WO2022017931A1 - Utilisation de cannabidiol dans le traitement de crises associées au syndrome d'ohtahara ou au syndrome d'ohtahara secondaire à une mutation d'aimp1 - Google Patents

Utilisation de cannabidiol dans le traitement de crises associées au syndrome d'ohtahara ou au syndrome d'ohtahara secondaire à une mutation d'aimp1 Download PDF

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WO2022017931A1
WO2022017931A1 PCT/EP2021/069860 EP2021069860W WO2022017931A1 WO 2022017931 A1 WO2022017931 A1 WO 2022017931A1 EP 2021069860 W EP2021069860 W EP 2021069860W WO 2022017931 A1 WO2022017931 A1 WO 2022017931A1
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preparation
seizures
ohtahara syndrome
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Daniel Adam CHECKETTS
Kevin James CRAIG
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GW Research Limited
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    • A61K31/197—Carboxylic acids, e.g. valproic acid having an amino group the amino and the carboxyl groups being attached to the same acyclic carbon chain, e.g. gamma-aminobutyric acid [GABA], beta-alanine, epsilon-aminocaproic acid or pantothenic acid
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    • A61P25/12—Antiepileptics; Anticonvulsants for grand-mal

Definitions

  • the present invention relates to the use of cannabidiol (CBD) for the treatment of seizures associated with rare epilepsy syndromes.
  • CBD cannabidiol
  • the seizures associated with rare epilepsy syndromes that are treated are those which are experienced in patients diagnosed with Ohtahara Syndrome or Ohtahara Syndrome secondary to mutation of the aminoacyl tRNA synthetase complex interacting multifunctional protein 1 (AIMP1) gene.
  • the types of seizures include tonic, atonic, myoclonic, absence and focal seizures with impairment.
  • the dose of CBD is between 5 mg/kg/day to 50 mg/kg/day.
  • the CBD used is in the form of a highly purified extract of cannabis such that the CBD is present at greater than 95% of the total extract (w/w) and the cannabinoid tetrahydrocannabinol (THC) has been substantially removed, to a level of not more than 0.15% (w/w).
  • the CBD used is in the form of a botanically derived purified CBD which comprises greater than or equal to 98% (w/w) CBD and less than or equal to 2% (w/w) of other cannabinoids. More preferably the other cannabinoids present are THC at a concentration of less than or equal to 0.1% (w/w); CBD-C1 at a concentration of less than or equal to 0.15% (w/w); CBDV at a concentration of less than or equal to 0.8% (w/w); and CBD-C4 at a concentration of less than or equal to 0.4% (w/w).
  • the botanically derived purified CBD preferably also comprises a mixture of both trans-THC and cis-THC. Alternatively, a synthetically produced CBD is used.
  • the other cannabinoids present are THC at a concentration of about 0.01% to about 0.1% (w/w); CBD-C1 at a concentration of about 0.1% to about 0.15% (w/w); CBDV at a concentration of about 0.2% to about 0.8% (w/w); and CBD-C4 at a concentration of about 0.3% to about 0.4% (w/w).
  • THC is present at a concentration of about 0.02% to about 0.05% (w/w).
  • the CBD may be formulated for administration separately, sequentially or simultaneously with one or more AED or the combination may be provided in a single dosage form.
  • Epilepsy occurs in approximately 1% of the population worldwide, (Thurman et ai, anti-epileptic drugs (AED). However, 30% of this patient group, (Eadie etal., 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).
  • Thurman et ai anti-epileptic drugs
  • 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).
  • 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.
  • the main symptom of epilepsy is repeated seizures.
  • Clinical observations and electroencephalography (EEG) tests are conducted and the type(s) of seizures are classified according to the ILEA classification.
  • Generalized 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 generalized seizures (generalized seizures that have evolved from focal seizures and are no longer remain localized).
  • focal seizures with impairment Focal seizures where the subject’s awareness / responsiveness is altered are referred to as focal seizures with impairment and focal seizures where the awareness or responsiveness of the subject is not impaired are referred to as focal seizures without impairment.
  • Ohtahara syndrome is an uncommon type of epilepsy characterized by hard to control seizures and developmental delays. The disorder affects infants, usually within the first three months of life in the form of epileptic seizures. Infants have primarily tonic seizures, but may also experience focal seizures and rarely, myoclonic seizures.
  • the typical cause is abnormal brain structure which may be due to damage or abnormal development.
  • the syndrome may also be caused by metabolic disorders or genetic epilepsy syndromes. However, the causes for many cases cannot be determined.
  • Antiseizure drugs are used to control seizures but are not usually very effective for this disorder. Corticosteroids are occasionally helpful, and the ketogenic diet may be appropriate in some cases. In cases where there is a focal brain lesion, epilepsy surgery may be beneficial.
  • the protein encoded by the AIMP1 gene plays an important role in the development and maintenance of axon-cytoskeleton integrity and regulating neurofilaments. Mutations in this gene can cause neurodegeneration of variable severity and white matter abnormalities in the brain.
  • CBD Cannabidiol
  • a paper published in 2017 describes using CBD to treat a number of different childhood epilepsy syndromes.
  • An online survey was used to explore the experience of parents administering CBD to children. 53 completed surveys were reviewed, one patient was reported to suffer from Ohtahara Syndrome. There is no data in this document to demonstrate or suggest that treatment with a CBD product was effective in the treatment of Ohtahara Syndrome 1 .
  • Laux et al. (2019) 6 and Szaflarski et al. (2016) 7 describe results from an Expanded Access Program whereby children with severe treatment-resistant epilepsies, Lennox-Gastaut syndrome or Dravet syndrome, received CBD treatment. Ohtahara syndrome is not mentioned as any of the conditions treated.
  • Ohtahara syndrome is a phenotype linked with CDKL5, SCN2A and STXBP1.
  • CBD cannabidiol
  • the seizures associated with Ohtahara Syndrome or Ohtahara Syndrome secondary to AIMP1 mutation are tonic, atonic, myoclonic, absence and focal seizures.
  • the CBD preparation comprises greater than 95% (w/w) CBD and not more than 0.15% (w/w) tetrahydrocannabinol (THC).
  • the CBD preparation comprises greater than or equal to 98% (w/w) CBD and less than or equal to 2% (w/w) other cannabinoids, wherein the less than or equal to 2% (w/w) 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.
  • THC cannabinoids tetrahydrocannabinol
  • CBD-C1 cannabidiol- C1
  • CBDDV cannabidivarin
  • CBD-C4 cannabidiol-C4
  • the CBD preparation is used in combination with one or more concomitant anti-epileptic drugs (AED).
  • AED concomitant anti-epileptic drugs
  • the one or more AED is selected from the group consisting of: levetiracetam, clobazam, vigabatrin, zonisamide, rufinamide, lacosamide, phenytoin, midazolam, adrenocorticotropic hormone, phenobarbital and lorazepam.
  • the CBD is present is isolated from cannabis plant material.
  • the CBD is present as a synthetic preparation.
  • the dose of CBD is greater than 5 mg/kg/day. More preferably the dose of CBD is 20 mg/kg/day. More preferably the dose of CBD is 25 mg/kg/day. More preferably the dose of CBD is 50 mg/kg/day.
  • a method of treating seizures associated with Ohtahara Syndrome or Ohtahara Syndrome secondary to AIMP1 mutation comprising administering a cannabidiol (CBD) preparation to the subject in need thereof.
  • CBD cannabidiol
  • cannabinoids Over 100 different cannabinoids have been identified, see for example, Handbook of Cannabis, Roger Pertwee, Chapter 1, pages 3 to 15. These cannabinoids can be split into different groups as follows: 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 cannabinoids” are defined as cannabinoids that have been extracted from the cannabis plant and purified to the extent that other cannabinoids and non-cannabinoid components that are co-extracted with the cannabinoids have been removed, such that the highly purified cannabinoid is greater than or equal to 95% (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.
  • Atonic seizures also known as drop attacks, occur when a person suddenly loses muscle tone resulting in their head or body possibly going limp. In some children, only their head drops suddenly. They can begin in one area or side of the brain (focal onset) or both sides of the brain (generalized onset).
  • Tonic seizures can be generalised onset, affecting both sides of the brain, or they can be focal onset, starting in just one side of the brain. If a tonic seizure starts in both sides of the brain, all muscles tighten and the subject’s body goes stiff. If standing, they may fall to the floor, their neck may extend, eyes open wide and roll upwards, whilst their arms may raise upwards and legs stretch or contract. If a tonic seizure starts in one side of the brain muscles tighten in just one area of the body. Tonic seizures usually last less than one minute.
  • “Myoclonic seizures” are characterised by a ‘muscle jerk’. Myoclonic seizures are brief but can happen in clusters (many happening close together in time) and often happen shortly after waking. In myoclonic seizures the person is conscious, but they are classified as generalised seizures.
  • “Absence seizures” are also called “petit mal” seizures. These types of seizure cause a loss of awareness for a short time. They mainly affect children although can happen at any age. During an absence seizure, a person may: stare blankly into space; look like they are "daydreaming”; flutter their eyes; make slight jerking movements of their body or limbs. The seizures usually only last up to 15 seconds and may occur several times a day.
  • “Focal Seizures” are defined as seizures which originate within networks limited to only one hemisphere. What happens during the seizure depends on where in the brain the seizure happens and what that part of the brain normally does.
  • 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 or equal to 95% 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 A below.
  • the drug substance used in the trials 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 95% CBD w/w, typically greater than 98% w/w.
  • Cannabis sativa L. plants are grown, harvested, and processed to produce a botanical extract (intermediate) and then purified by crystallization to yield the CBD (botanically derived purified CBD).
  • the plant starting material is referred to as Botanical Raw Material (BRM); the botanical extract is the intermediate; and the active pharmaceutical ingredient (API) is CBD, the drug substance.
  • BRM Botanical Raw Material
  • API active pharmaceutical ingredient
  • the purity of the botanically derived purified CBD preparation was greater than or equal to 98%.
  • the botanically derived purified CBD includes THC and other cannabinoids, e.g., CBDA, CBDV, CBD-C1, and CBD-C4.
  • the CBD preparation comprises not more than 0.15% THC based on total amount of cannabinoid in the preparation. In some embodiments, the CBD preparation comprises about 0.01% to about 0.1% THC based on total amount of cannabinoid in the preparation. In some embodiments, the CBD preparation comprises about 0.02% to about 0.05% THC based on total amount of cannabinoid in the preparation.
  • the CBD preparation comprises about 0.2% to about 1.0% CBDV based on total amount of cannabinoid in the preparation. In some embodiments, the CBD preparation comprises about 0.2% to about 0.8% CBDV based on total amount of cannabinoid in the preparation. [0061] In some embodiments, the CBD preparation comprises about 0.3% to about 0.5%
  • CBD-C4 based on total amount of cannabinoid in the preparation.
  • the CBD preparation comprises about 0.3% to about 0.4% CBD-C4 based on total amount of cannabinoid in the preparation.
  • the CBD preparation comprises about 0.1% to about 0.15% CBD-C1 based on total amount of cannabinoid in the preparation.
  • Distinct chemotypes of the Cannabis sativa L. plant have been produced to maximize the output of the specific chemical constituents, the cannabinoids. Certain chemovars produce predominantly CBD. Only the (-)-trans isomer of CBD is believed to occur naturally. During purification, the stereochemistry of CBD is not affected.
  • High CBD chemovars were grown, harvested, dried, baled and stored in a dry room until required.
  • the botanical raw material (BRM) was finely chopped using an Apex mill fitted with a 1 mm screen. The milled BRM was stored in a freezer prior to extraction.
  • the BDS produced using the methodology above was dispersed in C5-C12 straight chain or branched alkane.
  • the mixture was manually agitated to break up any lumps and the sealed container then placed in a freezer for approximately 48 hours.
  • the crystals were isolated via vacuum filtration, washed with aliquots of cold C5-C12 straight chain or branched alkane, and dried under a vacuum of ⁇ 10mb at a temperature of 60°C until dry.
  • the botanically derived purified CBD preparation was stored in a freezer at -20°C in a pharmaceutical grade stainless steel container, with FDA food grade approved silicone seal and clamps.
  • the botanically derived purified CBD used in the clinical trial described in the invention comprises greater than or equal to 98% (w/w) CBD and less than or equal to 2% (w/w) of other cannabinoids.
  • the other cannabinoids present are THC at a concentration of less than or equal to 0.1% (w/w); CBD-C1 at a concentration of less than or equal to 0.15% (w/w); CBDV at a concentration of less than or equal to 0.8% (w/w); and CBD-C4 at a concentration of less than or equal to 0.4% (w/w).
  • the botanically derived purified CBD used additionally comprises a mixture of both trans-THC and cis-THC. It was found that the ratio of the trans-THC to cis-THC is altered and can be controlled by the processing and purification process, ranging from 3.3:1 (trans-THC:cis- THC) in its unrefined decarboxylated state to 0.8:1 (trans-THC:cis-THC) when highly purified. [0072] Furthermore, the cis-THC found in botanically derived purified CBD is present as a mixture of both the (+)-cis-THC and the (-)-cis-THC isoforms.
  • CBD preparation could be produced synthetically by producing a composition with duplicate components.
  • Example 1 describes the use of a botanically derived purified CBD in an open label, expanded-access program to investigate the clinical efficacy and safety of purified pharmaceutical cannabidiol formulation (CBD) in the treatment of Ohtahara Syndrome or Ohtahara Syndrome secondary to AIMP1 mutation.
  • CBD cannabidiol formulation
  • EXAMPLE 1 CLINICAL EFFICACY AND SAFETY OF PURIFIED PHARMACEUTICAL CANNABIDIOL (CBD) IN THE TREATMENT OF PATIENTS DIAGNOSED WITH OHTAHARA SYNDROME OR OHTAHARA SYNDROME SECONDARY TO AIMP1 MUTATION Study design
  • Subjects were required to be on one or more AEDs at stable doses for a minimum of two weeks prior to baseline and to have stable vagus nerve stimulation (VNS) settings and ketogenic diet ratios for a minimum of four weeks prior to baseline.
  • VNS vagus nerve stimulation
  • Patients were administered botanically derived purified CBD in a 100 mg/ml_ sesame oil- based solution at an initial dose of between 5 and 23 milligrams per kilogram per day (mg/kg/day) in two divided doses. Dose was then increased weekly by 5mg/kg/day to a goal of 20 to 25 mg/kg/day.
  • a maximum dose of 50 mg/kg/day could be utilised for patients who were tolerating the medication but had not achieved seizure control; these patients had further weekly titration by 5mg/kg/day.
  • Seizure frequency, intensity, and duration were recorded by caregivers in a diary during a baseline period of at least 28 days. Changes in seizure frequency relative to baseline were calculated after at least 2 weeks and at defined timepoints of treatment.
  • Patients may be defined as responders if they had more than 50% reduction in seizure frequency compared to baseline.
  • the percent change in seizure frequency was calculated as follows:
  • % change ((weekly seizure frequency time interval)-( weekly seizure frequency Baseline)) x100 seizure (weekly seizure frequency Baseline) frequency
  • the percent change of seizure frequency may be calculated for any time interval where seizure number has been recorded.
  • the percent change of seizure frequency for the end of the treatment period was calculated as follows:
  • % reduction ((weekly seizure frequency Baseline) - (weekly seizure frequency End)) x100 seizure frequency (weekly seizure frequency Baseline)
  • the five patients enrolled in the open label, expanded-access program were diagnosed with Ohtahara Syndrome or Ohtahara Syndrome secondary to AIMP1 mutation. These patients experienced several different seizure types including tonic, atonic, myoclonic, absence and focal seizures with impairment and were taking several concomitant AEDs. [0083] The age of patients ranged from 0.53-16.84 years and all five were female as detailed in Table 1 below.
  • Table 1 Patient demographics, seizure type and concomitant medication
  • LEV levetiracetam
  • CLB clobazam
  • VGB vigabatrin
  • ZNS zonisamide
  • RFN rufinamide
  • LCS lacosamide
  • PHY phenytoin
  • MDZ midazolam
  • ACTH Adrenocorticotropic hormone
  • PHB phenobarbital
  • LZP lorazepam
  • the average number of concomitant AEDs at the time of starting CBD was three per patient (range: 2-5, median: 3).
  • Tables 2A-E illustrate the seizure frequency for each patient as well as the dose of CBD given.
  • Table 2A Seizure frequency data for Patient 1
  • Patient 5 was treated for 48 weeks and experienced a 73.0% reduction in tonic seizures over the treatment period.
  • this study signifies the use of CBD for treatment of seizures associated with Ohtahara Syndrome or Ohtahara Syndrome secondary to AIMP1 mutation.
  • Seizure types include tonic, atonic, myoclonic, absence and focal seizures with impairment for which seizure frequency rates decreased by significant rates, by an average of 73.9%.

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Abstract

La présente invention concerne l'utilisation de cannabidiol (CBD) pour le traitement de crises associées à des syndromes épileptiques rares. En particulier, les crises associées à des syndromes épileptiques rares qui sont traitées sont celles survenant chez des patients chez lesquels on a diagnostiqué un syndrome d'Ohtahara ou un syndrome d'Ohtahara secondaire à une mutation du gène de la protéine multifonctionnelle 1 interagissant avec un complexe aminoacyl-ARNt synthétase (AIMP1). Dans un autre mode de réalisation, les types de crises comprennent des crises toniques, atoniques, myocloniques, d'absence et focales avec altération de la conscience. De préférence, la dose de CBD est comprise entre 5 mg/kg/jour et 50 mg/kg/jour.
PCT/EP2021/069860 2020-07-20 2021-07-15 Utilisation de cannabidiol dans le traitement de crises associées au syndrome d'ohtahara ou au syndrome d'ohtahara secondaire à une mutation d'aimp1 WO2022017931A1 (fr)

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Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2015193668A1 (fr) * 2014-06-17 2015-12-23 Gw Pharma Limited Utilisation de cannabidiol dans le traitement de l'épilepsie
GB2539472A (en) * 2015-06-17 2016-12-21 Gw Res Ltd Use of cannabinoids in the treatment of epilepsy

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2015193668A1 (fr) * 2014-06-17 2015-12-23 Gw Pharma Limited Utilisation de cannabidiol dans le traitement de l'épilepsie
GB2539472A (en) * 2015-06-17 2016-12-21 Gw Res Ltd Use of cannabinoids in the treatment of epilepsy

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AGUIRRE-VELAZQUEZ: "Report from a Survey of Parents Regarding the Use of Cannabidiol (Medicinal cannabis) in Mexican Children with Refractory Epilepsy", NEUROLOGY RESEARCH INTERNATIONAL. V, 2017
ANONYMOUS: "Local says medical marijuana saved daughter's life", 18 August 2016 (2016-08-18), XP055854481, Retrieved from the Internet <URL:https://www.airdrietoday.com/local-news/local-says-medical-marijuana-saved-daughters-life-1417299> [retrieved on 20211025] *
GUPTA ET AL.: "Rare homozygous nonsense variant in AIMP1 causing Early Onset Epileptic Encephalopathy with Burst Suppression (EOEE-BS", EUROPEAN JOURNAL OF MEDICAL GENETICS, 2020
GUPTA SIDDHARTH ET AL: "Rare homozygous nonsense variant in AIMP1 causing Early Onset Epileptic Encephalopathy with Burst Suppression (EOEE-BS)", EUROPEAN JOURNAL OF MEDICAL GENETICS, ELSEVIER, NL, vol. 63, no. 9, 10 June 2020 (2020-06-10), XP086247122, ISSN: 1769-7212, [retrieved on 20200610], DOI: 10.1016/J.EJMG.2020.103970 *
MASATAKA ET AL.: "Report of a 6 month old Asian infant with early-infantile epileptic encephalpathy whose seizures were eliminated by cannabidiol", EPILEPSY & BEHAVIOR REPORTS, 2020
MASATAKA YUJI ET AL: "Report of a 6-month-old Asian infant with early infantile epileptic encephalopathy whose seizures were eliminated by cannabidiol", EPILEPSY & BEHAVIOR REPORTS, vol. 14, 1 January 2020 (2020-01-01), pages 100373, XP055854476, ISSN: 2589-9864, DOI: 10.1016/j.ebr.2020.100373 *
SZAFLARSKI: "Long-term safety and treatment effects of cannabidiol in children and adults with treatment-resistant epilepsies", EPILEPSIA, vol. 59, 2018, pages 1540 - 1548
VON DEIMLING: "Epileptic encephalopathies - clinical syndromes and pathophysiological concepts", CURR NEUROL NEUROSCI REP, vol. 17, 2017, pages 10

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