neutral form.

[79] Treatment-resistant epilepsy (TRE) or intractable epilepsy is defined according to the 2009 ILAE guidelines as epilepsy that is not adequately controlled by trials of one or more AEDs.

[80] Childhood epilepsy refers to the many different syndromes and genetic mutations that can occur to cause epilepsy in childhood. Some examples of these are: Dravet syndrome; myoclonic absence epilepsy; Lennox-Gastaut syndrome; generalized epilepsy of unknown origin; CDKL5 mutation; Aicardi syndrome; bilateral polymicrogyria; Dupl5q; SNAP25; and febrile infection-related epilepsy (FIRES) syndrome; benign rolandic epilepsy; juvenile myoclonic epilepsy; infantile spasm (West syndrome); and Landau-Kleffner syndrome. The above list is not exhaustive since there are many childhood epilepsies; different.

[81] Focal seizures are defined as seizures that originate within networks limited to only one hemisphere. What happens during the seizure depends on which part of the brain the seizure occurs in and which part of that brain normally does.

[82] The term focal seizure with altered consciousness / consciousness has replaced the term complex partial seizure. These seizures usually begin in a small area of ​​the temporal or frontal lobe of the brain and involve other brain areas within the same hemisphere, affecting alertness and consciousness. Most subjects experience automatisms during a focal seizure with altered consciousness.

[83] Mixed seizures are defined as the existence of generalized and focal seizures in the same patient.

[84] The terms 50% responded and 50% seizure reduction are both terms used in clinical studies. In this application, the terms define the percentage of subjects who experienced a reduction of 50% or more in the number of seizures during CBD treatment compared to the number experienced during the baseline period before CBD administration. Detailed description of the invention Preparation of highly purified CBD extract

[85] The following describes the production of the highly purified (>98% w / w) cannabidiol extract having a known and constant composition that was used for the expanded access trials described in the Examples below.

[86] In summary, the drug substance used in the trials is a liquid carbon dioxide extract with a high CBD content containing Cannabis sativa L. chemotypes, which have been further purified by a solvent crystallization method to produce CBD. The crystallization process specifically removes other cannabinoids and plant components to produce more than 98% CBD.

[87] Cannabis sativa L. plants are grown, harvested and processed to produce a botanical extract (intermediate) and then purified by crystallization to produce CBD (drug substance).

[88] The plant starting material is called botanical raw material (BRM); the botanical extract is the intermediate; and the active pharmaceutical ingredient (API) is CBD, the drug substance.

[89] Both the botanical starting material and the botanical extract are controlled by specifications. The specification of the drug substance is described in the Table 5 below. Table 5. CBD Specification Test Method of Test Limits Visual Appearance Whitish / pale yellow crystals Identification A HPLC-UV The highest peak retention time corresponds to certified CBD reference standard Identification B GC-FID / MS The highest peak retention time and mass spectrum corresponds to certified CBD reference standard Identification C FT-IR Conforms to the reference spectrum for certified CBD reference standard Identification D Melting point 65-67°C Identification E Specific optical rotation Conforms to certified CBD reference standard; -110°C to -140°C (in 95% ethanol) Total purity Calculation >98.0% Chromatographic purity 1 HPLC-UV >98.0% Chromatographic purity 2 GC-FID / MS >98.0% Other cannabinoids: - CBDA - CBDV - Δ9 THC - CBD-C4 HPLC-UV NMT 0.15% w / w NMT 1.0% w / w NMT 0.15% w / w NMT 0.5% w / w Residual solvents: - Alkane - Ethanol GC NMT 0.5% w / w NMT 0.5% w / w Karl Fischer residual water NMT 1.0% w / w NMT - No more than

[90] The purity of the pharmacological substance of CBD achieved is greater than 98%. Other cannabinoids that may appear in the extract are: CBDA, CBDV, CBD-C4 and THC.

[91] Different chemotypes of the Cannabis sativa L. plant have been produced to maximize the production of specific chemical constituents, the cannabinoids. One type of plant predominantly produces CBD. Only the (-)-trans isomer occurs naturally. Furthermore, during purification, the stereochemistry of CBD is unaffected. Intermediary production

[92] An overview of the steps for producing a botanical extract, the intermediate, is as follows: 1. Growth 2. Decarboxylation 3. Extraction No. 1 - using liquid CO2 4. Extraction No. 2 - 'winterization' using ethanol 5. Filtration 6. Evaporation

[93] High-CBD chemovars were grown, harvested, dried, and stored in a dry room until required. The botanical raw material (BRM) was finely ground using an Apex mill equipped with a 1 mm sieve. The ground BRM was stored in a freezer for up to 3 months prior to extraction.

[94] The decarboxylation of CBDA to CBD was carried out using a large Heraeus tray oven. The batch size for decarboxylation in the Heraeus was approximately 15 kg. The trays were placed in the oven and heated to 105°C; the BRM took 96.25 minutes to reach 105°C. It was held at 105°C for 15 minutes. The oven was then set to 150°C; the BRM took 75.7 minutes to reach 150°C; the BRM was held at 150°C for 130 minutes. The total time in the oven was 380 minutes, including 45 minutes of cooling and 15 minutes of venting.

[95] Extraction No. 1 was performed using liquid CO2 at 60 bar / 10°C to produce botanical drug substance (BDS).

[96] The crude CBD BDS was winterized in extraction No. 2 under standard conditions (2 volumes of ethanol at -20°C for approximately 50 hours). The precipitated waxes were removed by filtration and the solvent was evaporated using the rotary evaporator (water bath up to 60°C) to produce the BDS, which was then used for crystallization to produce the test material. Production of the drug substance

[97] The manufacturing steps for producing the drug substance from the intermediate botanical extract are as follows: 1. Crystallization using linear or branched chain alkanes of C5-C12 2. Filtration 3. Optional recrystallization of linear or branched chain alkanes from C5-C12 4. Vacuum drying

[98] The intermediate botanical extract (12 kg) produced using the above methodology was dispersed in C5-C12 linear or branched chain alkane (9000 ml, 0.75 volumes) in a 30 litre stainless steel container.

[99] The mixture was manually stirred to break up any lumps and the sealed container was then placed in a freezer for approximately 48 hours.

[100] The crystals were isolated by vacuum filtration, washed with cold C5-C12 linear or branched chain alkane aliquots (total 12000 ml) and dried under a vacuum of <10 mb at a temperature of 60 °C until dry before submitting the drug substance for analysis.

[101] The dried product was stored in a freezer at minus 20°C in a pharmaceutical-grade stainless steel container, with an approved food-grade silicone seal and clamps. Drug Product Production

[102] 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 flavoring. Two product strengths are available to allow dose titration across a wide dosage range.

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

[104] The formulation of the drug product is as described in Table 6 below: Table 6: Drug Product Specifications Component Qualitative Composition Function Reference to quality standard Cannabidiol (CBD) 25 mg / ml or 100 mg / ml Active Ingredient Proprietary Anhydrous Ethanol 79.0 mg / ml Excipient Ph.Eur. Sucralose 0.5 mg / ml Sweetener Proprietary Strawberry Flavor 0.2 mg / ml Flavoring Proprietary Sesame Oil q.s. 1.0 ml Excipient Ph. Eur.

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

[106] A sweetener and fruit flavoring are required to improve the palatability of the garlic oil solution.

[107] Ethanol was required to solubilize the sweetener and flavoring.

[108] The composition may be substantially equivalent, meaning that the functional ingredients may vary from the specified qualitative composition in Table 6 by up to 10%.

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

[110] Example 1 describes the data produced in an expanded access treatment program in children with TRE. Example 1: Efficacy of reducing focal seizures in children and young adults with intractable epilepsy, using cannabidiol Materials and methods

[111] Of 137 children and young adults with severe, childhood-onset treatment-resistant epilepsy (TRE), 51 suffered from epilepsy characterized by focal seizures. These subjects were tested with a highly purified cannabidiol (CBD) extract obtained from a cannabis plant. All subjects presented with focal seizures, often in addition to generalized seizures. The study participants were part of an expanded-access compassionate use program for CBD.

[112] The epileptic syndromes that these patients suffered from were the following: Lennox-Gastaut syndrome; tuberous sclerosis complex; Dravet syndrome; CDKL5; neuronal ceroid lipofuscinosis (NCL); febrile infection-related epilepsy syndrome (FIRES); Aicardi syndrome and brain abnormalities.

[113] Other types of seizures experienced by these patients include: tonic, clonic, tonic-clonic, myoclonic, atonic, absence, myoclonic-absence, focal seizures without deterioration, focal seizures with deterioration, and focal seizures that evolve into bilateral seizures.

[114] All patients entered a 4-week reference period when parents / caregivers kept diaries of possible seizures, taking into account all countable seizure types.

[115] Patients then received 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.

[116] The daily dose was gradually increased in increments of 2 to 5 mg / kg until intolerance occurred or a maximum dose of 25 mg / kg / day was achieved.

[117] Patients were observed at regular intervals of 2 to 4 weeks. Laboratory tests for hematologic, liver function, renal function and concomitant AED levels were performed at baseline, and after each week of CBD therapy.

[118] All patients in the study were taking at least one concomitant AED. These included: carbamazepine, clobazam, clonazepam, clonidine, clorazepate, desmethylclobazam, diazepam, ethosuximide, felbamate, ketogenic diet, lacosamide, lamotrigine, levetiracetam, lorazepam, midazolam, N-desmethylclobazam, nordiazepam, oxicarbamezapine, perampanel, phenobarbital, phenytoin, pregabalin, rufinamide, stiripentol, topiramate, trazodone, vagus nerve stimulation, valproic acid, vigabatrin, and zonisamide. Results

[119] The 51 child and young adult patients, all of whom suffered from focal seizures, were treated with CBD for at least 12 weeks.

[120] A summary of 50% responders, based on 12 weeks of treatment, is given in Table 7 below. Table 7. Summary of 50% responders after 12 weeks of treatment for focal seizures Focal seizures (n=51) Total seizures (n=137) > 50% reduction in seizures 63% (n=32) 46% (n=63) < 50% reduction in seizures 37% (n=19) 54% (n=74)

[121] Table 7 shows that after 3 months of therapy, a remarkable 63% of patients had equal to or greater than > 50%, these data suggest that CBD is very effective in reducing this type of seizure. Conclusions

[122] These data indicate that CBD significantly reduces the number of focal seizures in a high proportion of patients who do not respond well to existing AEDs.

[123] It was surprising that such a high number of patients in this group, who were resistant to treatment, were able to achieve an effect. The fact that almost two-thirds of the patients (63%) benefited from at least a fifty percent reduction in the number of focal seizures they experienced was remarkable. Example 2: Efficacy of reducing focal seizures with deterioration in children and young adults with intractable epilepsy, using cannabidiol Materials and methods

[124] Of 137 children and young adults with severe childhood-onset treatment-resistant epilepsy (TRE), 37 suffered from epilepsy characterized by focal seizures with deterioration. These subjects were tested with a highly purified cannabidiol (CBD) extract obtained from a cannabis plant. All subjects experienced focal seizures with deterioration, often in addition to other generalized and / or focal seizures. The study participants were part of an expanded access compassionate use program for CBD.

[125] The epileptic syndromes that these patients suffered from were the following: Lennox-Gastaut syndrome; tuberous sclerosis complex; Dravet syndrome; CDKL5; febrile infection-related epilepsy (FIRES) syndrome; Aicardi syndrome and brain abnormalities.

[126] All patients entered a 4-week reference period when parents / caregivers kept diaries of possible seizures, taking into account all countable seizure types.

[127] Patients then received 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.

[128] The daily dose was gradually increased in increments of 2 to 5 mg / kg until intolerance occurred or a maximum dose of 25 mg / kg / day was achieved.

[129] Patients were observed at regular intervals of 2 to 4 weeks. Laboratory tests for hematologic, liver function, renal function and concomitant AED levels were performed at baseline, and after every 4 weeks of CBD therapy.

[130] All patients in the study were taking at least one concomitant AED. These included: carbamazepine, clobazam, clonazepam, clorazepate, desmethylclobazam, diazepam, ethosuximide, felbamate, ketogenic diet, lacosamide, lamotrigine, levetiracetam, lorazepam, midazolam, N-desmethylclobazam, nordiazepam, oxicarbamezapine, perampanel, phenobarbital, phenytoin, pregabalin, rufinamide, topiramate, vagus nerve stimulation, valproic acid, vigabatrin, and zonisamide. Results

[131] The 37 child and young adult patients, all of whom suffered from focal seizures with deterioration, were treated with CBD for at least 12 weeks.

[132] A summary of the 50% responders, based on 12 weeks of treatment, is given in Table 8 below. Table 8. Summary of 50% responders, after weeks of treatment for focal seizures with deterioration Focal seizures with deterioration (n=37) Total seizures (n=137) > 50% reduction in seizures 63% (n=24) 46% (n=63) < 50% reduction in seizures 35% (n=13) 54% (n=74)

[133] Table 8 shows that after 3 months of therapy, a remarkable 65% of patients had a reduction in focal seizures with impairment equal to or greater than > 50%, these data suggest that CBD is very effective in reducing this type of seizure.

[134] Furthermore, when these data are compared with the other subtypes of focal seizures, namely focal seizures without impairment and focal seizures leading to secondary generalization, it becomes clear that CBD was able to selectively reduce the occurrence of focal seizures with impairment. Table 9 shows detailed information on these findings. Table 9. Summary of 50% responders after 12 weeks of treatment for all types of focal seizures Focal seizures with deterioration (n=37) Focal seizures without deterioration (n=6) Focal seizures leading to secondary generalization (n=15) Total focal seizures (n=51) > 50% reduction in seizures 65% (n=24) 50% (n=3) 47% (n=7) 63% (n=32) < 50% reduction in seizures 35% (n=13) 50% (n=3) 53% (n=8) 37% (n=19) Conclusions

[135] These data indicate that CBD significantly reduces the number of focal seizures with impairment in a selective manner.

[136] It was surprising that in this group of patients, 10 of whom were resistant to treatment, such a high number were able to achieve an effect. The fact that more than two-thirds of the patients (65%) benefited from at least a fifty percent reduction in the number of focal seizures with deterioration they experienced was remarkable. References Ames FR and Cridland S (198 6) . Anticonvulsant effects of cannabidiol. S Afr Med J 69:14. Consroe P, Martin P, Eisenstein D. (1977). Anticonvulsant drug antagonism of delta-9tetrahydrocannabinol induced seizures in rabbits. Res Commun Chem Pathol Pharmacol. 16:1-13. Consroe P, Benedicto MA, Leite JR, Carlini EA, Mechoulam R. (1982). Effects of cannabidiol on behavioural seizures caused by convulsant drugs or current in mice. Eur J Pharmaco. 83:293-8. Cunha JM, Carlini EA, Pereira AE, Ramos OL, Pimental C, Gagliardi R et al. (1980). Chronic administration of cannabidiol to healthy volunteers and epileptic patient. Pharmacology. 21:175-85. Dravet C. The core Dravet syndrome phenotype. Epilepsia. 2011 Apr; 52 Suppl 2:3-9. Eadie, MJ (Diciembre de 2012). Shortcomings in the current treatment of epilepsy. Expert Review of Neurotherapeutics 12 (12):1419-27. Kwan P, Arzimanoglou A, Berg AT, Brodie MJ, Hauser WA, Mathern G, Moshé SL, Perucca E, Wiebe S, French J. (2009) Definition of drug resistant epilepsy: Consensus proposal by the ad hoc Task Forcé of the ILAE Commission on Therapeutic Strategies. Epilepsia. Mechoulam R y Carlini EA (1978) . Toward drugs derived from cannabis. Die naturwissenschaften 65:174-9. Porter BE, Jacobson C (Diciembre de 2013). Report of a parent survey of cannabidiol-enriched cannabis use in paediatric treatment resistant epilepsy Epilepsy Behaviour. 29(3) 574-7. Thurman, DJ; Beghi, E; Begley, CE; Berg, AT; Buchhalter, JR; Ding, D; Hesdorffer, DC; Hauser, WA; Kazis, L; Kobau, R; Kroner, B; Labiner, D; Liow, K; Logroscino, G; Medina, MT; Newton, CR; Parko, K; Paschal, A; Preux, PM; Sander, JW; Selassie, A; Theodore, W; Tomson, T; Wiebe, S; ILAE Commission on, Epidemiology (Septiembre de 2011) . Standards for epidemiologic studies and surveillance of epilepsy. Epilepsia. 52 Supl 7:2-26.

Claims

1. Cannabidiol (CBD) for use in the treatment of focal seizures in Dravet syndrome, wherein the CBD is in the form of a highly purified cannabis extract comprising at least 98% (w / w) CBD or is present as a synthetic compound.

2. CBD for use in accordance with claim 1, wherein focal seizures are focal seizures with impairment.

3. Cannabidiol (CBD) for use in accordance with claim 1 or claim 2, wherein Dravet syndrome is resistant to treatment.

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

5. CBD for use in accordance with any of the preceding claims, wherein the extract comprises less than 0.15% THC.

6. The CBD for use in accordance with any of the preceding claims, wherein the extract further comprises up to 1% CBDV.

7. CBD for use according to claim 4, wherein the one or more AEDs are selected from the group consisting of: carbamazepine, clobazam, clonazepam, clonidine, clorazepate, desmethylclobazam, diazepam, ethosuximide, felbamate, ketogenic diet, lacosamide, lamotrigine, levetiracetam, lorazepam, midazolam, N-desmethylclobazam, nordiazepam, oxicarbamezapine, perampanel, phenobarbital, phenytoin, pregabalin, rufinamide, stiripentol, topiramate, trazodone, vagus nerve stimulation, valproic acid, vigabatrin, and zonisamide.

8. CBD for use in accordance with any of the preceding claims, wherein the number of different anti-epileptic drugs used in combination with CBD is reduced relative to the number of AEDs prior to CBD treatment.

9. CBD for use in accordance with any of the preceding claims, wherein the dose of the anti-epileptic drugs used in combination with CBD is reduced relative to the dose of AED prior to treatment with CBD.

10. CBD for use in accordance with any of the preceding claims, wherein the CBD dose is greater than 5 mg / kg / day.

11. CBD for use in accordance with any of the preceding claims, wherein the CBD is provided in a composition comprising a solvent, a co-solvent, a sweetener, and a flavoring.

12. The composition according to claim 11, wherein the solvent is garlic oil.

13. The composition according to claim 11, wherein the co-solvent is ethanol.

14. The composition according to claim 11, wherein the sweetener is sucralose.

15. The composition according to claim 11, wherein the flavoring is strawberry flavor.

16. The composition according to claim 11, wherein CBD is present at a concentration of between 25 mg / ml and 100 mg / ml.

17. A composition according to any of claims 11 to 16, comprising cannabidiol (CBD) at a concentration of 25 to 100 mg / ml, ethanol at a concentration of 79 mg / ml, sucralose at a concentration of 0.5 mg / ml, strawberry flavor at a concentration of 0.2 mg / ml and sesame q.s. 1.0 ml.