GB2597314A - Use of cannabidiol in the treatment of seizures associated with rare epilepsy syndromes related to genetic abnormalities - Google Patents
Use of cannabidiol in the treatment of seizures associated with rare epilepsy syndromes related to genetic abnormalities Download PDFInfo
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Abstract
A cannabidiol (CBD) preparation for use in the treatment of seizures associated with CASK related disorders. The seizures can be spasms. The CBD preparation can comprise greater than 95% (w/w) CBD and not more than 0.15% (w/w) tetrahydrocannabinol (THC). The CBD preparation can comprise less than or equal to 2% (w/w) other cannabinoids comprising THC, cannabidiol C-1 (CBD-C1), cannabidivarin (CBDV), or cannabidiol C-4 (CBD-C4). The THC can be present as a mixture of trans-THC and cis-THC. The CBD preparation can be used in combination with other anti-epileptic drugs (AED). The AED can be clobazam, vigabatrin, and lacosamide. The CBD can be isolated from cannabis plant material. The CBD can be present as a synthetic preparation. The CBD preparation can be used at a dose greater than 5 mg/kg/day (e.g. 20, 25, or 50 mg/kg/day). A further aspect of the invention is a method of treating seizures associated with CASK related disorders comprising administering a CBD preparation to a subject.
Description
USE OF CANNABIDIOL IN THE TREATMENT OF SEIZURES ASSOCIATED WITH RARE
EPILEPSY SYNDROMES RELATED TO GENETIC ABNORMALITIES
FIELD OF THE INVENTION
[0001] The present invention relates to the use of cannabidiol (CBD) for the treatment of seizures associated with rare epilepsy syndromes. In particular the seizures associated with rare epilepsy syndromes that are treated are those which are experienced in patients diagnosed with CASK-related disorders. In a further embodiment the types of seizures include spasms. Preferably the dose of CBD is between 5 mg/kg/day to 50 mg/kg/day.
[0002] In a further embodiment 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).
[0003] Preferably 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.
[0004] Where the CBD is given concomitantly with one or more other anti-epileptic drugs (AED), 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.
BACKGROUND TO THE INVENTION
[0005] 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 (AED). However, 30% of this patient group, (Eadie et aL, 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).
[0006] Intractable or treatment-resistant epilepsy was defined in 2009 by the International League Against Epilepsy (ILAE) as "failure of adequate trials of two tolerated and appropriately 35 chosen and used AED schedules (whether as monotherapies or in combination) to achieve sustained seizure freedom" (Kwan et al., 2009).
[0007] Individuals who develop epilepsy during the first few years of life are often difficult to treat and as such are often termed treatment resistant. Children who undergo frequent seizures in childhood are often left with neurological damage which can cause cognitive, behavioral and motor delays.
[0008] 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.
[0009] 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.
[0010] The main symptom of epilepsy is repeated seizures. In order to determine the type of epilepsy or the epileptic syndrome that a patient is suffering from 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 ILEA classification.
[0011] Generalized seizures, where the seizure arises within and rapidly engages bilaterally distributed networks, can be split into six subtypes: tonic-clonic (grand map seizures; absence (petit mal) seizures; clonic seizures; tonic seizures; atonic seizures and myoclonic 20 seizures.
[0012] Focal (partial) seizures where the seizure originates within networks limited to only one hemisphere, are also split into sub-categories. Here the seizure is characterized according to one or more features of the seizure, including aura, motor, autonomic and awareness! responsiveness. Where 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).
[0013] 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.
[0014] CASK-related disorders are a group of genetic disorders that affect brain development. The two main related conditions are microcephaly with pontine and cerebellar hypoplasia and X-linked intellectual disability with or without nystagmus.
[0015] CASK-related disorders are caused by mutations in the CASK gene and are inherited in an X-linked manner. Males with these disorders usually have more severe symptoms than females.
[0016] The CASK gene encodes calcium/calmodulin-dependent serine protein kinase (CASK) protein, which is found in neurons in the brain and is involved in regulating the activity of other genes involved in brain development and neurotransmitter movement.
[0017] Symptoms appear in infancy and typically progress over time. Symptoms include autism spectrum disorders, intellectual disability, epilepsy disorders, seizures, microcephaly with ponfine and cerebellar hypoplasia, delayed growth, vision and hearing issues, and low muscle tone.
[0018] Treatment is focused on alleviating symptoms and may include medication to control seizures, nutritional support, hearing and vision aids, and physical therapy.
[0019] Cannabidiol (CBD), a non-psychoactive derivative from the cannabis plant, has demonstrated anti-convulsant properties in several anecdotal reports, pre-clinical and clinical studies both in animal models and humans. Three randomized control trials showed efficacy of the purified pharmaceutical formulation of CBD in patients with Dravet and Lennox-Gastaut syndrome.
[0020] Based on these three trials, a botanically derived purified CBD preparation was approved by FDA in June 2018 for the treatment of seizures associated with Dravet and Lennox-Gastaut syndromes.
[0021] The applicant has found by way of an open label, expanded-access program that treatment with CBD resulted in a significant reduction in spasms in patients with CASK-related 20 disorders.
BRIEF SUMMARY OF THE DISCLOSURE
[0022] In accordance with a first aspect of the present invention there is provided a cannabidiol (CBD) preparation for use in the treatment of seizures associated with CASK-related disorders.
[0023] In a further embodiment, the seizures associated with CASK-related disorders are spasms.
[0024] In a further embodiment, the CBD preparation comprises greater than 95% (w/w) CBD and not more than 0.15% (w/w) tetrahydrocannabinol (THC).
[0025] Preferably 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); cannabidiolC1 (CBD-C1); cannabidivarin (CBDV); and cannabidiol-C4 (CBD-C4), and wherein the THC is present as a mixture of trans-THC and cis-THC.
[0026] Preferably the CBD preparation is used in combination with one or more concomitant anti-epileptic drugs (AED).
[0027] Preferably the one or more AED is selected from the group consisting of: clobazam, vigabatrin and lacosamide.
[0028] In one embodiment the CBD is present is isolated from cannabis plant material.
Preferably at least a portion of at least one of the cannabinoids present in the CBD preparation is isolated from cannabis plant material.
[0029] In a further embodiment the CBD is present as a synthetic preparation. Preferably at least a portion of at least one of the cannabinoids present in the CBD preparation is prepared synthetically.
[0030] Preferably 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.
[0031] In accordance with a second aspect of the present invention there is provided a method of treating seizures associated with CASK-related disorders comprising administering a cannabidiol (CBD) preparation to the subject in need thereof.
DEFINITIONS
[0032] Definitions of some of the terms used to describe the invention are detailed below: [0033] 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).
[0034] "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.
[0035] "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.
[0036] "Synthetic cannabinoids" are compounds that have a cannabinoid or cannabinoid-like structure and are manufactured using chemical means rather than by the plant.
[0037] 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.
[0038] "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.
[0039] "Epileptic spasm", "spasms", "infantile spasm", "juvenile spasm" or "West syndrome" is defined as sudden flexion, extension or mixed flexion-extension of proximal and truncal muscles, lasting 1-2 seconds. Spasms typically occur in a series, usually on wakening. Subtle forms may occur with only chin movement, grimacing, or head nodding. Spasms may be bilaterally symmetric, asymmetric, or unilateral, depending on whether they are generalised onset or focal onset.
DETAILED DESCRIPTION
PREPARATION OF HIGHLY PURIFIED CBD EXTRACT
[0040] The following describes the production of the highly-purified (>95% w/w) cannabidiol extract which has a known and constant composition.
[0041] In summary 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 95% CBD. Although the 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 quantifies in which they are present in the medication are as described in Table A below.
Table A: Composition of high y purified CBD extract Cannabinoid Concentration CBD > 95% w/w CBDA NMT 0.15% w/w CBDV N MT 1.0% w/w A' TEC NMT 0.15% w/w CBD-C4 NMT 0.5% w/w > -greater than NMT -not more than
PREPARATION OF BOTANICALLY DERIVED PURIFIED CBD
[0042] The following describes the production of the botanically derived purified CBD which comprises greater than or equal to 98% w/w CBD and less than or equal to other cannabinoids was used in the open label, expanded-access program described in Example 1 below.
[0043] In summary 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.
[0044] The 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).
[0045] 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.
[0046] All parts of the process are controlled by specifications. The botanical raw material specification is described in Table B and the CBD API is described in Table C.
Table B: CBD botanical raw material specification
Test Method Specification
Identification: Visual TLC Complies -A HPLC/UV Corresponds to standard (for CBD & CBDA) Positive for CBDA
-B
-C
Assay: In-house (HPLC/UV) NLT 90% of assayed CBDA + CBD cannabinoids by peak area Loss on Drying Ph.Eur. NMT 15% Aflatoxin UKAS method NMT 4ppb Microbial: -TVC -Fungi -E.coli Ph.Eur. NMT107cfu/g NMT105cfu/g NMT102cfu/g Foreign Matter: Ph.Eur. NMT 2% Residual Herbicides and Pesticides Ph.Eur. Complies Table C: Specification of an exemplary botanically derived purified CBD preparation Test Test Method Limits Appearance Visual Off-white / pale yellow crystals Identification A HPLC-UV Retention time of major peak corresponds to certified CBD Reference Standard Identification B GC-FID/MS Retention time and mass spectrum of major peak corresponds to certified CBD Reference Standard Identification C FT-IR Conforms to reference spectrum for certified CBD Reference Standard Identification D Melting Point 65 -67°C Identification E Specific Optical Conforms with certified CBD Reference Rotation Standard; -110° to -140° (in 95% ethanol) Total Purity Calculation 98.0% Chromatographic Purity 1 HPLC-UV 98.0% Chromatographic Purity 2 GC-FID/MS 98.0 % CBDA HPLC-UV NMT 0.15% w/w NMT 1.0% w/w NMT 0.1% w/w NMT 0.5% w/w
CBDV
THC
CBD-C4 Residual Solvents: GC NMT 0.5% w/w Alkane NMT 0.5% w/w Ethanol Residual Water Karl Fischer NMT 1.0% w/w [0047] 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., 5 CBDA, CBDV, CBD-C1, and CBD-C4.
[0048] 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.
Production of CBD botanical drug substance [0049] An overview of the steps to produce a botanical extract, the intermediate, are as follows: a) Growing b) Direct drying c) Decarboxylation d) Extraction -using liquid CO2 e) Winterization using ethanol f) Filtration O) Evaporation [0050] 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.
[0051] Decarboxylation of CBDA to CBD was carried out using heat. BRM was decarboxylated at 115°C for 60 minutes.
[0052] Extraction was performed using liquid CO2 to produce botanical drug substance (BDS), which was then crystalized to produce the test material. The crude CBD BDS was winterized to refine the extract 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 removed to yield the BDS.
Production of botanically derived purified CBD preparation [0053] The manufacturing steps to produce the botanically derived purified CBD preparation from BDS were as follows: a) Crystallization using C5-C12 straight chain or branched alkane b) Filtration c) Vacuum drying [0054] 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.
Physicochemical properties of the botanically derived purified CBD [0055] 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).
[0056] 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 (transTHC:cis-THC) in its unrefined decarboxylated state to 0.8:1 (trans-THC:cis-THC) when highly purified.
[0057] 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.
[0058] Clearly a CBD preparation could be produced synthetically by producing a composition with duplicate components.
[0059] Example 1 below 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 CASK-related disorders.
EXAMPLE 1: CLINICAL EFFICACY AND SAFETY OF PURIFIED PHARMACEUTICAL CANNABIDIOL (CBD) IN THE TREATMENT OF PATIENTS DIAGNOSED WITH CASK RELATED DISORDERS Study design [0060] The subject was 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.
[0061] The patient was administered botanically derived purified CBD in a 100 mg/mL sesame oil-based solution at an initial dose of 15 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 25 mg/kg/day.
[0062] A maximum dose of 50 mg/kg/day could be utilised for the patient if they were tolerating the medication but had not achieved seizure control; the patient had further weekly titration by 5mg/kg/day.
[0063] There was one patient in this study, and they received CBD for 132 weeks. Modifications were made to concomitant AEDs as per clinical indication.
[0064] 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.
Statistical Methods: [0065] 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 interva/)-(weekly seizure frequency Baseline)) x100 seizure (weekly seizure frequency Baseline) frequency [0066] The percent change of seizure frequency may be calculated for any time interval where seizure number has been recorded. For the purpose of this example 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) Results
Patient description
[0067] One patient enrolled in the open label, expanded-access program was diagnosed with CASK-related disorder. The patient experienced spasms and was taking several concomitant AEDs.
[0068] The patient was 8 years old and she was female as detailed in Table 1 below.
Table 1: Patient demographics, seizure type and concomitant medication Patient Age Sex Seizure types Concomitant AEDs Number (years) 1 8.24 F Spasms CLB, [CS, VGB CLB = clobazam, VGB = vigabatrin, LCS = lacosamide Study medication and concomitant medications [0069] The patient on the study was titrated up to 25 mg/kg/day of CBD. The patient was on three concomitant AEDs at the time of starting CBD.
Clinical changes [0070] Table 2 illustrates the seizure frequency for the patient as well as the dose of CBD given Table 2: Seizure frequency data for Patient 1 Patient 1 Time Seizure Type Dose CBD (mg/kg/day) Spasms Baseline 90.8 2 weeks 59.7 15.0 4 weeks 43.1 20.0 8 weeks 58.6 25.0 16 weeks 56.0 25.0 24 weeks 74.8 25.0 36 weeks 102.7 20.0 48 weeks 92.6 20.0 96 weeks 46.9 17.0 132 weeks 0.0 18.0 [0071] Patient 1 was treated for 132 weeks and experienced a 100% reduction in spasms over the treatment period.
[0072] Significantly, the patient became completely seizure free after 132 weeks of treatment with CBD.
Conclusions
[0073] These data indicate that CBD was able to significantly reduce the number of seizures associated with CASK-related disorders. Clearly the treatment is of significant benefit in this difficult to treat epilepsy syndrome given the high response rate experienced in the patient.
[0074] In conclusion, this study signifies the use of CBD for treatment of seizures associated with CASK-related disorders. Seizure types include spasms for which seizure frequency rates decreased significantly, by 100%.
Claims (15)
- CLAIMS1. A cannabidiol (CBD) preparation for use in the treatment of seizures associated with CASK-related disorders.
- A CBD preparation for use according to claim 1, wherein the seizures associated with CASK-related disorders are spasms.
- A CBD preparation for use according to any of the preceding claims, wherein the CBD preparation comprises greater than 95% (w/w) CBD and not more than 0.15% (w/w) tetrahydrocannabinol (THC).
- A CBD preparation for use according to any of the preceding claims, wherein 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-04 (CBD-C4), and wherein the THC is present as a mixture of trans-THC and cis-THC.
- A CBD preparation to any of the preceding claims, wherein the CBD preparation is used in combination with one or more concomitant anti-epileptic drugs (AED).
- A CBD preparation for use according to claim 5, wherein the one or more AED is selected from the group consisting of: clobazam, vigabatrin and lacosamide.
- A CBD preparation for use according to any of the preceding claims, wherein the CBD is present is isolated from cannabis plant material.
- A CBD preparation for use according to any of the preceding claims, wherein at least a portion of at least one of the cannabinoids present in the CBD preparation is isolated from cannabis plant material.
- A CBD preparation for use according to claims 1 to 6, wherein the CBD is present as a synthetic preparation.
- A CBD preparation for use according to claim 9, wherein at least a portion of at least one of the cannabinoids present in the CBD preparation is prepared synthetically. 3. 4. 5. 6. 8. 9. 10.
- 11. A CBD preparation for use according to any of the preceding claims, wherein the dose of CBD is greater than 5 mg/kg/day.
- 12. A CBD preparation for use according to any of the preceding claims, wherein the dose of CBD is 20 mg/kg/day.
- 13. A CBD preparation for use according to any of the preceding claims, wherein the dose of CBD is 25 mg/kg/day.
- 14. A CBD preparation for use according to any of the preceding claims, wherein the dose of CBD is 50 mg/kg/day.
- 15. A method of treating seizures associated with CASK-related disorders comprising administering a cannabidiol (CBD) preparation to the subject in need thereof.
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| US20190091174A1 (en) * | 2017-09-26 | 2019-03-28 | Zogenix International Limited | Method of reducing seizure type experienced by a dravet patient |
| US20190247333A1 (en) * | 2017-09-26 | 2019-08-15 | Zogenix International Limited | Method of reduction in convulsive seizure frequency |
| WO2020105005A1 (en) * | 2018-11-19 | 2020-05-28 | Zogenix International Limited | Methods of treating rett syndrome using fenfluramine |
| WO2020112460A1 (en) * | 2018-11-30 | 2020-06-04 | Zogenix International Limited | A method of treating refractory epilepsy syndromes using fenfluramine enantiomers |
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| US20190247333A1 (en) * | 2017-09-26 | 2019-08-15 | Zogenix International Limited | Method of reduction in convulsive seizure frequency |
| WO2020105005A1 (en) * | 2018-11-19 | 2020-05-28 | Zogenix International Limited | Methods of treating rett syndrome using fenfluramine |
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