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  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/658—Medicinal preparations containing organic active ingredients o-phenolic cannabinoids, e.g. cannabidiol, cannabigerolic acid, cannabichromene or tetrahydrocannabinol
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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• • A—HUMAN NECESSITIES
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• • A—HUMAN NECESSITIES
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• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P25/00—Drugs for disorders of the nervous system
  • A61P25/08—Antiepileptics; Anticonvulsants
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K2300/00—Mixtures or combinations of active ingredients, wherein at least one active ingredient is fully defined in groups A61K31/00 - A61K41/00

Definitions

• the present invention relates to the use of cannabidiol (CBD) in the treatment of patients with Lennox-Gastaut syndrome (LGS) who are deemed to be treatment failures on their existing medication.
• CBD cannabidiol
• LGS Lennox-Gastaut syndrome
• CBD was found to provide a statistically significant reduction in both drop seizures and total seizure frequency in patients who have tried and failed anti-epileptic drugs (AEDs) or those who were currently taking AEDs but have uncontrolled seizures.
• the AEDs which have been shown to be treatment failures are one or more of rufinamide, lamotrigine, topiramate and / or felbamate.
• the CBD used is in the form of a highly purified extract of cannabis such that the CBD is present at greater than 98% of the total extract (w/w) and the other components of the extract are characterised.
• the cannabinoid tetrahydrocannabinol (THC) has been substantially removed, to a level of not more than 0.15% (w/w) and the propyl analogue of CBD, cannabidivarin, (CBDV) is present in amounts of up to 1 %.
• the CBD may be a synthetically produced CBD.
• Epilepsy occurs in approximately 1% of the population worldwide, (Thurman et al., 2011) of which 70% are able to adequately control their symptoms with the available existing anti-epileptic drugs (AEDs). However, 30% of this patient group, (Eadie et ai, 2012), are unable to obtain seizure freedom from the AED that are available and as such are termed as suffering from intractable or“treatment-resistant epilepsy” (TRE).
• TRE treatment-resistant epilepsy
• Intractable or treatment-resistant epilepsy was defined in 2009 by the International League against Epilepsy (I LAE) as“failure of adequate trials of two tolerated and appropriately chosen and used AED schedules (whether as monotherapies or in combination) to achieve sustained seizure freedom” (Kwan et al., 2009).
• I LAE International League against Epilepsy
• 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. [0008] When a child or young adult presents with a seizure, investigations are normally undertaken in order to investigate the cause. Childhood epilepsy can be caused by many different syndromes and genetic mutations and as such diagnosis for these children may take some time.
• the main symptom of epilepsy is repeated seizures.
• an investigation into the type of seizures that the patient is experiencing is undertaken.
• Clinical observations and electroencephalography (EEG) tests are conducted and the type(s) of seizures are classified according to the I LAE classification described below.
• the International classification of seizure types proposed by the I LAE was adopted in 1981 and a revised proposal was published by the I LAE in 2010 and has not yet superseded the 1981 classification.
• the 2010 proposal for revised terminology includes the proposed changes to replace the terminology of partial with focal.
• the term“simple partial seizure” has been replaced by the term“focal seizure where awareness / responsiveness is not impaired”
• the term“complex partial seizure” has been replaced by the term“focal seizure where awareness / consciousness is impaired”.
• Generalised seizures where the seizure arises within and rapidly engages bilaterally distributed networks, can be split into six subtypes: Tonic-Clonic (grand mal) seizures; Absence (petit mal) Seizures; Clonic Seizures; Tonic Seizures; Atonic Seizures and Myoclonic Seizures.
• Focal (partial) seizures where the seizure originates within networks limited to only one hemisphere, are also split into sub-categories.
• the seizure is characterized according to one or more features of the seizure, including aura, motor, autonomic and awareness / responsiveness.
• a seizure begins as a localized seizure and rapidly evolves to be distributed within bilateral networks this seizure is known as a Bilateral convulsive seizure, which is the proposed terminology to replace Secondary Generalised Seizures (generalized seizures that have evolved from focal seizures and are no longer remain localized).
• Epileptic syndromes often present with many different types of seizure and identifying the types of seizure that a patient is suffering from is important as many of the standard AEDs are targeted to treat or are only effective against a given seizure type / sub- type.
• LGS Lennox-Gastaut syndrome
• seizures usually begin before the age of 4.
• Seizure types which vary among patients, include tonic (stiffening of the body, upward deviation of the eyes, dilation of the pupils, and altered respiratory patterns), atonic (brief loss of muscle tone and consciousness, causing abrupt falls), atypical absence (staring spells), and myoclonic (sudden muscle jerks).
• tonic tonic
• atonic brief loss of muscle tone and consciousness, causing abrupt falls
• atypical absence staring spells
• myoclonic sinden muscle jerks
• Drop seizures are defined as an attack or spell (atonic, tonic or tonic-clonic) involving the entire body, trunk or head that led or could have led to a fall, injury, slumping in a chair or hitting the patient’s head on a surface.
• LGS can be caused by brain malformations, perinatal asphyxia, severe head injury, central nervous system infection and inherited degenerative or metabolic conditions. In 30-35% of cases, no cause can be found.
• the first line treatment for drop seizures usually comprises a broad-spectrum AED, such as sodium valproate often in combination with rufinamide or lamotrigine.
• AEDs that may be considered include felbamate, clobazam and topiramate.
• AEDs such as carbamezapine, gabapentin, oxcarbazepine, pregabalin, tiagabineor and vigabatrin are contra-indicated in drop seizures.
• the present invention describes surprising data from two placebo-controlled studies of CBD as treatment for seizures associated with LGS.
• the CBD was used as add-on treatment in patients who were defined as treatment-resistant. Patients had previously tried and stopped using (failed) a median of 6 AEDs, and were being maintained on a median of 3 AEDs.
• CBD cannabidiol
• LGS Lennox-Gastaut syndrome
• AEDs anti-epileptic drugs
• the one or more AEDs is taken from rufinamide; lamotrigine; topiramate; and / or felbamate.
• the CBD is in the form of a highly purified extract of cannabis which comprises at least 98% (w/w) CBD.
• the CBD is present as a synthetic compound.
• the extract comprises less than 0.15% THC. More preferably the extract further comprises up to 1 % CBDV.
• the dose of CBD is below 50 mg/kg/day, more preferably below 30 mg/kg/day, more preferably still the dose of CBD is 20 mg/kg/day or greater, more preferably still the dose of CBD is 10 mg/kg/day or greater.
• a method of treating seizures associated with Lennox-Gastaut syndrome comprising administering cannabidiol (CBD) to a subject diagnosed with LGS who are deemed to be a treatment failure.
• CBD cannabidiol
• the subject is a human.
• Phytocannabinoids Phytocannabinoids; Endocannabinoids and Synthetic cannabinoids (which may be novel cannabinoids or synthetically produced phytocannabinoids or endocannabinoids).
• phytocannabinoids are cannabinoids that originate from nature and can be found in the cannabis plant.
• the phytocannabinoids can be isolated from plants to produce a highly purified extract or can be reproduced synthetically.
• “Highly purified cannabinoid extracts” are defined as cannabinoids that have been extracted from the cannabis plant and purified to the extent that other cannabinoids and non- cannabinoid components that are co-extracted with the cannabinoids have been substantially removed, such that the highly purified cannabinoid is greater than or equal to 98% (w/w) pure.
• Synthetic cannabinoids are compounds that have a cannabinoid or cannabinoid-like structure and are manufactured using chemical means rather than by the plant.
• Phytocannabinoids can be obtained as either the neutral (decarboxylated form) or the carboxylic acid form depending on the method used to extract the cannabinoids. For example, it is known that heating the carboxylic acid form will cause most of the carboxylic acid form to decarboxylate into the neutral form.
• Treatment-resistant epilepsy (TRE) or“intractable epilepsy” is defined as per the I LAE guidance of 2009 as epilepsy that is not adequately controlled by trials of one or more AED.
• Childhood epilepsy refers to the many different syndromes and genetic mutations that can occur to cause epilepsy in childhood. Examples of some of these are as follows:
• Dravet Syndrome Myoclonic-Absence Epilepsy; Lennox-Gastaut syndrome; Generalized Epilepsy of unknown origin; CDKL5 mutation; Aicardi syndrome; tuberous sclerosis complex; bilateral polymicrogyria; Dup15q; SNAP25; and febrile infection related epilepsy syndrome (FIRES); benign rolandic epilepsy; juvenile myoclonic epilepsy; infantile spasm (West syndrome); and Landau- Kleffner syndrome.
• FIRES febrile infection related epilepsy syndrome
• benign rolandic epilepsy juvenile myoclonic epilepsy
• infantile spasm West syndrome
• Landau- Kleffner syndrome Landau- Kleffner syndrome.
• “Drop seizures” are defined as a seizure involving the entire body, trunk or head that led or could have led to a fall, injury, slumping in a chair or hitting the patient’s head on a surface. Seizure types classed as resulting in a drop seizure are atonic, tonic or tonic-clonic seizures.
• “Treatment failure” is defined as patients who were currently taking an AED but continued to have uncontrolled seizures, or had previously taken and stopped treatment with an AED due to lack of efficacy in controlling seizures. DETAILED DESCRIPTION
• the drug substance used is a liquid carbon dioxide extract of high-CBD containing chemotypes of Cannabis sativa L. which had been further purified by a solvent crystallization method to yield CBD.
• the crystallisation process specifically removes other cannabinoids and plant components to yield greater than 98% CBD.
• CBD is highly purified because it is produced from a cannabis plant rather than synthetically there is a small number of other cannabinoids which are co-produced and co-extracted with the CBD. Details of these cannabinoids and the quantities in which they are present in the medication are as described in Table 5 below.
• EXAMPLE 1 EFFICACY OF CANNABIDIOL IN THE TREATMENT OF LENNOX-GASTAUT SYNDROME (LGS) IN PATIENTS DEEMED TO BE ANTI-EPILEPTIC DRUG (AED) TREATMENT FAILURES [0049] Currently only four products have been authorised in the EU for the treatment of
• LGS These medications are rufinamide, lamotrigine, topiramate and felbamate. Details of these can be found in Table 6 below.
• NICE National Institute for Clinical Excellence
• first line treatment is sodium valproate. If this is not effective or tolerated then lamotrigine should be prescribed as adjunctive treatment.
• Other AEDs that may be used are rufinamide, topiramate and felbamate. Usually, it takes a combination of more than one AED to gain any seizure control.
• Table 7 Modes of action of antiepileptic drugs authorised in the EU specifically to treat Lennox-Gastaut Syndrome
• CBD cannabidiol
• the first study was a 1 :1 randomised, double-blind, 14-week comparison of cannabidiol oral solution (CBD-OS) versus placebo.
• the treatment period consisted of a two- week titration period followed by a 12-week maintenance period.
• the treatment period was followed by a 10-day taper period and a four-week follow-up period.
• the study aimed to determine the efficacy, safety and tolerability of 20 mg/kg/day cannabidiol compared with placebo.
• the second study was a 1 :1 :1 randomised, 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 two-week titration period followed by a 12-week maintenance period. The treatment period was followed by a 10-day taper period and a four-week follow-up period.
• the study aimed to determine the efficacy, safety and tolerability of two dose levels of CBD-OS compared with placebo. Patients in the placebo group were split into two equivalent cohorts; half receiving 10 mg/kg/day dosing volumes and half receiving 20 mg/kg/day dosing volumes.
• Tables 8 to 10 below show the results in patients who have tried and failed rufinamide, or those who are currently taking it but have uncontrolled seizures. There was a significantly greater reduction in drop and total seizure frequency and a significantly greater proportion of patients with a 3 50% reduction in drop seizure frequency at the 20 mg/kg/day dose of cannabidiol compared with placebo.
• Table 1 Percentage Change from Baseline in Drop Seizure Frequency in Patients who are Rufinamide Treatment Failures
• Table 2 Patients who are Rufinamide Treatment Failures Who Achieved At Least a 50% Reduction in Drop Seizure Frequency from Baseline
• Tables 11 to 13 below show the results in patients who have tried and failed lamotrigine, and those who are currently taking it but have uncontrolled seizures. There is a significantly greater reduction in both drop and total seizure frequency and a significantly greater proportion of patients with a 3 50% reduction in drop seizure frequency at both doses of cannabidiol compared with placebo.
• Table 4 Percentage Change from Baseline in Drop Seizure Frequency in Patients who are Lamotrigine Treatment Failures
• Table 5 Proportion of Patients who are Lamotrigine Treatment Failures Who Achieved At Least a 50% Reduction in Drop Seizure Frequency from Baseline
• Tables 14 to 16 below show the results in patients who have tried and failed topiramate, and those who are currently taking it but have uncontrolled seizures. There is a significantly greater reduction in both drop and total seizure frequency at both doses of cannabidiol compared with placebo, and a greater proportion of patients with a 3 50% reduction in drop seizure frequency at both doses of cannabidiol compared with placebo (reaching statistical significance for the 20 mg/kg/day dose but only marginal statistical significance for the 10 mg/kg/day dose).
• Table 7 Percentage Change from Baseline in Drop Seizure Frequency in Patients who are Topiramate Treatment Failures
• Table 8 Proportion of Patients who are Topiramate Treatment Failures Who Achieved At Least a 50% Reduction in Drop Seizure Frequency from Baseline
• Tables 17 to 19 below show the results in patients who have tried and failed felbamate, and those who are currently taking it but have uncontrolled seizures. There is a marginally statistically significantly greater reduction in drop seizure frequency and a statistically significantly greater proportion of patients with a 3 50% reduction in drop seizure frequency at the 20 mg/kg dose of cannabidiol compared with placebo.
• Table 11 Proportion of Patients who are Felbamate Treatment Failures Who Achieved At Least a 50% Reduction in Drop Seizure Frequency from Baseline
• Table 12 Percentage Change from Baseline in Total Seizure Frequency in Patients who are Felbamate Treatment Failures
• CBD with one or more of the medications approved to treat LGS, namely rufinamide, lamotrigine, topiramate or felbamate enables a statistically significant reduction in drop and total seizure frequency in patients deemed to be treatment failures on their existing medication.

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