Use of cannabinoids in the treatment of seizures associated with Lennox-Gastaut syndrome

Abstract

To provide medicaments for the treatment of patients with Lennox-Gastaut syndrome (LGS) who are deemed to be failed in treatment failure with conventional pharmaceuticals.SOLUTION: The present invention relates to the use of cannabidiol (CD) in the treatment of patients with Lennox-Gastaut syndrome (LGS) who are deemed to be failed in treatment with conventional pharmaceuticals. In particular, the use of CBD has been found to provide a statistically significant reduction in both drop seizures and total seizure frequencies in patients who have tried and failed anti-epileptic drugs (AEDs) or those who are currently taking AEDs but cannot control seizures. Preferably, the AEDs which have been shown to be failed in treatment are one or more of rufinamide, lamotrigine, topiramate and / or felbamate. Preferably, 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 characterized. In particular, the cannabinoid tetrahydrocannabinol (THC) is substantially removed, to a level of at 0.15% (w / w) or less and cannabidivarin (CBDV) being the propyl analogue of CED is present in amounts of up to 1%. Alternatively, the CBD may be a synthetically produced CD.SELECTED DRAWING: None

Description

[Technical Field]

[0001] The present invention relates to the use of cannabidiol (CBD) in the treatment of patients with Lennox-Gastaut syndrome (LGS) who have reported failure of existing medications. In particular, the use of CBD has been found to provide a statistically significant reduction in both drop and total seizure frequency in patients who have either tried and failed antiepileptic drugs (AEDs) or who are currently taking AEDs but are unable to control their seizures.

[0002] Preferably, the AEDs for which treatment failure has been demonstrated are one or more of rufinamide, lamotrigine, topiramate, and / or felbamate.

[0003] Preferably, the CBD used is in the form of a highly purified cannabis extract in which CBD is present at greater than 98% of the total extract (w / w), and the other components of the extract are characterized. In particular, the cannabinoid tetrahydrocannabinol (THC) is substantially removed to a level of 0.15% (w / w) or less, and cannabidivarin (CBDV), the propyl analog of CBD, is present in amounts up to 1%. Alternatively, the CBD may be synthetically produced CBD. [Background technology]

[0004] Epilepsy affects approximately 1% of the population worldwide (Thurman et al., 2011), of whom 70% can adequately control their symptoms with currently available antiepileptic drugs (AEDs). However, 30% of this patient population (Eadie et al., 2012) are unable to achieve seizure freedom with available AEDs and are therefore referred to as suffering from intractable epilepsy or "treatment-resistant epilepsy (TRE)."

[0005] Refractory or treatment-resistant epilepsy was defined by the International League Against Epilepsy (ILAE) in 2009 as “the failure of adequate trials of two tolerated, appropriately selected, and used AED treatment regimens (either as monotherapy or in combination) to achieve sustained seizure freedom” ( Kwan et al., 2009 ).

[0006] Individuals who develop epilepsy during 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.

[0007] Pediatric epilepsy is a relatively common neurological disorder in children and young adults, with a prevalence of approximately 700 per 100,000, which is twice the number of adults with epilepsy per population.

[0008] When a child or young adult presents with seizures, an investigation is usually carried out to determine the cause. Childhood epilepsy can be caused by many different syndromes and genetic mutations, so it can take some time to diagnose these children.

[0009] The main symptom of epilepsy is recurrent seizures. To determine the type of epilepsy or epilepsy syndrome a patient suffers from, an investigation is conducted into the type of seizures the patient is experiencing. Clinical observations and electroencephalography (EEG) tests are performed and the type of seizure is classified according to the ILAE classification described below.

[0010] The International Classification of Seizure Types proposed by the ILAE was adopted in 1981, and a revised proposal was published by the ILAE in 2010, but it has not yet replaced the 1981 classification. The 2010 proposal for revised terminology includes a proposed change to replace the terminology of partial with focal. In addition, the term "simple partial seizure" was replaced with the term "focal seizure without impaired awareness / responsiveness," and the term "complex partial seizure" was replaced with the term "focal seizure with impaired awareness / responsiveness."

[0011] Generalized seizures, in which seizures arise within and rapidly involve bilaterally distributed networks, are divided into six subtypes: tonic-clonic (grand mal), absence (petit mal), clonic, tonic, atonic, and myoclonic.

[0012] Focal (partial) seizures, in which the seizures occur within a network restricted to one hemisphere, are also divided into subcategories. Here, the seizures are characterized according to one or more seizure features, including aura, motor, autonomic, and consciousness / reactivity. If a seizure begins as a focal seizure and rapidly evolves to distribute within bilateral networks, it is known as a bilateral convulsive seizure, a term proposed to replace secondarily generalized seizures (generalized seizures that evolve from focal seizures and are no longer focal).

[0013] Epilepsy syndromes often present with many different seizure types, and identifying the type of seizure a patient is suffering from is important because many standard AEDs are targeted to treat or are only effective against one specific seizure type / subtype.

[0014] One such childhood epilepsy syndrome is Lennox-Gastaut syndrome (LGS). LGS is a severe form of epilepsy, and seizures usually begin before the age of 4. Seizures vary among patients but include tonic seizures (rigidity of the body, upward deviation of the eyes, dilated pupils, and abnormal breathing patterns), atonic seizures (brief loss of muscle tone and consciousness that can result in a sudden fall), atypical absence seizures (staring spells), and myoclonic seizures (sudden muscle jerks). Periods of frequent seizures may be interspersed with short, relatively seizure-free periods.

[0015] Seizures in LGS are often referred to as "astatic seizures," which are defined as attacks or spells involving the whole body, trunk, or head (atonic, tonic, or tonic-clonic) that result or may result in a fall, injury, collapsing in a chair, or hitting one's head on the ground.

[0016] Most people with LGS experience some degree of intellectual impairment or information processing disorder, along with developmental delay and behavioral problems.

[0017] LGS can be caused by brain malformations, perinatal asphyxia, severe head injury, central nervous system infections, and inherited degenerative or metabolic disorders. In 30-35% of cases, no cause can be found.

[0018] 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 in combination with rufinamide or lamotrigine. Other possible AEDs include felbamate, clobazam, and topiramate.

[0019] AEDs such as carbamezapine, gabapentin, oxcarbazepine, pregabalin, tiagabine, or / and vigabatrin are contraindicated in isostatic seizures.

[0020] Common AEDs, defined by their mechanism of action, are listed in the table below.

[0021] [Table 1]

[0022] [Table 2]

[0023] [Table 3]

[0024] The present invention describes surprising data from two placebo-controlled trials of CBD as a treatment for seizures associated with LGS. CBD was used as an add-on treatment in patients who were defined as treatment-resistant. Patients had previously tried and discontinued a median of six AEDs (failed), and were supported on a median of three AEDs.

[0025] Despite this intensive treatment, the median number of astatic seizures at baseline exceeded 75 per month in both studies. This was a patient population with a high unmet medical need who had already tried and failed numerous AEDs. In many cases, the AEDs they were using included rufinamide, lamotrigine, or topiramate, all approved for the treatment of LGS.

[0026] Data collected on patients who were deemed to have failed treatment with one or more existing approved medications for LGS showed that the use of CBD in combination with these medications resulted in a statistically significant reduction in the frequency of both astatic and total seizures.

[0027] In August 2017, Gaston et al. reported that in an open-label study, when CBD was administered to patients with epilepsy, serum levels of several AEDs were found to increase in the presence of CBD. The study did not find that such increases resulted in a reduction in seizures in patients who were thought to have failed treatment. [Prior art documents] [Non-patent literature]

[0028] [Non-Patent Document 1] Thurman et al., 2011 [Non-patent document 2] Eadie et al., 2012 [Non-patent document 3] Kwan et al., 2009 Summary of the Invention [Means for solving the problem]

[0029] According to a first aspect of the present invention there is provided cannabidiol (CBD) for use in the treatment of seizures associated with Lennox-Gastaut syndrome (LGS), characterised in that LGS patients have been shown to have failed treatment with one or more antiepileptic drugs (AEDs).

[0030] Preferably, the one or more AEDs are selected from rufinamide, lamotrigine, topiramate, and / or felbamate.

[0031] Preferably, the CBD is in the form of a highly purified cannabis extract containing at least 98% (w / w) CBD. Alternatively, CBD exists as a synthetic compound.

[0032] Preferably, the extract contains less than 0.15% THC. More preferably, the extract further contains up to 1% CBDV.

[0033] Preferably, the dose of CBD is less than 50 mg / kg / day, more preferably less than 30 mg / kg / day, even more preferably the dose of CBD is 20 mg / kg / day or more, and even more preferably the dose of CBD is 10 mg / kg / day or more.

[0034] According to a second aspect of the present invention, there is provided a method of treating seizures associated with Lennox-Gastaut syndrome (LGS), comprising administering cannabidiol (CBD) to a subject diagnosed with LGS who has previously been diagnosed with LGS and who has previously been diagnosed with LGS and who has previously been diagnosed with LGS but who has previously been diagnosed with LGS but who has previously been diagnosed with LGS and ...

[0035] Preferably, the patient is a human.

[0036] [Definition] Listed below are definitions of some terms used to describe this invention.

[0037] The cannabinoids mentioned in this application are listed below along with their standard abbreviations.

[0038] [Table 4]

[0039] The above table is not exhaustive and merely provides a detailed list of the cannabinoids identified in this application for reference purposes. Over 60 different cannabinoids have been identified to date, which can be divided into different groups: phytocannabinoids, endocannabinoids, and synthetic cannabinoids (which may be new cannabinoids or synthetic phytocannabinoids or endocannabinoids).

[0040] "Phytocannabinoids" are cannabinoids that are naturally occurring and found in the cannabis plant. Phytocannabinoids can be isolated from the plant to produce highly purified extracts, or they can be reproduced synthetically.

[0041] A "highly purified cannabinoid extract" is defined as cannabinoids that have been extracted from the cannabis plant and purified to such an extent that non-cannabinoid components and other cannabinoid components extracted with the cannabinoids have been substantially removed, such that the highly purified cannabinoids are at least 98% (w / w) pure.

[0042] "Synthetic cannabinoids" are compounds with cannabinoid or cannabinoid-like structures that are produced using chemical means, rather than from plants.

[0043] Phytocannabinoids can be obtained in either the neutral (decarboxylated) or carboxylic acid form, depending on the method used to extract the cannabinoids. For example, it is known that heating the carboxylic acid form will decarboxylate most of the carboxylic acid form to the neutral form.

[0044] "Treatment-resistant epilepsy" (TRE) or "refractory epilepsy" is defined as epilepsy that is not adequately controlled by one or more attempts with AEDs, as per the 2009 ILAE guidance.

[0045] "Childhood epilepsy" refers to the many different syndromes and genetic mutations that can cause epilepsy in childhood. 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 polygyria, Dup15q, SNAP25, and febrile infection-associated epilepsy syndrome (FIRES), benign rolandic epilepsy, juvenile myoclonic epilepsy, infantile spasms (West syndrome), and Landau-Kleffner syndrome. Because there are many different childhood epilepsies, the above list is not exhaustive.

[0046] An "atonic seizure" is defined as a seizure involving the whole body, trunk, or head that results or may result in a fall, injury, collapsing in a chair, or hitting one's head on the ground. The types of seizures classified as causing atonic seizures are atonic, tonic, or tonic-clonic.

[0047] "Treatment failure" was defined as a patient who was currently taking an AED but continued to have uncontrolled seizures, or a patient who had previously taken an AED but discontinued treatment with the AED due to insufficient seizure control. DETAILED DESCRIPTION OF THE INVENTION

[0048] Preparation of highly purified CBD extracts The production of highly purified (>98% w / w) cannabidiol extracts of known and consistent composition was used in the following examples, as described below.

[0049] In summary, the drug substance used was a liquid carbon dioxide extract of Cannabis sativa L., a CBD-rich chemotype, which was further purified by solvent crystallization to produce CBD. The crystallization process specifically removes other cannabinoids and plant components to produce greater than 98% CBD. Although the CBD is highly purified, because it is produced from the cannabis plant rather than synthetically, there are small amounts of other cannabinoids that are produced and extracted along with the CBD. Details of these cannabinoids and their amounts present in the drug product are set forth in Table 5 below.

[0050] [Table 5] [Example]

[0051] Example 1: Efficacy of cannabidiol in treating Lennox-Gastaut syndrome (LGS) in patients who have previously failed antiepileptic drugs (AEDs) Currently, only four products are licensed in the EU for the treatment of LGS. These drugs are rufinamide, lamotrigine, topiramate, and felbamate. Details of these are listed in Table 6 below.

[0052] [Table 6]

[0053] The UK National Institute for Clinical Excellence (NICE) has put forward a recommended pathway for the treatment of LGS (NICE, 2016). NICE suggests that the first-line treatment is sodium valproate. If this is ineffective or tolerance is observed, lamotrigine should then be prescribed as an adjunctive treatment. Other AEDs that may be used are rufinamide, topiramate, and felbamate. Usually, a combination of more than one AED is taken to control any seizures.

[0054] Specifically, all four compounds approved in the EU for the treatment of LGS appear to act via sodium channel blockade (see Table 7). CBD has a different mechanism of action for these treatments, offering prescribers and patients a viable alternative for treating this disease, which is notoriously unresponsive to conventional antiepileptic treatments.

[0055] [Table 7]

[0056] In two placebo-controlled studies of CBD as a treatment for seizures associated with LGS, cannabidiol was used as an add-on treatment in patients who were defined as treatment-resistant. Patients had previously tried and discontinued a median of six AEDs and were supported on a median of three AEDs.

[0057] 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 20 mg / kg / day cannabidiol compared to placebo.

[0058] 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 tapering 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 groups: half receiving the 10 mg / kg / day dose and half receiving the 20 mg / kg / day dose.

[0059] To ensure that caregivers were able to interpret seizures correctly, all caregivers received preliminary training, and their seizure descriptions and classifications were independently verified by a committee appointed by the Epilepsy Study Consortium.

[0060] Despite the number of medications patients were already taking, the median number of astatic seizures at baseline was over 75 per month in both studies. This was a patient population with a high unmet medical need who had already tried and failed numerous AEDs. In many cases, the AEDs they were taking included rufinamide, lamotrigine, or topiramate, all approved for the treatment of LGS.

[0061] We analyzed the change in seizure frequency for CBD versus placebo in patients who were currently taking or had previously stopped taking rufinamide, lamotrigine, or topiramate or felbamate, respectively, and who could reasonably be defined as having failed treatment with an AED.

[0062] Rufinamide Tables 8 through 10 below show results in patients who had tried and failed rufinamide or who were currently taking rufinamide but were unable to control their seizures. Compared to placebo, cannabidiol at a dose of 20 mg / kg / day resulted in a significantly greater reduction in the frequency of hypostatic and total seizures, with a significantly larger group of patients experiencing a 50% or greater reduction in the frequency of hypostatic seizures.

[0063] [Table 8]

[0064] [Table 9]

[0065] [Table 10]

[0066] Lamotrigine Tables 11 to 13 below show the results in patients who had tried lamotrigine unsuccessfully and in patients currently taking lamotrigine but whose seizures were not controlled. There was a significantly greater reduction in both astatic and total seizure frequency with both doses of cannabidiol compared to placebo, with a significantly larger group of patients experiencing a 50% or greater reduction in astatic seizure frequency.

[0067] [Table 11]

[0068] [Table 12]

[0069] [Table 13]

[0070] Topiramate Tables 14 to 16 below show results in patients who had tried topiramate unsuccessfully and in patients currently taking topiramate but whose seizures were not being controlled. There was a significantly greater reduction in both astatic and total seizure frequency with both doses of cannabidiol compared to placebo, with a larger group of patients experiencing a 50% or greater reduction in astatic seizure frequency with both doses of cannabidiol compared to placebo (achieving statistical significance for the 20 mg / kg / day dose but only marginally achieving statistical significance for the 10 mg / kg / day dose).

[0071] [Table 14]

[0072] [Table 15]

[0073] [Table 16]

[0074] Felbamate Tables 17-19 below show the results in patients who had tried felbamate unsuccessfully and in patients currently taking felbamate but whose seizures were not being controlled. Compared to placebo, cannabidiol at a dose of 20 mg / kg / day resulted in a small but statistically significant greater reduction in the frequency of isostatic seizures, with a statistically significantly larger group of patients experiencing a 50% or greater reduction in isostatic seizure frequency.

[0075] [Table 17]

[0076] [Table 18]

[0077] [Table 19]

[0078] [Conclusion] Accumulated data from two well-controlled, multicenter, multinational randomized studies indicate that patients who are taking AEDs approved for use in LGS in the EU but whose seizures are not controlled, or who have previously taken them but have since stopped, derive significant benefit from CBD, with the effect being most significant at a daily dose of 20 mg / kg / day.

[0079] These data indicate that add-on treatment with CBD can confer clinically relevant benefits beyond those provided by lamotrigine, rufinamide, felbamate, and topiramate, consistent with cannabidiol's mechanism of action, which differs from that of these AEDs.

[0080] Surprisingly, the use of CBD in combination with one or more of the above-mentioned approved medications for treating LGS, namely rufinamide, lamotrigine, topiramate, or felbamate, allows for a statistically significant reduction in the frequency of astatic and total seizures in patients who have previously failed existing medications.

Claims

1. A pharmaceutical agent for use in the treatment of astatic seizures associated with Lennox-Gastaut syndrome (LGS) in patients who have failed rufinamide, topiramate and / or felbamate treatment, comprising cannabidiol (CBD), The CBD is in the form of a cannabis extract containing at least 98% (w / w) CBD, or is present as a synthetic compound. Medicine.

2. The pharmaceutical described in claim 1, wherein the patient is a patient in whom rufinamide and / or topiramate treatment has failed.

3. 3. A medicament according to claim 1 or 2, wherein the extract contains less than 0.15% tetrahydrocannabinol.

4. 4. A medicament according to any one of claims 1 to 3, wherein the extract further comprises up to 1% cannabidivarin.

5. The pharmaceutical composition of any one of claims 1 to 4, wherein the dose of CBD is less than 50 mg / kg / day.

6. The pharmaceutical composition of any one of claims 1 to 5, wherein the dose of CBD is greater than 20 mg / kg / day.

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