Cannibidiol in combination with cenobamate for use in treating seizures

Abstract

The present disclosure relates to methods for treating seizures in a subject in need thereof, more particularly to methods involving administration of a therapeutically effective amount of cannabidiol, or a pharmaceutically acceptable salt thereof, in combination with a therapeutically effective amount of cenobamate, or a pharmaceutically acceptable salt thereof. The disclosure also relates to said combination for use as a medicament for the treatment of seizures; and to kits comprising a pharmaceutical composition comprising cannabidiol, or a pharmaceutically acceptable salt thereof, and a pharmaceutical composition comprising a cenobamate, or a pharmaceutically acceptable salt thereof.

Description

COMBINATION THERAPYFIELD OF THE INVENTION

[0001] The present invention relates to methods for treating seizures in a subject in need thereof, more particularly to methods involving administration of a therapeutically effective amount of cannabidiol, or a pharmaceutically acceptable salt thereof, in combination with a therapeutically effective amount of cenobamate, or a pharmaceutically acceptable salt thereof. The invention also relates to said combination for use as a medicament for the treatment of seizures; and to kits comprising a pharmaceutical composition comprising cannabidiol, or a pharmaceutically acceptable salt thereof, and a pharmaceutical composition comprising a cenobamate, or a pharmaceutically acceptable salt thereof.BACKGROUND TO THE INVENTION

[0002] Epilepsy is a disabling neurological disorder, characterized by a predisposition to epileptic seizures caused by abnormal, excessive, or synchronous neuronal activity in the brain. People with epilepsy may experience a substantially impaired quality of life as a result of seizures, comorbid mood and psychiatric disorders, cognitive deficits and the adverse effects of epilepsy medication [Devinsky et al, 2018], Furthermore, seizures can be fatal, either directly due to effects on autonomic and arousal functions, or indirectly due to accidents such as drowning, or motor vehicle accidents.

[0003] Epilepsy is reported to affect 65 million people worldwide [Devinsky et al, 2018], with a lifetime prevalence of 7.6 per 1 ,000 people [Fiest et al, 2017], Whilst the prevalence does not appear to differ by age group or sex, the prevalence and incidence rate of epilepsy are higher in low to middle income countries [Fiest et al, 2017],

[0004] The causes of epilepsy include acquired structural changes to the brain (e.g. as a result of traumatic brain injury, brain tumour, or stroke), infectious diseases (e.g. viral or bacterial disorders), and genetic mutations.

[0005] The International League Against Epilepsy (I LAE) epilepsy classification framework begins with the diagnosis of the type of epileptic seizure and assumes that nonepileptic events have been ruled out. The classification proposes a three-level classification approach for a patient presenting with epileptic seizures, wherein the first level is seizure type, the second level is epilepsy type and the third level is an epilepsy syndrome diagnosis [Scheffer et al, 2017],

[0006] Seizure type classification begins with the determination of whether the initial manifestations of the seizure are of focal onset or generalised onset. If the onset is missed or obscured the seizure is categorised as being of unknown onset [Fisher et al, 2017], Focal onset seizures may be further defined according to the level of awareness and all threeseizure types (focal, generalised and unknown) may be further characterised by motor or nonmotor onset symptoms.

[0007] Epilepsy type classification divides into focal epilepsies, generalised epilepsies, combined generalised & focal epilepsies, and unknown epilepsies. Focal epilepsies include unifocal and multifocal disorders as well as seizures involving one hemisphere. For a diagnosis of Generalised Epilepsy, the patient would typically show generalised spike-wave activity on EEG. Individuals with generalised epilepsies may have a range of seizure types including absence, myoclonic, atonic, tonic, and tonic-clonic seizures. Combined Generalised and Focal Epilepsies covers patients who have both generalised and focal seizures, whereas unknown epilepsies covers situations where the patient has epilepsy but the clinician is unable to determine if the epilepsy type is focal or generalised, because there is insufficient information available [Scheffer et al., 2017],

[0008] An epilepsy syndrome refers to a characteristic cluster of clinical and EEG features, often supported by specific etiological findings (structural, genetic, metabolic, immune, and infectious) [Wirrell et al., 2022], The epilepsy syndrome groups include syndromes with onset in neonates and infancy (up to 24 months of age); syndromes with onset in childhood; syndromes with onset at a variable age; and idiopathic generalised epilepsy syndromes (IGEs). The syndrome groups may also encompass self-limited epilepsies, developmental and epileptic encephalopathies (DEE) and aetiology-specific syndromes.

[0009] Examples of neonate and infant epilepsy syndromes include self-limited neonatal epilepsy, infantile epileptic spasms syndrome, Dravet syndrome, glucose transporter 1 deficiency syndrome and Sturge Weber syndrome [Zuberi et al., 2022],

[0010] Examples of syndromes with onset in childhood include childhood occipital visual epilepsy (COVE), Lennox-Gastaut syndrome (LGS), epilepsy with myoclonic atonic seizures (previously known as Doose syndrome) and epilepsy with eyelid myoclonia (previously known as Jeavons syndrome) [Specchio et al., 2022],

[0011] Examples of syndromes with onset at a variable age include sleep-related hypermotor / hyperkinetic epilepsy (SHE), progressive myoclonus epilepsies (PME), febrile- infection related epilepsy syndrome (FIRES) and Rasmussen syndrome [Riney et al., 2022],

[0012] Idiopathic generalised epilepsy syndromes (IGEs) include childhood absence epilepsy (CAE), juvenile absence epilepsy (JAE), juvenile myoclonic epilepsy (JME), and epilepsy with generalised tonic-clonic seizures alone (GTCA) [Hirsch et al., 2022],

[0013] In terms of the management of epilepsy, options include anti-seizure drugs (ASDs), dietary therapies, neurostimulation and surgery. ASDs are the primary therapy for epilepsy and aim to reduce the seizure occurrence and severity. Over 20 ASDs have been approved for clinical use. Strict patient adherence to their ASD treatment regimen is important, as ASDs must be taken between one and four times daily and a single missed dose can lead to recurrence of seizures [Devinsky et al, 2018],

[0014] Cannabidiol is one such ASD. In 2018, cannabidiol (Epidiolex®) was approved in the United States for the treatment of seizures associated with Dravet syndrome or Lennox- Gastaut syndrome in patients 2 years of age and older. Cannabidiol (Epidiolex®) has since been approved in the United States for the treatment of seizures associated with Lennox- Gastaut syndrome, Dravet syndrome, or tuberous sclerosis complex in patients 1 year of age and older. Cannabidiol is a naturally occurring cannabinoid compound derived from cannabis species, such as the hemp plant (Cannabis sativa). Unlike other cannabinoids, such as tetrahydrocannabinol, cannabidiol does not bind to CB1 or CB2 receptors (or its binding to the receptors is negligible in terms of inducing a pharmacological effect) and it does not induce the psychotropic effects associated with cannabis.

[0015] Despite the wide range of ASDs available, approximately one-third of patients do not achieve seizure control, no matter how many ASDs are tried as monotherapy or in combination [Devinsky et al, 2018], Drug- or treatment-resistant epilepsy is associated with increased risk of injury and death, greater medication burden and adverse effects, and reduced quality-of-life. For these patients, surgery offers the greatest chance of achieving long-term seizure control, but only a minority of patients are good candidates for surgery. Clearly, alternative treatment methods for seizures are desirable.

[0016] The present invention was devised with the foregoing in mind.SUMMARY OF THE INVENTION

[0017] In a first aspect of the present invention, there is provided a method of treating seizures in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of cannabidiol, or a pharmaceutically acceptable salt thereof, in combination with a therapeutically effective amount of cenobamate, or a pharmaceutically acceptable salt thereof.

[0018] Achieving a desirable level of seizure control in a subject requires treatment with an ASD that exhibits a sufficient level of efficacy against the seizure type(s) experienced by the subject. Attempts to improve seizure control, e.g. reduce seizure occurrence and / or severity, by increasing the dose of an ASD and / or by introducing multiple ASDs can be unpredictable and are often unsuccessful. Such approaches can also lead to an increased incidence of adverse drug reactions. Indeed, taking more than one ASD often significantly increases the risk of unwanted side effects. Unfortunately, a substantial portion of patients with epilepsy need to discontinue ASD treatment because of intolerable side effects, diminishing their ability to achieve seizure control.

[0019] The applicants have surprisingly found that cannabidiol and cenobamate exhibit a positive pharmacodynamic drug-drug interaction in respect to the suppression of seizures in a mouse model. Moreover, the interaction is supra-additive (synergistic). Thus, this improved therapeutic effect provides the potential for improved seizure control, e.g., a reduction in the number and / or the severity of seizures, as compared to the effect of cannabidiol or cenobamate when administered independently. In certain embodiments, thecombination may also allow cannabidiol or cenobamate, or even both drugs, to be administered to reduce seizures (number and / or severity) at lower doses and / or reduced dosing frequencies when compared to either drug when administered independently.

[0020] The applicants have also found that the combination of cannabidiol and cenobamate is well tolerated. The evaluation of the combination of cannabidiol and cenobamate on motor coordination using an accelerating rotarod model in mice showed no impact on motor coordination and balance, thereby indicating a lack of CNS-related adverse effects such as somnolence, sedation or other muscle coordination related side effects. Moreover, co-administration of multiple doses (7.5 mg / kg BID) of a cannabidiol oral solution and 200 mg once daily cenobamate was also well tolerated by healthy participants in a phase 1 , open-label, human clinical study.

[0021] In a second aspect of the present invention, there is provided a method of treating seizures in a subject in need thereof, wherein the method comprises the steps of: a. administering to the subject a starting dosage of cannabidiol, or a pharmaceutically acceptable salt thereof, for a first period of time; b. after the first period of time, increasing the dosage of cannabidiol, or a pharmaceutically acceptable salt thereof, to achieve a maintenance dosage for a second period of time; c. after the second period of time, reducing the maintenance dosage of cannabidiol, or a pharmaceutically acceptable salt thereof, by up to 4-fold for a third period of time; and d. after the third period of time, administering cenobamate, or a pharmaceutically acceptable salt thereof; wherein optionally steps c. and d. are carried out concurrently.

[0022] In a third aspect of the present invention, there is provided a method of treating seizures in a subject in need thereof, wherein the method comprises the steps of: a. administering to the subject a starting dosage of cenobamate, or a pharmaceutically acceptable salt thereof, for a first period of time; b. after the first period of time, increasing the dosage of cenobamate, or a pharmaceutically acceptable salt thereof, to achieve a maintenance dosage for a second period of time; c. after the second period of time, reducing the maintenance dosage of cenobamate, or a pharmaceutically acceptable salt thereof, by up to 4-fold for a third period of time; and d. after the third period of time, administering cannabidiol, or a pharmaceutically acceptable salt thereof; wherein optionally steps c. and d. are carried out concurrently.

[0023] In a fourth aspect of the invention, there is provided a method of initiating treatment with cenobamate, or a pharmaceutically acceptable salt thereof, in a subject who is suffering from seizures and who is already being treated with cannabidiol, or a pharmaceutically acceptable salt thereof, the method comprising the steps of: a. administering a starting dosage of cenobamate, or a pharmaceutically acceptable salt thereof, to the subject for a first period; b. optionally, increasing the dosage of cenobamate, or a pharmaceutical acceptable salt thereof, following a cenobamate titration regimen for a cenobamate titration period; and c. administering a reduced maintenance dosage of cenobamate, or a pharmaceutically acceptable salt thereof, to the subject, wherein, the reduced maintenance dosage of cenobamate, or a pharmaceutically acceptable salt thereof, is reduced in comparison to treatment with cenobamate independently.

[0024] In a fifth aspect of the present invention, there is provided a method of initiating treatment with cannabidiol, or a pharmaceutically acceptable salt thereof, in a subject who is suffering from seizures and who is already being treated with cenobamate, or a pharmaceutically acceptable salt thereof, the method comprising the steps of: a. administering a starting dosage of cannabidiol, or a pharmaceutically acceptable salt thereof, to the subject for a first period; b. optionally, increasing the dosage of cannabidiol, or a pharmaceutical acceptable salt thereof, following a cannabidiol titration regimen for a cannabidiol titration period; and c. administering a reduced maintenance dosage of cannabidiol, or a pharmaceutically acceptable salt thereof, to the subject, wherein the reduced maintenance dosage of cannabidiol, or a pharmaceutically acceptable salt thereof, is reduced in comparison to treatment with cannabidiol independently.

[0025] In a sixth aspect of the invention, there is provided a method of initiating treatment with cenobamate, or a pharmaceutically acceptable salt thereof, in a subject who is suffering from seizures and who is already being treated with cannabidiol, or a pharmaceutically acceptable salt thereof, the method comprising the steps of: a. reducing the dosage of cannabidiol, or a pharmaceutically acceptable salt thereof, being administered to the subject; b. administering a reduced maintenance dosage of cannabidiol, or a pharmaceutically acceptable salt thereof, to the subject; and c. administering a starting dosage of cenobamate, or a pharmaceutically acceptable salt thereof to the subject.

[0026] In a seventh aspect of the invention, there is provided a method of initiating treatment with cannabidiol, or a pharmaceutically acceptable salt thereof, in a subject who issuffering from seizures and who is already being treated with cenobamate, or a pharmaceutically acceptable salt thereof, the method comprising the steps of: a. reducing the dosage of cenobamate, or a pharmaceutically acceptable salt thereof, being administered to the subject; b. administering a reduced maintenance dosage of cenobamate, or a pharmaceutically acceptable salt thereof, to the subject; and c. administering a starting dosage of cannabidiol, or a pharmaceutically acceptable salt thereof to the subject.

[0027] In an eighth aspect of the present invention, there is a provided a pharmaceutical composition comprising cannabidiol, or a pharmaceutically acceptable salt thereof, together with one or more pharmaceutically acceptable ingredients, for use in a method according to the first, second, third, fourth, fifth, sixth or seventh aspects.

[0028] In a ninth aspect of the present invention, there is provided a pharmaceutical composition comprising cenobamate, or a pharmaceutically acceptable salt thereof, together with one or more pharmaceutically acceptable ingredients, for use in a method according to the first, second, third, fourth, fifth, sixth or seventh aspects.

[0029] In a tenth aspect of the invention, there is provided a kit comprising a pharmaceutical composition comprising cannabidiol, or a pharmaceutically acceptable salt thereof, for oral administration and a pharmaceutical composition comprising cenobamate, or a pharmaceutically acceptable salt thereof, wherein said kit is for use in a combination therapy as defined in the first, second, third, fourth, fifth, sixth or seventh aspects.

[0030] These and other aspects and embodiments of the invention are described in further detail below.BRIEF DESCRIPTION OF THE DRAWINGS

[0031] Embodiments of the invention are further described hereinafter with reference to the accompanying drawings, in which:

[0032] Figure 1 shows the dose-dependent effects of cannabidiol and cenobamate on MES in mouse. *p<0.05,***p<0.001 and ****p<0.0001 significant inhibition of tonic hindlimb seizures when compared to 1 :1 :18 vehicle control group (Fisher’s Exact test; n=10, i.p.). Bars plotted for reference control, VPA (grey), cannabidiol (green) and cenobamate (pink).

[0033] Figure 2 shows the log(dose)-probit(anticonvulsive efficacy) analysis to determine accurate values of ED50. Linear regression equations were used to determine ED50 values of cannabidiol and cenobamate. Data points for cannabidiol (green circles) and cenobamate (pink squares) (MES; n=10, i.p.).

[0034] Figure 3 shows the log(brain exposure)-probit(anticonvulsant efficacy) analysis to determine accurate values of b-EEso. Linear regression equations were used to determineb-EE5o values of cannabidiol and cenobamate. Data points for cannabidiol (green circles) and cenobamate (pink squares) (MES; n=10, i.p.).

[0035] Figure 4 shows the linear dose-exposure relationships based on post MES test bioanalysis of brain and plasma samples from mouse treated with (top figures) cannabidiol and (bottom figures) cenobamate. The R2values>0.9. Data points for cannabidiol (green solid circles), 7-hydroxy-cannabidiol (green open circles, dashed line) and cenobamate (pink solid squares) (MES; n=10, i.p.).

[0036] Figure 5 shows the linear relationships of cannabidiol and cenobamate doses versus median brain exposures using mouse brain samples post-MES efficacy test. Data points for cannabidiol (green circles) and cenobamate (pink squares) (MES; n=10; i.p.).

[0037] Figure 6 shows the anticonvulsive efficacies of cannabidiokcenobamate ratio-dose combinations in the mouse MES. *p<0.05 significant inhibition of tonic hindlimb seizures when compared to 1 :1 :18 vehicle group (Fisher’s Exact test). Bars are plotted for cannabidiol (green), cenobamate (pink), cannabidiokcenobamate (green and pink) (MES; n=10, i.p.).

[0038] Figure 7 shows the isobolographic quantitative DDI analysis using non-constant ratios of cannabidiokcenobamate (b-EEso+ADD) at 1 :3, 1 :1 and 3:1. (A) All data points, brain exposures of parent plus any active metabolite normalized to parent drug potency, depict synergism on the isobologram, being under the theoretical line of additivity (purple). Synergy also quantified by (B) Combination Index <1 and Exposure Reduction Index >1. Descriptors for moderate synergism (++) and synergism (+++) [Chou et al., 2006, and Chou et al., 2010],

[0039] Figure 8 shows that cannabidiokcenobamate coadministration at (b-EEso+ADD) 1 :3, 1 :1 and 3:1 ratios resulted in no PK DDI. Overall brain exposures of (A) [cannabidiol + 7- hydroxy-cannabidiol] and (B) [cenobamate] compared with / out coadministration (Kruskall- Wallis and Dunn’s comparison tests; data (n=10; i.p.) for cannabidiol (green) and cenobamate (pink) presented as box (median / interquartile range) and whisker (minimum and maximum) plots). PK changes are indicated in the direction of the single ASM versus the combination therapy.

[0040] Figure 9 shows a plot of Mean (+ SD) CBD Plasma Concentration Versus Time.

[0041] Figure 10 shows a plot of Mean (+ SD) CNB Plasma Concentrations Versus Time.

[0042] Figure 11 shows a forest Plot of 90% Confidence Intervals of GLSM Ratios forDrug-Drug Interaction (CNB on CBD and its Metabolites). Note: The dose level for CBD-OS was 7.5 mg / kg BID. The dose level for CNB was 200 mg once daily.

[0043] Figure 12 shows a forest Plot of 90% Confidence Intervals of GLSM Ratios for Drug-Drug Interaction (CBD-OS on CNB and its Metabolite). Note: The dose level for CBD- OS was 7.5 mg / kg BID. The dose level for CNB was 200 mg once daily.DETAILED DESCRIPTION OF THE INVENTION

[0044] The present invention relates to methods for treating seizures in a subject in need thereof, the method comprising administering a therapeutically effective amount of cannabidiol, or a pharmaceutically acceptable salt thereof, in combination with a therapeutically effective amount of cenobamate, or a pharmaceutically acceptable salt thereof. The inventors have shown that such a combination provides an improved anticonvulsant effect in a mouse model of generalised seizure in comparison to treatment with either component alone. Accordingly, the inventors believe that treatment with such a combination may provide an improved therapeutic effect in comparison to treatment with either component independently. Moreover, the applicants have also found that the combination of cannabidiol and cenobamate is well tolerated. The evaluation of the combination of cannabidiol and cenobamate on motor coordination using an accelerating rotarod model in mice showed no impact on motor coordination and balance, thereby indicating a lack of CNS-related adverse effects such as somnolence, sedation or other muscle coordination related side effects. Co-administration of multiple doses (7.5 mg / kg BID) of a cannabidiol oral solution and 200 mg once daily cenobamate was also well tolerated by healthy participants in a phase 1 , open-label, human clinical study.Combination Therapy

[0045] In a first aspect, the invention provides a method of treating seizures in a subject in need of treatment, the method comprising administering to the subject a therapeutically effective amount of cannabidiol, or a pharmaceutically acceptable salt thereof, in combination with a therapeutically effective amount of cenobamate, or a pharmaceutically acceptable salt thereof.

[0046] The invention also provides cannabidiol, or a pharmaceutically acceptable salt thereof, for use in a method of the first aspect.

[0047] The invention also provides cenobamate, or a pharmaceutically acceptable salt thereof, for use in a method of the first aspect.

[0048] The invention also provides the use of cannabidiol, or a pharmaceutically acceptable salt thereof, in a method of the first aspect.

[0049] The invention also provides the use of cenobamate, or a pharmaceutically acceptable salt thereof, in a method of the first aspect.

[0050] In one embodiment, there is provided the use of cannabidiol, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for treating seizures, wherein the cannabidiol, or a pharmaceutically acceptable salt thereof, is administered to a subject in need thereof in combination with a therapeutically effective amount of cenobamate, or a pharmaceutically acceptable salt thereof.

[0051] In one embodiment, there is provided the use of cenobamate, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for treatingseizures, wherein the cenobamate, or a pharmaceutically acceptable salt thereof, is administered to a subject in need thereof in combination with a therapeutically effective amount of cannabidiol, or a pharmaceutically acceptable salt thereof.

[0052] In one embodiment, the cannabidiol, or a pharmaceutically acceptable salt thereof, and the cenobamate, or a pharmaceutically acceptable salt thereof, are administered simultaneously.

[0053] In one embodiment, the cannabidiol, or a pharmaceutically acceptable salt thereof, and the cenobamate, or a pharmaceutically acceptable salt thereof, are administered sequentially.

[0054] In one embodiment, the cannabidiol, or a pharmaceutically acceptable salt thereof, and the cenobamate, or a pharmaceutically acceptable salt thereof, are administered in the same dosage form.

[0055] In a preferred embodiment, the cannabidiol, or a pharmaceutically acceptable salt thereof, and the cenobamate, or a pharmaceutically acceptable salt thereof, are administered in separate dosage forms.:ic Effect

[0056] The inventors have shown that administration of a combination of cannabidiol and cenobamate provides an improved anticonvulsant effect in a mouse model of generalised seizure in comparison to treatment with either component alone. Accordingly, the inventors believe that treatment with such a combination will provide an improved therapeutic effect in comparison to treatment with either component independently.

[0057] In one embodiment, the method of treating seizures provides an improved therapeutic effect.

[0058] In one embodiment, the improved therapeutic effect is a reduction in seizure frequency (per 28 days) in comparison to treatment without cannabidiol. In such embodiments, the median percentage reduction in seizure frequency (per 28 days) is at least 10%, such as at least 15%, at least 20%, at least 25%, or at least 30%.

[0059] In one embodiment, the improved therapeutic effect is a reduction in seizure frequency (per 28 days) in comparison to treatment without cannabidiol. In such embodiments, the median percentage reduction in seizure frequency (per 28 days) is at least 50%, such as at least 75%, or at least 100%.

[0060] In one embodiment, the improved therapeutic effect is a reduction in seizure frequency (per 28 days) in comparison to treatment without cenobamate. In such embodiments, the median percentage reduction in seizures frequency (per 28 days) is at least 10%, such as at least 15%, at least 20%, at least 25%, or at least 30%.

[0061] In one embodiment, the improved therapeutic effect is a reduction in seizure frequency (per 28 days) in comparison to treatment with placebo. In such embodiments, themedian percentage reduction in seizure frequency (per 28 days) is at least 50%, such as at least 60%, at least 70%, at least 80%, or at least 90%.

[0062] In one embodiment, the improved therapeutic effect is an increase in seizure-free days (per 28 days) in comparison to treatment without cannabidiol. In such embodiments, the median increase in seizure free days (per 28 days) is at least 1 day, such as least 2 days, at least 3 days, at least 4 days, or at least 5 days.

[0063] In one embodiment, the improved therapeutic effect is an increase in seizure-free days (per 28 days) in comparison to treatment without cenobamate. In such embodiments, the median increase in seizure free days (per 28 days) is at least 1 day, such as at least 2 days, at least 3 days, at least 4 days, or at least 5 days.

[0064] In one embodiment, the improved therapeutic effect is an increase in seizure-free days (per 28 days) in comparison to treatment with placebo. In such embodiments, the median increase in seizure free days (per 28 days) is at least 6 days, such as at least 7 days, at least 8 days, at least 9 days, or at least 10 days.

[0065] In one embodiment, the improved therapeutic effect is completed seizure freedom.

[0066] In one embodiment, the improved therapeutic effect is a pharmacodynamic therapeutic effect. In one embodiment, the improved therapeutic effect is independent of any pharmacokinetic effects. That is, independent of any changes in the absorption, distribution, metabolism, and excretion characteristics of either cannabidiol or cenobamate.

[0067] In one embodiment, the improved therapeutic effect is a reduction in countable seizure frequency, such as countable focal seizure frequency. In one embodiment, the reduction in countable seizure frequency, such as countable focal seizure frequency, is compared to baseline. The baseline is the frequency of countable seizures, such as countable focal seizures, prior to initiation of treatment. In one embodiment, the time period in which the baseline is determined is at least 1 week, such as at least 2 weeks prior to initiation of treatment. In one embodiment, the time period in which the baseline is determined is about 6 weeks prior to initiation of treatment. In one embodiment, the reduction in countable seizure frequency, such as countable focal seizure frequency, is at least 50%, such as at least 75% compared to baseline. In one embodiment, the reduction in countable seizure frequency, such as countable focal seizure frequency, is 100% compared to baseline.

[0068] In one embodiment, the improved therapeutic effect is a reduction in total seizure frequency (per 28 days). In one embodiment, the reduction in total seizure frequency (per 28 days) is compared to baseline. The baseline is the frequency of total seizures prior to initiation of treatment. In one embodiment, the time period in which the baseline is determined is at least 1 week, such as at least 2 weeks prior to initiation of treatment. In one embodiment, the time period in which the baseline is determined is about 6 weeks prior to initiation of treatment. In one embodiment, the reduction in total seizure frequency (per 28 days) is at least 50%, such as at least 75% compared to baseline. In one embodiment, the reduction in total seizure frequency (per 28 days) is 100% compared to baseline.

[0069] In one embodiment, the improved therapeutic effect is a reduction in focal to bilateral seizure frequency (per 28 days). In one embodiment, the reduction in focal to bilateral seizure frequency (per 28 days) is compared to baseline. The baseline is the frequency of focal to bilateral seizure frequency prior to initiation of treatment. In one embodiment, the time period in which the baseline is determined is at least 1 week, such as at least 2 weeks prior to initiation of treatment. In one embodiment, the time period in which the baseline is determined is about 6 weeks prior to initiation of treatment. In one embodiment, the reduction in focal to bilateral seizure frequency (per 28 days) is at least 50%, such as at least 75% compared to baseline. In one embodiment, the reduction in focal to bilateral seizure frequency (per 28 days) is 100% compared to baseline.

[0070] In one embodiment, the improved therapeutic effect is an increase in total seizure free days (per 28 days). In one embodiment, the increase in total seizure free days (per 28 days) is compared to baseline. The baseline is the number of total seizure free days prior to initiation of treatment. In one embodiment, the time period in which the baseline is determined is at least 1 week, such as at least 2 weeks prior to initiation of treatment. In one embodiment, the time period in which the baseline is determined is about 6 weeks prior to initiation of treatment. In one embodiment, the increase in total seizure free days (per 28 days) is at least 50%, such as at least 75% compared to baseline. In one embodiment, the increase in total seizure free days (per 28 days) is 100% compared to baseline.Synergistic Therapeutic Effect

[0071] The inventors have shown that administration of a combination of cannabidiol and cenobamate provides a synergistic anticonvulsant effect in a mouse model of generalised seizure in comparison to treatment with either component alone. Accordingly, treatment with such a combination may provide a synergistic therapeutic effect in comparison to treatment with either component independently.

[0072] In a preferred embodiment, the method of treating seizures provides a synergistic therapeutic effect.

[0073] In an embodiment, the method provides a synergistic therapeutic effect in the treatment of seizures as compared to the effect of cannabidiol or cenobamate when administered independently. This synergistic therapeutic effect comprises a reduction in the occurrence and / or severity of seizures.

[0074] In one embodiment, the synergistic therapeutic effect is a pharmacodynamic synergistic therapeutic effect. In one embodiment, the synergistic therapeutic effect is independent of any pharmacokinetic effects. That is, independent of any changes in the absorption, distribution, metabolism, and excretion characteristics of either cannabidiol or cenobamate.

[0075] In one embodiment, the synergistic therapeutic effect is characterised by a Combination Index of less than 1. In one embodiment, the synergistic therapeutic effect is characterised by a Combination Index of less than 0.8.

[0076] In one embodiment, the synergistic therapeutic effect is characterised as an Exposure Reduction Index for cannabidiol and / or cenobamate of greater than 1.Lack of CNS related adverse effects

[0077] As described herein, the inventors have shown that administration of a combination of cannabidiol and cenobamate provides an improved anticonvulsant effect in a mouse model of generalised seizure in comparison to treatment with either component alone. Accordingly, the inventors believe that treatment with such a combination will provide an improved therapeutic effect in comparison to treatment with either component independently.

[0078] Additionally, the inventors have also shown that the combination of cannabidiol and cenobamate is well tolerated. The evaluation of the combination of cannabidiol and cenobamate on motor coordination using an accelerating rotarod model in mice showed no impact on motor coordination and balance, thereby indicating a lack of CNS related adverse effects such as somnolence, sedative or muscle coordination related effects. Coadministration of multiple doses (7.5 mg / kg BID) of a cannabidiol oral solution and 200 mg once daily cenobamate was also well tolerated by healthy participants in a phase 1, openlabel, human clinical study.

[0079] Achieving a desirable level of seizure control in a subject requires treatment with an ASD that exhibits a sufficient level of efficacy against the seizure type(s) experienced by the subject. Attempts to improve seizure control, e.g. reduce seizure occurrence and / or severity, by introducing further ASDs, particularly ASDs with complicated pharmacokinetics and pharmacodynamics, can be unpredictable and often unsuccessful. Such approaches can lead to an increased incidence of adverse drug reactions and these adverse reactions can often be additive in nature. Treatment with cenobamate is commonly associated with central nervous system-related adverse effects, such as somnolence. In some cases, somnolence related adverse reactions can be serious leading to discontinuation of the treatment. Based on the findings disclosed herein, the inventors believe that treatment with a combination of cannabidiol and cenobamate provides an improved therapeutic effect in comparison to treatment with either component independently. Additionally, the inventors believe the combination will be well tolerated, lacking (or exhibiting a reduction in) CNS related adverse effects, such as somnolence and / or sedative and / or other muscle coordination related adverse effects.

[0080] Accordingly, in one embodiment, the method of treating seizures provides treatment without CNS related adverse effects, such as somnolence and / or sedative and / or other muscle coordination related adverse effects. In such embodiments, the subject exhibits CNS related adverse effect free days (per 28 days) of at least 20 days, such as least 25 days, at least 26 days, at least 27 days, or 28 days.

[0081] In one embodiment, the method of treating seizures provides treatment without somnolence and / or sedation.

[0082] In one embodiment, the method of treating seizures provides treatment without somnolence.

[0083] In one embodiment, the method of treating seizures provides treatment without sedation.

[0084] In one embodiment, the method of treating seizures provides treatment without an increase in CNS related adverse effects, such as somnolence and / or sedative and / or other muscle coordination related adverse effects, in comparison to treatment without cannabidiol. In such embodiments, the occurrence of CNS related adverse effects (per 28 days) is within 35%, such as within 20%, such as within 15%, or such as within 10%, of the occurrence in treatment without cannabidiol.

[0085] In one embodiment, the method of treating seizures provides treatment without an increase in somnolence and / or sedation, in comparison to treatment without cannabidiol.

[0086] In one embodiment, the method of treating seizures provides treatment without an increase in somnolence, in comparison to treatment without cannabidiol.

[0087] In one embodiment, the method of treating seizures provides treatment without an increase in sedation, in comparison to treatment without cannabidiol.

[0088] In one embodiment, the method of treating seizures provides treatment without an increase in CNS related adverse effects, such as somnolence and / or sedative and / or other muscle coordination related adverse effects, in comparison to treatment without cenobamate. In such embodiments, the occurrence of CNS related adverse effects (per 28 days) is within 35%, such as within 20%, such as within 15%, or such as within 10%, of the occurrence in treatment without cenobamate.

[0089] In one embodiment, the method of treating seizures provides treatment without an increase in somnolence and / or sedation, in comparison to treatment without cenobamate.

[0090] In one embodiment, the method of treating seizures provides treatment without an increase in somnolence, in comparison to treatment without cenobamate.

[0091] In one embodiment, the method of treating seizures provides treatment without an increase in sedation, in comparison to treatment without cenobamate.

[0092] In one embodiment, the method of treating seizures provides an improved safety effect. Conveniently, the improved safety effect is a reduction in CNS-related adverse effects, such as somnolence and / or sedative and / or other muscle coordination related adverse effects, in comparison to treatment without cannabidiol. In such embodiments, the median percentage reduction in frequency (per 28 days) of CNS-related adverse effects is at least 10%, such as at least 20%, at least 50%, at least 75%, or at least 100%, in comparison to treatment without cannabidiol.

[0093] In one embodiment, the method of treating seizures provides a reduction in somnolence and / or sedation, in comparison to treatment without cannabidiol.

[0094] In one embodiment, the method of treating seizures provides a reduction in somnolence, in comparison to treatment without cannabidiol.

[0095] In one embodiment, the method of treating seizures provides a reduction in sedation, in comparison to treatment without cannabidiol.

[0096] In one embodiment, the method of treating seizures provides a reduction in CNS- related adverse effects, such as somnolence and / or sedative and / or other muscle coordination related adverse effects, in comparison to treatment without cenobamate. In such embodiments, the median percentage reduction frequency (per 28 days) of CNS- related adverse effects is at least 10%, such as at least 20%, at least 50%, at least 75%, or at least 100%, in comparison to treatment without cenobamate.

[0097] In one embodiment, the method of treating seizures provides a reduction in somnolence and / or sedation, in comparison to treatment without cenobamate.

[0098] In one embodiment, the method of treating seizures provides a reduction in somnolence, in comparison to treatment without cenobamate.

[0099] In one embodiment, the method of treating seizures provides a reduction in sedation, in comparison to treatment without cenobamate.

[0100] In addition to providing improvements in the treatment of seizures in subjects receiving cannabidiol or cenobamate alone or independently, the improved therapeutic effect provided by the combination may provide a new treatment option for patients whose seizures do not respond to treatment with either cannabidiol or cenobamate (“non-responders”), or whose seizures are inadequately controlled by treatment with either cannabidiol or cenobamate (“inadequate responders”). That is, the combination may provide a treatment option for a new subgroup of patients who are cannabidiol or cenobamate non- responders, or cannabidiol or cenobamate inadequate responders.

[0101] In one embodiment, the subject is a cannabidiol non-responder.

[0102] In one embodiment, the subject is a cenobamate non-responder.

[0103] In one embodiment, the subject shows inadequate response to cannabidiol.

[0104] In one embodiment, the subject shows inadequate response to cenobamate.

[0105] The inventors have also shown that the combination of cannabidiol and cenobamate is well tolerated. As disclosed herein, evaluation of the combination of cannabidiol and cenobamate on motor coordination using an accelerating rotarod model in mice showed no impact on motor coordination and balance, thereby indicating a lack of CNS related adverse effects such as somnolence, sedative or muscle coordination related effects. Co-administration of multiple doses (7.5 mg / kg BID) of a cannabidiol oral solution and 200 mg once daily cenobamate was also well tolerated by healthy participants in a phase 1, open-label, human clinical study.

[0106] Based on these findings, the inventors believe that treatment with a combination of cannabidiol and cenobamate may be particularly suitable for patients whose seizures do not respond to treatment with either cannabidiol or cenobamate (“non-responders”), or whose seizures are inadequately controlled by treatment with either cannabidiol or cenobamate (“inadequate responders”), because adverse side effects prevent such patients from achieving a therapeutic dose with either cannabidiol or cenobamate. That is, the combination may provide a treatment option for a new subgroup of patients who are cannabidiol or cenobamate non-responders, or cannabidiol or cenobamate inadequate responders, wherein adverse side effects prevent such patients from achieving adequate seizure control.

[0107] Conveniently, the adverse side effects preventing a patient from achieving a therapeutic dose and / or achieving seizure control with either cannabidiol or cenobamate are CNS related adverse effects, such as somnolence and / or sedative and / or other muscle coordination related adverse effects. More conveniently, the adverse side effects preventing the subject from achieving a therapeutic dose and / or achieving seizure control with either cannabidiol or cenobamate are somnolence and / or sedation. Conveniently, the adverse effect is somnolence.

[0108] In one embodiment, the subject is a cannabidiol non-responder, wherein adverse side effects prevent the subject from achieving a therapeutic dose and / or achieving adequate seizure control with cannabidiol without cenobamate. In one embodiment, the adverse side effects are CNS related adverse effects, such as somnolence and / or sedative and / or other muscle coordination related adverse effects. Conveniently, the adverse side effects are somnolence and / or sedation. More conveniently, the adverse effect is somnolence.

[0109] In one embodiment, the subject is a cenobamate non-responder, wherein adverse side effects prevent the subject from achieving a therapeutic dose and / or achieving adequate seizure control with cenobamate without cannabidiol. In one embodiment, the adverse side effects are CNS related adverse effects, such as somnolence and / or sedative and / or other muscle coordination related adverse effects. Conveniently, the adverse side effects are somnolence and / or sedation. More conveniently, the adverse effect is somnolence.

[0110] In one embodiment, the subject shows inadequate response to cannabidiol, wherein adverse side effects prevent the subject from achieving a therapeutic dose and / or achieving adequate seizure control with cannabidiol without cenobamate. In one embodiment, the adverse side effects are CNS related adverse effects, such as somnolence and / or sedative and / or other muscle coordination related adverse effects. Conveniently, the adverse side effects are somnolence and / or sedation. More conveniently, the adverse effect is somnolence.

[0111] In one embodiment, the subject shows inadequate response to cenobamate, wherein adverse side effects prevent the subject from achieving a therapeutic dose and / or achieving adequate seizure control with cenobamate without cannabidiol. In oneembodiment, the adverse side effects are CNS related adverse effects, such as somnolence and / or sedative and / or other muscle coordination related adverse effects. Conveniently, the adverse side effects are somnolence and / or sedation. More conveniently, the adverse effect is somnolence.Dose Adjustment

[0112] In addition to providing improvements in the treatment of seizures in subjects receiving treatment with cannabidiol or cenobamate, the improved therapeutic effect provided by the combination may permit a reduction in the dosage of either component while retaining an acceptable response (acceptable efficacy). A reduction in dosage may be advantageous as it may be accompanied by a corresponding reduction in side-effects, or may permit a simplified dosing regimen (e.g. a reduced pill burden).

[0113] The inventors have shown that administration of a combination of cannabidiol and cenobamate provides an improved anticonvulsant effect in a mouse model of generalised seizure when the two components are administered to provide ratios of from 3:1 to 1:3 based on brain exposure (b-EEso), in comparison to treatment with either component alone. Thus, when translated to clinical practice, it may be possible to reduce the current maintenance dosage of one component by at least 3-fold (approx. 67% reduction) when administered with the other component while maintaining an acceptable response. It may also be possible to reduce the maintenance dosing frequency of one or both components.

[0114] The recommended maintenance dosage of cenobamate is 200 mg once daily for an adult and the maximum dosage is 400 mg once daily for an adult (XCOPRI® prescribing information, April 2024).

[0115] In one embodiment, the amount of cenobamate, or a pharmaceutically acceptable salt thereof, is reduced in comparison to administration of cenobamate independently. That is, the amount of cenobamate, or a pharmaceutically acceptable salt thereof, is reduced in comparison to administration without cannabidiol. Typically, the amount of cenobamate, or a pharmaceutically acceptable salt thereof, is reduced in comparison to the recommended maintenance dosage (200 mg one daily for an adult).

[0116] In one embodiment, the amount of cenobamate is reduced by up to 4-fold, such as reduced by up to 3-fold, up to 2-fold, or up to 1.5-fold in comparison to administration of cenobamate independently.

[0117] In one embodiment, the amount of cenobamate is reduced by up to 65%, such as reduced by up to 60%, up to 50%, up to 40%, or up to 30% in comparison to administration of cenobamate independently.

[0118] In one embodiment, the amount of cenobamate is reduced by a quarter, such as a reduced by a third, a half, two thirds, or three quarters in comparison to administration of cenobamate independently.

[0119] In one embodiment, cenobamate is administered at a reduced maintenance dosage of 50 to 200 mg / day, such as 60 to 200 mg / day, 70 to 200 mg / day, 80 to 200 mg / day, or 100 to 200 mg / day.

[0120] In one embodiment, cenobamate is administered at a reduced maintenance dosage of 50 to 150 mg / day, such as 60 to 150 mg / day, 70 to 150 mg / day, 80 to 150 mg / day, or 100 to 150 mg / day.

[0121] In one embodiment, cenobamate is administered at a reduced maintenance dosage of 50 to 100 mg / day, such as 60 to 100 mg / day, 70 to 100 mg / day, or 80 to 100 mg / day.

[0122] In one embodiment, cenobamate is administered at a reduced maximum dosage of less than 400 mg / day, such as less than 387.5 mg / day, 375 mg / day, 350 mg / day, 325 mg / day, 300 mg / day, 250 mg / day, 200 mg / day, 150 mg / day, 100 mg / day, or 75 mg / day.

[0123] In one embodiment, cenobamate is administered at a reduced maximum dosage of 100 to 387.5 mg / day, such as 125 to 387.5 mg / day 150 to 387.5 mg / day, 200 to 387.5 mg / day, or 250 to 387.5 mg / day.

[0124] In one embodiment, cenobamate is administered at a reduced maximum dosage of 50 to 300 mg / day, such as 100 to 300 mg / day, 150 to 300 mg / day, 200 to 300 mg / day, or 250 to 300 mg / day.

[0125] The recommended maintenance dosage of cannabidiol is between 10 mg per kg per day and 25 mg per kg per day (Epidiolex® prescribing information, March 2024).

[0126] In one embodiment, the amount of cannabidiol, or a pharmaceutically acceptable salt thereof, is reduced in comparison to administration of cannabidiol independently. That is, the amount of cannabidiol, or a pharmaceutically acceptable salt thereof, is reduced in comparison to administration without cenobamate. Typically, the amount of cannabidiol, or a pharmaceutically acceptable salt thereof, is reduced in comparison to the recommended maintenance dosage (between 10 mg per kg per day and 25 mg per kg per day).

[0127] In one embodiment, the amount of cannabidiol is reduced by up to 4-fold, such as reduced by up to 3-fold, up to 2-fold, or up to 1.5-fold in comparison to administration of cannabidiol independently.

[0128] In one embodiment, the amount of cannabidiol is reduced by a quarter, such as a reduced by a third, a half, two thirds, or three quarters in comparison to administration of cannabidiol independently.

[0129] In one embodiment, the amount of cannabidiol is reduced by up to 65%, such as reduced up to 60%, up to 50%, up to 40%, or up to 30% in comparison to administration of cannabidiol independently.

[0130] In one embodiment, cannabidiol is administered at a reduced maintenance dosage of 2.5 to 10 mg / kg / day, such as 3 to 10 mg / kg / day, 4 to 10 mg / kg / day, 5 to 10 mg / kg / day, or 6 to 10 mg / kg / day.

[0131] In one embodiment, cannabidiol is administered at a reduced maintenance dosage of 2.5 to 8 mg / kg / day, such as 3 to 8 mg / kg / day, 4 to 8 mg / kg / day, 5 to 8 mg / kg / day, or 6 to 8 mg / kg / day.

[0132] In one embodiment, cannabidiol is administered at a reduced maintenance dosage of 2.5 to 6 mg / kg / day, such as 3 to 6 mg / kg / day, 4 to 6 mg / kg / day, or 5 to 6 mg / kg / day.

[0133] In an alternative embodiment, cannabidiol is administered at a reduced maintenance dosage of 8.5 to 25 mg / kg / day, such as 10 to 25 mg / kg / day, 12.5 to 25 mg / kg / day 15 to 25 mg / kg / day, or 17.5 to 25 mg / kg / day.

[0134] In one embodiment, cannabidiol is administered at a reduced maximum dosage of less than 25 mg / kg / day, such as less than 20 mg / kg / day, 15 mg / kg / day, or 10 mg / kg / day.

[0135] In one embodiment, cannabidiol is administered at a reduced maximum dosage of 8.5 to 25 mg / kg / day, such as 10 to 25 mg / kg / day, 12.5 to 25 mg / kg / day, 15 to 25 mg / kg / day, or 17.5 to 25 mg / kg / day.

[0136] In one embodiment, cannabidiol is administered at the recommended maintenance dosage and cenobamate is administered at a reduced maintenance dosage.

[0137] In an alternative embodiment, cenobamate is administered at the recommended maintenance dosage and cannabidiol is administered at a reduced maintenance dosage.

[0138] In an alternative embodiment, both cenobamate and cannabidiol are administered at reduced maintenance dosages.

[0139] In one embodiment, the method involves the administration of cannabidiol, or a pharmaceutically acceptable salt thereof, and cenobamate, or a pharmaceutically acceptable salt thereof, to provide a fixed-exposure ratio for cannabidiokcenobamate in the subject of between about 1:3 to about 3:1, calculated based on b-EEso values of the individual compounds.Dose Frequency

[0140] In addition to providing improvements in the treatment of seizures in subjects receiving treatment with cannabidiol or cenobamate, the improved therapeutic effect provided by the combination may permit a reduction in the dose frequency of either component while retaining an acceptable response (acceptable efficacy). A reduction in dose frequency may be advantageous as it may be accompanied by a corresponding reduction in side-effects, or may permit a simplified dosing regimen (e.g. fewer administrations).

[0141] In one embodiment, cannabidiol, or a pharmaceutically acceptable salt thereof, is administered to the subject once daily.Dose Titration

[0142] In one embodiment, the method involves administration of cannabidiol, or a pharmaceutically acceptable salt thereof, to the subject at a starting dose for a period of time, e.g. a week, followed by a maintenance dose, wherein the maintenance dose is lower than 10 mg / kg / day. Conveniently, the maintenance dose is lower than would otherwise be administered if cannabidiol were being dosed without cenobamate.

[0143] In a second aspect of the present invention, there is provided a method of treating seizures in a subject in need thereof, wherein the method comprises the steps of: a. administering to the subject a starting dosage of cannabidiol, or a pharmaceutically acceptable salt thereof, for a first period of time; b. after the first period of time, increasing the dosage of cannabidiol, or a pharmaceutically acceptable salt thereof, to achieve a maintenance dosage for a second period of time; c. after the second period of time, reducing the maintenance dosage of cannabidiol, or a pharmaceutically acceptable salt thereof, by up to 4-fold for a third period of time; and d. after the third period of time, administering cenobamate, or a pharmaceutically acceptable salt thereof; wherein optionally steps c. and d. are carried out concurrently.

[0144] In one embodiment, the starting dosage of cannabidiol is 5 mg / kg / day.

[0145] In one embodiment, the first period of time is at least 1 week, such as from 1 to 4 weeks, from 1 to 3 weeks, or about 1 week.

[0146] In one embodiment, the maintenance dosage of cannabidiol is 10 to 25 mg / kg / day.

[0147] After the maintenance dosage has been achieved, the maintenance dosage is administered for a second period of time. In one embodiment, the second period of time is at least 1 week, such as at least 1 month, at least 2 months, at least 3 months, at least 6 months, at least 1 year, or at least 2 years.

[0148] In one embodiment, the maintenance dosage of cannabidiol is reduced by up to 4-fold, such as reduced by up to 3-fold, by up to 2-fold, or by up to 1.5-fold in comparison to administration of cannabidiol independently.

[0149] In one embodiment, the reduced maintenance dosage of cannabidiol is up to 65% lower, such as up to 60% lower, up to 50% lower, up to 40% lower, or up to 30% lower in comparison to administration of cannabidiol independently.

[0150] In one embodiment, the reduced maintenance dosage of cannabidiol is a quarter, such as a third, a half, two thirds, or three quarters reduced in comparison to administration of cannabidiol independently.

[0151] In one embodiment, the reduced maintenance dosage of cannabidiol is 2.5 to 10 mg / kg / day, such as 3 to 10 mg / kg / day, 4 to 10 mg / kg / day, 5 to 10 mg / kg / day, or 6 to 10 mg / kg / day.

[0152] In one embodiment, the reduced maintenance dosage of cannabidiol is 2.5 to 8 mg / kg / day, such as 3 to 8 mg / kg / day, 4 to 8 mg / kg / day, 5 to 8 mg / kg / day, or 6 to 8 mg / kg / day.

[0153] In one embodiment, the reduced maintenance dosage of cannabidiol is 2.5 to 6 mg / kg / day, such as 3 to 6 mg / kg / day, 4 to 6 mg / kg / day, or 5 to 6 mg / kg / day.

[0154] In an alternative embodiment, the reduced maintenance dosage of cannabidiol is 8.5 to 25 mg / kg / day, such as 10 to 25 mg / kg / day, 12.5 to 25 mg / kg / day, 15 to 25 mg / kg / day, or 17.5 to 25 mg / kg / day.

[0155] After the reduced maintenance dosage has been achieved, the reduced maintenance dosage is administered for a third period of time. In one embodiment, the third period of time is at least 1 day, such as at least 2 days, at least 5 days, at least 1 week, from 1 to 4 weeks, from 1 to 3 weeks, or about 1 week.

[0156] After the third period of time, cenobamate is administered to the subject. In one embodiment, the amount of cenobamate administered is 12.5 mg / day.

[0157] In one embodiment, steps c. and d. are carried out concurrently. This is, the maintenance dosage of cannabidiol is reduced by up to 4-fold and cenobamate is administered to the subject concurrently. In one embodiment, the maintenance dosage of cannabidiol is reduced by up to 4-fold and cenobamate is administered to the subject within approximately 24 hours, such as within approximately 12 hours, 6 hours, 2 hours, or 1 hour, of administration of the reduced maintenance dosage of cannabidiol.

[0158] In a third aspect of the present invention, there is provided a method of treating seizures in a subject in need thereof, wherein the method comprises the steps of: a. administering to the subject a starting dosage of cenobamate, or a pharmaceutically acceptable salt thereof, for a first period of time; b. after the first period of time, increasing the dosage of cenobamate, or a pharmaceutically acceptable salt thereof, to achieve a maintenance dosage for a second period of time; c. after the second period of time, reducing the maintenance dosage of cenobamate, or a pharmaceutically acceptable salt thereof, by up to 4-fold for a third period of time; and d. after the third period of time, administering cannabidiol, or a pharmaceutically acceptable salt thereof; wherein optionally steps c. and d. are carried out concurrently.

[0159] In one embodiment, the starting dosage of cenobamate is 12.5 mg / day.

[0160] In one embodiment, the first period of time is at least 1 week, such as from 1 to 4 weeks, from 1 to 3 weeks, or about 1 week.

[0161] In one embodiment, the maintenance dosage of cenobamate is 200 mg / day.

[0162] After the maintenance dosage has been achieved, the maintenance dosage is administered for a second period of time. In one embodiment, the second period of time is at least 1 week, such as at least 1 month, at least 2 months, at least 3 months, at least 6 months, at least 1 year, or at least 2 years.

[0163] In one embodiment, the maintenance dosage of cenobamate is reduced by up to 4-fold, such as reduced by up to 3-fold, up to 2-fold, or up to 1.5-fold in comparison to administration of cannabidiol independently.

[0164] In one embodiment, the reduced maintenance dosage of cenobamate is up to 65% lower, such as up to 60% lower, up to 50% lower, up to 40% lower, or up to 30% lower in comparison to administration of cannabidiol independently.

[0165] In one embodiment, the reduced maintenance dosage of cenobamate is a quarter, such as a third, a half, two thirds, or three quarters reduced in comparison to administration of cannabidiol independently.

[0166] In one embodiment, the reduced maintenance dosage of cenobamate is 50 to 200 mg / day, such as 60 to 200 mg / day, 70 to 200 mg / day, 80 to 200 mg / day, or 100 to 200 mg / day.

[0167] In one embodiment, the reduced maintenance dosage of cenobamate is 50 to 150 mg / day, such as 60 to 150 mg / day, 70 to 150 mg / day, 80 to 150 mg / day, or 100 to 150 mg / day.

[0168] In one embodiment, the reduced maintenance dosage of cenobamate is 50 to 100 mg / day, such as 60 to 100 mg / day, 70 to 100 mg / day, or 80 to 100 mg / day.

[0169] After the reduced maintenance dosage of cenobamate has been achieved, the reduced maintenance dosage is administered for a third period of time. In one embodiment, the third period of time is at least 1 day, such as at least 2 days, at least 5 days, at least 1 week, from 1 to 4 weeks, from 1 to 3 weeks, or about 1 week.

[0170] After the third period of time, cannabidiol is administered to the subject. In one embodiment, the amount of cannabidiol administered is 5 mg / kg / day.

[0171] In one embodiment, steps c. and d. are carried out concurrently. This is, the maintenance dosage of cenobamate is reduced by up to 4-fold and cannabidiol is administered to the subject concurrently. In one embodiment, the maintenance dosage of cenobamate is reduced by up to 4-fold and cannabidiol is administered to the subject within approximately 24 hours, such as within approximately 12 hours, 6 hours, 2 hours, or 1 hour, of administration of the reduced maintenance dosage of cenobamate.Treatment Initiation

[0172] The invention also provides a method of safely initiating treatment with a combination of cenobamate and cannabidiol in a subject who is already receiving either component independently. The method of initiating treatment may involve continuing the maintenance dosage of the first drug while introducing and adjusting the dosage of the second drug to a reduced maintenance dosage. Alternatively, the method of initiating treatment may involve proactively decreasing the dosage of the first drug to a reduced maintenance dosage prior to initiating and adjusting the dosage of the second drug to a standard maintenance dosage.

[0173] In a fourth aspect of the invention, there is provided a method of initiating treatment with cenobamate, or a pharmaceutically acceptable salt thereof, in a subject who is suffering from seizures and who is already being treated with cannabidiol, or a pharmaceutically acceptable salt thereof, the method comprising the steps of: a. administering a starting dosage of cenobamate, or a pharmaceutically acceptable salt thereof, to the subject for a first period; b. optionally, increasing the dosage of cenobamate, or a pharmaceutical acceptable salt thereof, following a cenobamate titration regimen for a cenobamate titration period; and c. administering a reduced maintenance dosage of cenobamate, or a pharmaceutically acceptable salt thereof, to the subject, wherein the reduced maintenance dosage of cenobamate, or a pharmaceutically acceptable salt thereof, is reduced in comparison to treatment with cenobamate independently.

[0174] The reduced maintenance dosage of cenobamate, or a pharmaceutically acceptable salt thereof, is reduced in comparison to treatment without cannabidiol. Typically, the reduced maintenance dosage of cenobamate, or a pharmaceutically acceptable salt thereof, is reduced in comparison to the recommended maintenance dosage (200 mg once daily for an adult).

[0175] In one embodiment, the maintenance dosage of cannabidiol, or a pharmaceutically acceptable salt thereof, is from 10 mg / kg / day to 25 mg / kg / day.

[0176] In one embodiment, the starting dosage of cenobamate is 12.5 mg / day.

[0177] In one embodiment, the first period is at least 2 weeks, such as from 2 to 4 weeks, such as about 2 weeks.

[0178] In one embodiment, the cenobamate titration regimen comprises increasing the dosage of carbonate by from 10 to 50 mg / day every 2 weeks, such as from 12.5 mg / day to 50 mg / day every 2 weeks.

[0179] In one embodiment, the cenobamate titration period is at least 2 weeks, such as from 2 to 8 weeks, from 2 to 6 weeks, or from 2 to 4 weeks.

[0180] In one embodiment, the reduced maintenance dosage of cenobamate is up to 4-fold lower, such as up to 3-fold lower, up to 2-fold lower, or up to 1.5-fold lower in comparison to administration of cenobamate independently.

[0181] In one embodiment, the reduced maintenance dosage of cenobamate is up to 65% lower, such as up to 60% lower, up to 50% lower, up to 40% lower, or up to 30% lower in comparison to administration of cenobamate independently.

[0182] In one embodiment, the reduced maintenance dosage of cenobamate is a quarter, such as a third, a half, two thirds, or three quarters reduced in comparison to administration of cenobamate independently.

[0183] In one embodiment, the reduced maintenance dosage of cenobamate is 50 to 200 mg / day, such as 60 to 200 mg / day, 70 to 200 mg / day, 80 to 200 mg / day, or 100 to 200 mg / day.

[0184] In one embodiment, the reduced maintenance dosage of cenobamate is 50 to 150 mg / day, such as 60 to 150 mg / day, 70 to 150 mg / day, 80 to 150 mg / day, or 100 to 150 mg / day.

[0185] In one embodiment, the reduced maintenance dosage of cenobamate is 50 to 100 mg / day, such as 60 to 100 mg / day, 70 to 100 mg / day, or 80 to 100 mg / day.

[0186] In a fifth aspect of the invention, there is provided a method of initiating treatment with cannabidiol, or a pharmaceutically acceptable salt thereof, in a subject who is suffering from seizures and who is already being treated with cenobamate, or a pharmaceutically acceptable salt thereof, the method comprising the steps of: a. administering a starting dosage of cannabidiol, or a pharmaceutically acceptable salt thereof, to the subject for a first period; b. optionally, increasing the dosage of cannabidiol, or a pharmaceutical acceptable salt thereof, following a cannabidiol titration regimen for a cannabidiol titration period; and c. administering a reduced maintenance dosage of cannabidiol, or a pharmaceutically acceptable salt thereof, to the subject, wherein the reduced maintenance dosage of cannabidiol is reduced in comparison to treatment with cannabidiol independently.

[0187] The reduced maintenance dosage of cannabidiol, or a pharmaceutically acceptable salt thereof, is reduced in comparison to treatment without cenobamate. Typically, the reduced maintenance dosage of cannabidiol, or a pharmaceutically acceptable salt thereof, is reduced in comparison to the recommended maintenance dosage (between 10 mg per kg per day and 25 mg per kg per day).

[0188] In one embodiment, the maintenance dosage of cenobamate, or a pharmaceutically acceptable salt thereof, is 200 mg / day.

[0189] In one embodiment, the starting dosage of cannabidiol is 5 mg / kg / day.

[0190] In one embodiment, the first period is at least 1 week, such as from 1 to 4 weeks, from 1 to 3 weeks, or about 1 week.

[0191] In one embodiment the cannabidiol titration regimen comprises increasing the dosage of cannabidiol by from 1 mg / kg / day to 5 mg / kg / day every week.

[0192] In one embodiment, the cannabidiol titration period is at least 1 week, such as from 1 to 4 weeks, from 1 to 3 weeks, or from 1 to 2 weeks.

[0193] In one embodiment, the reduced maintenance dosage of cannabidiol is up to 4-fold lower, such as up to 3-fold lower, up to 2-fold lower, or up to 1.5-fold lower in comparison to administration of cannabidiol independently.

[0194] In one embodiment, the reduced maintenance dosage of cannabidiol is up to 65% lower, such as up to 60% lower, up to 50% lower, up to 40% lower, or up to 30% lower in comparison to administration of cannabidiol independently.

[0195] In one embodiment, the reduced maintenance dosage of cannabidiol is a quarter, such as a third, a half, two thirds, or three quarters reduced in comparison to administration of cannabidiol independently.

[0196] In one embodiment, the reduced maintenance dosage of cannabidiol is 2.5 to 10 mg / kg / day, such as 3 to 10 mg / kg / day, 4 to 10 mg / kg / day, 5 to 10 mg / kg / day, or 6 to 10 mg / kg / day.

[0197] In one embodiment, the reduced maintenance dosage of cannabidiol is 2.5 to 8 mg / kg / day, such as 3 to 8 mg / kg / day, 4 to 8 mg / kg / day, 5 to 8 mg / kg / day, or 6 to 8 mg / kg / day.

[0198] In one embodiment, the reduced maintenance dosage of cannabidiol is 2.5 to 6 mg / kg / day, such as 3 to 6 mg / kg / day, 4 to 6 mg / kg / day, or 5 to 6 mg / kg / day.

[0199] In an alternative embodiment, the reduced maintenance dosage of cannabidiol is 8.5 to 25 mg / kg / day, such as 10 to 25 mg / kg / day, 12.5 to 25 mg / kg / day, 15 to 25 mg / kg / day, or 17.5 to 25 mg / kg / day.

[0200] In a sixth aspect of the invention, there is provided a method of initiating treatment with cenobamate, or a pharmaceutically acceptable salt thereof, in a subject who is suffering from seizures and who is already being treated with cannabidiol, or a pharmaceutically acceptable salt thereof, the method comprising the steps of: a. reducing the dosage of cannabidiol, or a pharmaceutically acceptable salt thereof, being administered to the subject; b. administering a reduced maintenance dosage of cannabidiol, or a pharmaceutically acceptable salt thereof, to the subject; and c. administering a starting dosage of cenobamate, or a pharmaceutically acceptable salt thereof to the subject.

[0201] In one embodiment, the maintenance dosage of cannabidiol is reduced by up to 4-fold, such as reduced by up to 3-fold, up to 2-fold, or up to 1.5-fold in comparison to administration of cannabidiol independently. Accordingly, the reduced maintenance dosage of cannabidiol is up to 4-fold lower, such as up to 3-fold lower, up to 2-fold lower, or up to 1.5-fold lower in comparison to administration of cannabidiol independently.

[0202] In one embodiment, the maintenance dosage of cannabidiol is reduced by up to 65%, such as up to 60%, up to 50%, up to 40%, or up to 30% in comparison to administration of cannabidiol independently. Accordingly, the reduced maintenance dosage of cannabidiol is up to 65% lower, such as up to 60% lower, up to 50% lower, up to 40% lower, or up to 30% lower in comparison to administration of cannabidiol independently.

[0203] In one embodiment, the maintenance dosage of cannabidiol is reduced by a quarter, such as reduced by a third, a half, two thirds, or three quarters in comparison to administration of cannabidiol independently. Accordingly, the reduced maintenance dosage of cannabidiol is a quarter, such as a third, a half, two thirds, or three quarters reduced in comparison to administration of cannabidiol independently.

[0204] In one embodiment, the maintenance dosage of cannabidiol is reduced to 2.5 to 10 mg / kg / day, such as 3 to 10 mg / kg / day, 4 to 10 mg / kg / day, 5 to 10 mg / kg / day, or 6 to 10 mg / kg / day. Accordingly, the reduced maintenance dosage of cannabidiol is 2.5 to 10 mg / kg / day, such as 3 to 10 mg / kg / day, 4 to 10 mg / kg / day, 5 to 10 mg / kg / day, or 6 to 10 mg / kg / day.

[0205] In an alternative embodiment, the maintenance dosage of cannabidiol is reduced to 8.5 to 25 mg / kg / day, such as 10 to 25 mg / kg / day, 12.5 to 25 mg / kg / day, 15 to 25 mg / kg / day, or 17.5 to 25 mg / kg / day. Accordingly, the reduced maintenance dosage of cannabidiol is 8.5 to 25 mg / kg / day, such as 10 to 25 mg / day, 12.5 to 25 mg / kg / day 15 to 25 mg / kg / day, or 17.5 to 25 mg / kg / day.

[0206] In one embodiment, the starting dosage of cenobamate is 12.5 mg / day.

[0207] In a seventh aspect of the invention, there is provided a method of initiating treatment with cannabidiol, or a pharmaceutically acceptable salt thereof, in a subject who is suffering from seizures and who is already being treated with cenobamate, or a pharmaceutically acceptable salt thereof, the method comprising the steps of: a. reducing the dosage of cenobamate, or a pharmaceutically acceptable salt thereof, being administered to the subject; b. administering a reduced maintenance dosage of cenobamate, or a pharmaceutically acceptable salt thereof, to the subject; and c. administering a starting dosage of cannabidiol, or a pharmaceutically acceptable salt thereof to the subject.

[0208] In one embodiment, the maintenance dosage of cenobamate is reduced by up to 4-fold, such as reduced by up to 3-fold, up to 2-fold, or up to 1.5-fold in comparison to administration of cenobamate alone. Accordingly, the reduced maintenance dosage ofcenobamate is up to 4-fold lower, such as up to 3-fold lower, up to 2-fold lower, or up to 1.5- fold lower in comparison to administration of cenobamate independently.

[0209] In one embodiment, the maintenance dosage of cenobamate is reduced by up to 65%, such as reduced by up to 60%, up to 50%, up to 40%, or up to 30% in comparison to administration of cannabidiol alone. Accordingly, the reduced maintenance dosage of cenobamate is up to 65% lower, such as up to 60% lower, up to 50% lower, up to 40% lower, or up to 30% lower in comparison to administration of cenobamate independently.

[0210] In one embodiment, the maintenance dosage of cenobamate is reduced by a quarter, such as reduced by a third, a half, two thirds, or three quarters in comparison to administration of cenobamate independently. Accordingly, the reduced maintenance dosage of cenobamate is a quarter, such as a third, a half, two thirds, or three quarters reduced in comparison to administration of cannabidiol independently.

[0211] In one embodiment, the maintenance dosage of cenobamate is reduced to 50 to 200 mg / day, such as 60 to 200 mg / day, 70 to 200 mg / day, 80 to 200 mg / day, or 100 to 200 mg / day. Accordingly, the reduced maintenance dosage of cenobamate is 50 to 200 mg / day, such as 60 to 200 mg / day, 70 to 200 mg / day, 80 to 200 mg / day, or 100 to 200 mg / day.

[0212] In one embodiment, the starting dosage of cannabidiol is 5 mg / kg / day.Conditions Treated

[0213] The inventors have shown that administration of a combination of cannabidiol and cenobamate provides an improved anticonvulsant effect in a mouse model of generalised seizure in comparison to treatment with either component independently. Accordingly, the inventors believe that treatment with such a combination will provide an improved therapeutic effect in the treatment of seizures in comparison to treatment with either component independently.Seizure Type

[0214] In one embodiment, the seizures are focal onset seizures (focal seizures), generalised onset seizures (generalised seizure), or seizures with unknown onset.

[0215] In one embodiment, the seizures are focal onset seizures.

[0216] In one embodiment, the seizures are generalised onset seizures.

[0217] In a further embodiment, the seizures are a combination of focal onset seizures and generalised onset seizures.

[0218] Focal onset seizures may be further characterised by the level of awareness. In one embodiment, the focal onset seizure is focal onset seizure with awareness. In one embodiment, the focal onset seizure is a focal onset seizure with impaired awareness (with impairment).

[0219] Focal onset seizures may be further characterised by motor onset or non-motor onset features. In one embodiment, the focal onset seizure is a focal onset seizure with a motor onset feature, such as a motor onset feature selected from automatisms, atonic, clonic, epileptic spasms, hyperkinetic, myoclonic and tonic. In one embodiment, the focal onset seizure is a focal onset seizure with a non-motor onset feature, such as a nonmotor onset feature selected from autonomic, behaviour arrest, cognitive, emotional and sensory.

[0220] Focal onset seizures may also present with focal to bilateral tonic-clonic propagation. In one embodiment, the focal onset seizure is a focal to bilateral tonic-clonic seizure.

[0221] Generalised onset seizures may be characterised by motor or non-motor (absence) features. In one embodiment, the seizures are generalised onset seizures with a motor feature, such as a motor feature selected from tonic-clonic, clonic, tonic, myoclonic, myoclonic-tonic-clonic, myoclonic-atonic, atonic and epileptic spasms. In one embodiment, the seizures are generalised onset seizures with a non-motor (absence) feature, such as a non-motor feature selected from typical, atypical, myoclonic and eyelid myoclonia.

[0222] Seizures with unknown onset may be characterised by motor or non-motor (absence) features. In one embodiment, the unknown onset seizure is an unknown onset seizure with a motor feature, such as a motor feature selected from tonic-clonic and epileptic spasms. In one embodiment, the unknown onset seizure is an unknown onset seizure with a non-motor feature, such as behavioural arrest.

[0223] In one embodiment, the seizures are selected from typical absence seizures, atypical absence seizures, atonic seizures, clonic seizures, tonic seizures, tonic-clonic seizures, febrile seizures, focal to bilateral tonic clonic seizures, gelastic and dacrystic seizures, myoclonic seizures, myoclonic-tonic-clonic seizures, myoclonic-atonic seizures and epileptic (or infantile) spasms.

[0224] In one embodiment, the seizures are associated with epilepsy, such as an epilepsy selected from focal epilepsy, generalised epilepsy, and combined generalised & focal epilepsy.

[0225] In one embodiment, the epilepsy is an epileptic syndrome selected from syndromes with onset in neonates and infancy, syndromes with onset in childhood, syndromes with onset at a variable age, and idiopathic generalised epilepsy syndromes (IGEs).

[0226] In one embodiment, the epilepsy is an epilepsy syndrome with onset in neonates and infancy, such as an epilepsy syndrome with onset in neonates and infancy selected from self-limited epilepsies (such as self-limited neonatal epilepsy, self-limited familial neonatal- infantile epilepsy, self-limited infantile epilepsy, genetic epilepsy with febrile seizures plus, or myoclonic epilepsy in infancy), developmental and epileptic encephalopathies (DEEs, such as early infantile developmental and epileptic encephalopathy (EIDEE), epilepsy in infancywith migrating focal seizures (EIMFS), infantile epileptic spasms syndrome (West Syndrome), or Dravet syndrome), and aetiology-specific syndromes (such as KCNQ2-DEE, pyridoxine-dependent DEE, pyridox(am)ine 5’-phosphate deficiency DEE, CDKL5-DEE, PCDH19 clustering epilepsy, glucose transporter 1 deficiency syndrome, gelastic seizures with hypothalamic hamartoma, or Sturge Weber syndrome). Further information is provided in the aetiology section below.

[0227] In one embodiment, the epilepsy is an epilepsy syndrome with onset in childhood, such as an epilepsy syndrome with onset in childhood selected from self-limited focal epilepsies of childhood (such as childhood occipital visual epilepsy (COVE), self-limited epilepsy with autonomic seizures, self-limited epilepsy with centrotemporal spikes, or photosensitive occipital lobe epilepsy (POLE)), DEEs with onset in childhood (such as epilepsy with myoclonic atonic seizures, Lennox Gastaut syndrome, febrile infection-related epilepsy syndrome (FIRES), hemiconvulsion-hemiplegia-epilepsy syndrome, developmental and epileptic encephalopathy with spike-and-wave activation in sleep (DEE-SWAS), epileptic encephalopathy with spike-and-wave activation in sleep (EE-SWAS), or Landau- Kleffner syndrome), and genetic generalised epilepsies of childhood (such as epilepsy with eyelid myoclonia, or epilepsy with myoclonic absence).

[0228] In one embodiment, the epilepsy is an epilepsy syndrome with onset at a variable age, such as an epilepsy syndrome with onset at variable age selected from juvenile myoclonic epilepsy (JME), juvenile absence epilepsy (JAE), epilepsy with generalised tonic- clonic seizures alone (GTCA), childhood occipital visual epilepsy (COVE), photosensitive occipital lobe epilepsy (POLE), familial mesial temporal lobe epilepsy (FMTLE), epilepsy with auditory features (EAF), mesial temporal lobe epilepsy with hippocampal sclerosis (MTLE- HS), sleep-related hypermotor / hyperkinetic epilepsy (SHE), familial focal epilepsy with variable foci (FFEVF), epilepsy with reading induced seizures (EwRIS), progressive myoclonus epilepsies (PME), febrile-infection related epilepsy syndrome (FIRES) and Rasmussen syndrome.

[0229] In one embodiment, the epilepsy is an idiopathic generalised epilepsy syndrome (IGE), such as an IGE selected from childhood absence epilepsy (CAE), juvenile absence epilepsy (JAE), juvenile myoclonic epilepsy (JME), and epilepsy with generalised tonic-clonic seizures alone (GTCA).

[0230] In one embodiment, the epilepsy is selected from Dravet syndrome and Lennox Gastaut syndrome.

[0231] In one embodiment, the epilepsy is characterised as a refractory (or treatmentresistant) epilepsy. According to the International League Against Epilepsy (ILAE), drug resistant epilepsy occurs when a person has failed to become (and stay) seizure free with adequate trials of two antiseizure medications (called ASMs). These seizure medications must have been chosen appropriately for the person’s seizure type, tolerated by the person, and tried alone or together with other seizure medications [Kwan, et al., 2010],Aetiology

[0232] In one embodiment, the epilepsy has an aetiology selected from structural, genetic, infection, metabolic, and autoimmune.

[0233] In one embodiment, the epilepsy is an epilepsy having a structural aetiology ("structural epilepsy"), such as a structural aetiology selected from focal cortical dysplasia (FCD), hypothalamic hamartoma (HH), hypoxic ischemic encephalopathy (HIE), incontinent pigment (IP), mesial temporal sclerosis (MTS), neurofibromatosis type 1, multiple sclerosis (MS), encephalotrigeminal angiomatosis (Sturge Weber syndrome; SWS), traumatic brain injury (TBI); periventricular nodular heterotopia (PVNH), polymicrogyria (PMG), tuberous sclerosis complex (TSC), and brain tumours.

[0234] In one embodiment, the epilepsy is an epilepsy having a genetic aetiology (“genetic epilepsy”), such as a genetic aetiology selected from Angelman Syndrome, PCDH19 mutation, ring chromosome 20 syndrome (RC20), CACNA1A mutation, CDKL5 deficiency disorder, GRIN2A mutation, SCN8A mutation, SLC2A1 (Glutl deficiency syndrome), TBCK mutation, Rett (MECP2 mutation), SYNGAP1 mutation, KCNQ2 mutation, STXBP1 mutation, SCN1A mutation, CHD2 mutation, PRRT2 mutation, SLC6A1 mutation, and GATOR1- related epilepsy.

[0235] In one embodiment, the epilepsy is an epilepsy having an infection aetiology (“infection epilepsy”), such as an infection aetiology selected from neurocysticercosis, cerebral malaria, TORCH infections (toxoplasmosis, other agents, rubella / German measles, cytomegalovirus, and herpes simplex), bacterial meningitis, viral encephalitis, tuberculosis, and human immunodeficiency virus (HIV).

[0236] In one embodiment, the epilepsy is an epilepsy having a metabolic aetiology (“metabolic epilepsy”), such as a metabolic aetiology selected from glucose transport (Glut 1) deficiency syndrome (SLC2A1), vitamin dependent metabolic disorders (such as pyridoxine, P5P or folinic acid dependent disorders), creatine transporter disorders, mitochondrial disorders, and storage disorders.

[0237] In one embodiment, the epilepsy is an epilepsy having an autoimmune aetiology (“autoimmune epilepsy”), such as an autoimmune aetiology selected from Rasmussen syndrome, antiNMDA receptor encephalitis, limbic encephalitis (e.g. LGI1 antibody, or CASPR2 antibody related limbic encephalitis), and GAD65 antibody related epilepsy.Subject / Patient

[0238] The methods of treating seizures, and the methods of initiating treatment, comprise administering cannabidiol, or a pharmaceutically acceptable salt thereof, in combination with a therapeutically effective amount of cenobamate, or a pharmaceutically acceptable salt thereof, to a subject.

[0239] The subject / patient may be any of its forms of development, for example, the subject / patient may be a neonate, an infant, a child, or an adult.

[0240] In a preferred embodiment, the subject is a human. In an embodiment, the subject is an adult human.

[0241] In an alternative embodiment, the subject may also be a non-human mammal used in laboratory research, such as a rodent. Rodents include rats, mice, guinea pigs and chinchillas.Routes of Administration

[0242] The methods of treating seizures, and the methods of initiating treatment, comprise administering cannabidiol, or a pharmaceutically acceptable salt thereof, in combination with a therapeutically effective amount of cenobamate, or a pharmaceutically acceptable salt thereof, to a subject. The administration may be any convenient route, whether systemically / peripherally or topically (i.e. , at the site of desired action).

[0243] The route of administration may be oral (e.g., by ingestion); buccal; sublingual; transdermal (including, e.g., by a patch, plaster, etc.); transmucosal (including, e.g., by a patch, plaster, etc.); intranasal (e.g., by nasal spray); ocular (e.g., by eyedrops); pulmonary (e.g., by inhalation or insufflation therapy using, e.g., via an aerosol, e.g., through the mouth or nose); rectal (e.g., by suppository or enema); vaginal (e.g., by pessary); parenteral, for example, by injection or infusion, including subcutaneous, intradermal, intramuscular, intravenous, intraarterial, intracardiac, intrathecal, intraspinal, intracapsular, subcapsular, intraorbital, intraperitoneal, intratracheal, subcuticular, intraarticular, subarachnoid, and intrasternal; or by implant of a depot or reservoir, for example, subcutaneously or intramuscularly.

[0244] In a preferred embodiment, the route of administration is oral.Cannabidiol

[0245] The methods of treating seizures, and the methods of initiating treatment, comprise administering cannabidiol, or a pharmaceutically acceptable salt thereof, to a subject.

[0246] The chemical structure, chemical formula, chemical name and CAS registry number for cannabidiol are set out below:

[0247] The cannabidiol may be from any suitable source. Suitable sources include botanical extracts and a chemical synthesis.

[0248] In one embodiment, the cannabidiol is a botanical extract or a synthetic compound.

[0249] In one embodiment, the cannabidiol is a botanical extract. Methods of extracting and purifying cannabidiol are set out in WO 02 / 089945 and WO 2022 / 049007, each of which is incorporated by reference.

[0250] In one embodiment, the cannabidiol is an extract of a cannabis plant, such as an extract of Cannabis sativa, such as Cannabis sativa L.

[0251] In one embodiment, the cannabidiol is a purified botanical extract, such as a purified botanical extract comprising at least 95% (w / w) cannabidiol based on the total weight of the extract. In one embodiment, the cannabidiol is a highly purified botanical extract, such as a highly purified botanical extract comprising at least 98% (w / w) cannabidiol based on the total weight of the extract.

[0252] In some embodiments, the botanical extract may comprise additional noncannabinoid components extracted from the cannabis plant. Examples of such additional non-cannabinoid components include terpenes and sterols.

[0253] In some embodiments, the botanical extract may comprise additional cannabinoids extracted from the cannabis plant. Examples of such additional cannabinoids include cannabichromene (CBC), cannabichromenic acid (CBCV), cannabidiol (CBD), cannabidiolic acid (CBDA), cannabidivarin (CBDV), cannabigerol (CBG), cannabigerol propyl variant (CBGV), cannabicyclol (CBL), cannabinol (CBN), cannabinol propyl variant (CBNV), cannabitriol (CBO), tetrahydrocannabinol (THC), tetrahydrocannabinolic acid (THCA), tetrahydrocannabivarin (THCV), tetrahydrocannabivarinic acid (THCVA), cannabidibutol (CBD-C4) and cannabidiorcol (CBD-C1; CBDO).

[0254] In one embodiment, the botanical extract comprises not more than 0.15% (w / w) THC, such as not more than 0.10% (w / w) THC, based on the total weight of the extract.

[0255] In one embodiment, botanical extract comprises not more than 1.5% (w / w) CBDV, such as not more than 1.0% (w / w) CBDV, based on the total weight of the extract.

[0256] In one embodiment, botanical extract comprises not more than 0.20% (w / w) CBD-C1, such as not more than 0.15% (w / w) CBD-C1 , based on the total weight of the extract.

[0257] In one embodiment, botanical extract comprises not more than 1.0% (w / w) CBD-C4, such as not more than 0.5% (w / w) CBD-C1, based on the total weight of the extract.

[0258] In one embodiment, the cannabidiol comprises the following components based on the total weight of the extract:

[0259] In one embodiment, the cannabidiol is a botanical drug substance (BRM).

[0260] In an alternative embodiment, the cannabidiol is a synthetic compound. Methods of preparing synthetic cannabidiol are set out in Aisa et al., (2020), which is incorporated by reference.Cenobamate

[0261] The methods of treating seizures, and the methods of initiating treatment, comprise administering cenobamate, or a pharmaceutically acceptable salt thereof, to a subject.

[0262] The chemical structure, chemical formula, chemical name and CAS registry number for cenobamate are set out below:

[0263] Methods for the preparation of cenobamate are set out in WO 2006 / 112685, which is incorporated by reference.

[0264] In one embodiment, the cenobamate is administered in its free base form.

[0265] In one embodiment, the cenobamate is administered as a pharmaceutically acceptable salt.Salts

[0266] In some embodiments, cenobamate is provided in free base form.

[0267] Alternatively, it may be convenient or desirable to prepare, purify, and / or handle a corresponding salt of the compound, for example, a pharmaceutically-acceptable salt. Examples of pharmaceutically acceptable salts are discussed in “Pharmaceutical Salts: Properties, Selection, and Use”, 2ndEdition, 2002, Stahl and Wermuth (Eds), Wiley-VCH, Weinheim, Germany.

[0268] Accordingly, in some embodiments cenobamate is provided as a salt, for example in a protonated form together with a suitable counter anion.

[0269] Suitable counter anions include both organic and inorganic anions. Example of suitable inorganic anions include those derived from inorganic acids, including chloride (Cl’), bromide (Br), iodide (I’), sulfate (SO ), sulfite (SOs2’), nitrate (NOs’), nitrite (NO2 , phosphate (PC>43’), and phosphite (POs3’). Examples of suitable organic anions include 2-acetoxybenzoate, acetate, ascorbate, aspartate, benzoate, camphorsulfonate, cinnamate, citrate, edetate, ethanedisulfonate, ethanesulfonate, formate, fumarate, gluconate, glutamate, glycolate, hydroxymalate, carboxylate, lactate, laurate, lactate, maleate, malate, methanesulfonate, oleate, oxalate, palmitate, phenylacetate, phenylsulfonate, propionate, pyruvate, salicylate, stearate, succinate, sulfanilate, tartarate, toluenesulfonate, and valerate. Examples of suitable polymeric organic anions include those derived from tannic acid and carboxymethyl cellulose. In an embodiment, the counter anion is chloride or formate, such as formate.

[0270] Alternatively, in some embodiments cenobamate is provided as a salt, for example in a deprotonated form together with a suitable counter cation.

[0271] Accordingly, in some embodiments cannabidiol is provided as a salt, for example in a protonated form together with a suitable counter cation.

[0272] Suitable counter cations include both organic and inorganic cations. Examples of suitable inorganic cations include alkali metal ions such as Na+and K+, alkaline earth cations such as Ca2+and Mg2+, and other cations such as Al3+. Examples of suitable organic cations include the ammonium ion (i.e. , NH4+) and substituted ammonium ions (e.g., NHsR+, NH2R2+, NHRs+, NR4+). Examples of substituted ammonium ions include those derived from ethylamine, diethylamine, dicyclohexylamine, triethylamine, butylamine, ethylenediamine, ethanolamine, diethanolamine, piperazine, benzylamine, phenylbenzylamine, choline, meglumine, and tromethamine, as well as amino acids, such as lysine and arginine. An example of a common quaternary ammonium ion is N(CHs)4+.Pharmaceutical Compositions

[0273] While it is possible to administer the cannabidiol, cenobamate, and their pharmaceutically acceptable salts alone, it is preferable to administer a pharmaceutical composition (e.g., a formulation, preparation, or medicament) comprising the compound together with one or more other pharmaceutically acceptable ingredients.

[0274] Accordingly, the invention provides a pharmaceutical composition for use in a method of the first, second, third, fourth, fifth, sixth or seventh aspects, wherein the pharmaceutical composition comprises cannabidiol, or a pharmaceutically acceptable salt thereof, together with one or more pharmaceutically acceptable ingredients.

[0275] Similarly, the invention provides a pharmaceutical composition for use in a method of the first, second, third, fourth, fifth, sixth or seventh aspects, wherein the pharmaceutical composition comprises cenobamate, or a pharmaceutically acceptable salt thereof, together with one or more pharmaceutically acceptable ingredients.

[0276] Suitable pharmaceutically acceptable ingredients (e.g. carriers, diluents, excipients, etc.) can be found in standard pharmaceutical texts, for example, Remington: The Science and Practice of Pharmacy, 20th Edition, 2000, pub. Lippincott, Williams & Wilkins; and Handbook of Pharmaceutical Excipients, 9th edition, 2020, pub. Pharmaceutical Press.

[0277] Examples of suitable pharmaceutically acceptable ingredients include pharmaceutically acceptable carriers, diluents, excipients, adjuvants, fillers, buffers, binders, disintegrants, preservatives, antioxidants, lubricants, stabilisers, solubilisers, surfactants (e.g., wetting agents), masking agents, colouring agents, flavouring agents, and sweetening agents.

[0278] In one embodiment, the invention provides a pharmaceutical composition for use in a method of the first, second, third, fourth, fifth, sixth or seventh aspects, wherein the pharmaceutical composition comprises at least 5% (w / w) cannabidiol, or a pharmaceutical salt thereof. In one embodiment, the invention provides a pharmaceutical composition for use in a method of the first, second, third, fourth, fifth, sixth or seventh aspects, wherein the pharmaceutical composition comprises at least 10% (w / w), such as at least 10% (w / w), at least 15% (w / w), or at least 20% (w / w), cannabidiol, or a pharmaceutical salt thereof.

[0279] In one embodiment, the invention provides a pharmaceutical composition for use in a method of the first, second, third, fourth, fifth, sixth or seventh aspects, wherein the pharmaceutical composition comprises at least 5% (w / w) cenobamate, or a pharmaceutical salt thereof. In one embodiment, the invention provides a pharmaceutical composition for use in a method of the first, second, third, fourth, fifth, sixth or seventh aspects, wherein the pharmaceutical composition comprises at least 10% (w / w), such as at least 10% (w / w), at least 15% (w / w), or at least 20% (w / w), cenobamate, or a pharmaceutical salt thereof.

[0280] The pharmaceutical compositions may be in any suitable form. Examples of suitable forms include liquids, solutions (e.g., aqueous, nonaqueous), suspensions (e.g., aqueous, non-aqueous), emulsions (e.g., oil-in-water, water-in-oil), syrups, electuaries, mouthwashes, drops, tablets (including, e.g., coated tablets), granules, powders, losenges, pastilles, capsules (including, e.g., hard and soft gelatin capsules), cachets, pills, ampoules, boluses, suppositories, pessaries, tinctures, gels, pastes, ointments, creams, lotions, oils, foams, sprays, and aerosols.

[0281] In one embodiment, the pharmaceutical composition comprising cannabidiol is Epidiolex™ / Epidyolex™ .

[0282] In one embodiment, the pharmaceutical composition comprising cenobamate is Xcopri™ / Ontozry™Kits

[0283] In a tenth aspect of the invention, there is provided a kit for use in a method of the first, second, third, fourth, fifth, sixth or seventh aspects, wherein the kit comprises a pharmaceutical composition comprising cannabidiol, or a pharmaceutically acceptable saltthereof, and a pharmaceutical composition comprising cenobamate, or a pharmaceutically acceptable salt thereof.

[0284] In one embodiment, the kit further comprises instructions for carrying out the method of the first, second, third, fourth, fifth, sixth or seventh aspects.Other Aspects and Embodiments

[0285] Unless context dictates otherwise, the descriptions and definitions of the features set out above are not limited to any particular aspect or embodiment of the invention and apply equally to all aspects and embodiments which are described.

[0286] Each and every compatible combination of the embodiments described above is explicitly disclosed herein, as if each and every combination was individually and explicitly recited.

[0287] Various further aspects and embodiment of the present invention will be apparent to those skilled in the art in view of the present disclosure.Definitions

[0288] To aid understanding, certain terms employed in the specification, examples and appended claims are collected here. These definitions should be read in light of the remainder of the disclosure and as understood by a person of skill in the art. Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by a person of ordinary skill in the art.

[0289] Unless the context requires otherwise, throughout this specification and claims, the words “comprise,” “comprising” and the like are to be construed in an open, inclusive sense; the words “a,” “an,” and the like are to be considered as meaning at least one and are not limited to just one; and the term “about” is to be construed as meaning plus or minus 10%. Terms not specifically defined herein should be given the meanings that would be given to them by one of skill in the art in light of the disclosure and the context.

[0290] The Combination Index (Cl) as used herein provides a quantitative measure of the degree of drug interaction, where Cl < 1 indicates synergism, Cl = 1 indicates an additive effect, and Cl > 1 indicates antagonism, for a given endpoint of the measured effect [Chou, et al., 2006], The Cl for a drug combination is based on a unified theory for median-effect, combining major equations in biochemistry and biophysics, such as Michaelis-Menten, Hill, Henderson-Hasselback and Scatchard [Chou, et al., 2006 and Chou, et al., 2010],

[0291] Exposure Reduction Index (ERI) as used herein provides a quantitative measure of any reduction of each drug in a synergistic combination at a given effect level compared with the exposures of each drug when administered alone [Chou, et al., 2006 and Chou, et al., 2010],

[0292] The term “inadequate responder” as used herein refers to a patent or subject who does not achieve >50% seizure reduction when administered a given medication in comparison to treatment without that medication.

[0293] The terms “individual,” “patient,” or “subject” are used interchangeably and include any animal, including mammals, preferably mice, rats, other rodents, rabbits, dogs, cats, swine, cattle, sheep, horses, or primates, and most preferably humans. The compounds or pharmaceutical compositions of the disclosure can be administered to a mammal, such as a human, but can also be administered to other mammals such as an animal in need of veterinary treatment, e.g., domestic animals e.g., dogs, cats, and the like), farm animals {e.g., cows, sheep, pigs, horses, and the like) and laboratory animals {e.g., rats, mice, guinea pigs, dogs, primates, and the like). The mammal treated in the methods of the disclosure is desirably a mammal in which treatment of seizures is desired.

[0294] The term “maintenance dose” as used herein is the dosage of a drug administered to keep the plasma concentration of a drug within a desired level at steady-state.

[0295] The term “pharmaceutically acceptable” include molecular entities and compositions that do not produce an adverse, allergic or other untoward reaction when administered to an animal, or a human, as appropriate.

[0296] Throughout the specification, unless specified otherwise, references to the amount of cannabidiol will be understood to refer to the amount of cannabidiol on a free acid basis, even if the compound is present as a salt of cannabidiol. Purely by way of example, reference to 10 mg of cannabidiol or a pharmaceutically acceptable salt thereof, will be understood to refer to 10 mg of the free acid, or a pharmaceutically acceptable salt of cannabidiol with 10 mg of free acid equivalent.

[0297] Throughout the specification, unless specified otherwise, references to the amount of cenobamate will be understood to refer to the amount of cenobamate on a free base basis, even if the compound is present as a salt of cenobamate. Purely by way of example, reference to 10 mg of cenobamate or a pharmaceutically acceptable salt thereof, will be understood to refer to 10 mg of the free base, or a pharmaceutically acceptable salt of cannabidiol with 10 mg of free base equivalent.

[0298] The term “pharmaceutically acceptable carrier” or “pharmaceutically acceptable excipient” as used herein refers to any and all solvents, dispersion media, coatings, fillers, and the like, that are compatible with pharmaceutical administration. The use of such media and agents for pharmaceutically active substances is well known in the art. The compositions may also contain other active compounds providing supplemental, additional, or enhanced therapeutic functions.

[0299] The term “pharmaceutical composition” as used herein refers to a composition comprising at least one compound as disclosed herein formulated together with one or more pharmaceutically acceptable carrier, diluent or excipient.

[0300] The term “simultaneous” as used here refers to administration of two or more drugs on the same day. Suitably, the two or more drugs are administered within 5, 10, 15, 20, 30, 60, 120 minutes of each other.

[0301] The term “sequentially” as used herein means that one drug is administered after the other (i.e. separately), however, the time period between the administration of each drug is such that both agents are capable of acting therapeutically concurrently. Thus, administration "sequentially" may permit one drug to be administered within a matter of hours or even days after the other provided that the circulatory half-life of the first administered drug is such that they are both concurrently present in therapeutically effective amounts. The time delay between the administration of the drugs may vary depending on the exact nature of the drugs, the interaction therebetween, and their respective half-lives.

[0302] The term “therapeutically effective amount” or “effective amount” as used herein refers to the amount of the subject compound that will elicit the biological or medical response of a tissue, system or animal, (e.g. mammal or human) that is being sought by the researcher, veterinarian, medical doctor or other clinician. The compounds or pharmaceutical compositions of the disclosure are administered in therapeutically effective amounts to treat a disease. Alternatively, a therapeutically effective amount of a compound is the quantity required to achieve a desired therapeutic and / or prophylactic effect.

[0303] The term “treating” includes any effect, e.g., lessening, reducing, modulating, or eliminating, that results in the improvement of the disease.Abbreviations

[0304] To aid understanding, certain abbreviations employed in the specification, examples and appended claims are collected here.EmbodimentsThe following paragraphs are not claims, but represent preferred aspects and embodiments of the invention.1. A method of treating seizures in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of cannabidiol, or a pharmaceutically acceptable salt thereof, in combination with a therapeutically effective amount of cenobamate, or a pharmaceutically acceptable salt thereof.2. The method of paragraph 1 , wherein the seizures are focal onset seizures, generalised onset seizures, seizures with unknown onset, or a combination of any of these seizures.3. The method of paragraph 1 or 2, wherein the seizures are selected from absence seizures, atypical absence seizures, atonic seizures, clonic seizures, tonic seizures, tonic-clonic seizures, febrile seizures, focal to bilateral tonic clonic seizures, gelastic and dacrystic seizures, myoclonic seizures, myoclonic-tonic-clonic seizures, myoclonic-atonic seizures and epileptic (or infantile) spasms.4. The method of paragraph 1 , wherein the seizures are generalised onset seizures.5. The method of paragraph 1 , wherein the seizures are a combination of focal onset seizures and generalised onset seizures.6. The method of any one of paragraphs 1 to 5, wherein the seizures are associated with epilepsy.7. The method of paragraph 6, wherein the epilepsy is an epileptic syndrome selected from syndromes with onset in neonates and infancy, syndromes with onset in childhood,syndromes with onset at a variable age, and idiopathic generalised epilepsy syndromes (IGEs).8. The method of paragraph 6 or 7, wherein the epilepsy is characterised as a refractory epilepsy.9. The method of any one of paragraphs 1 to 8, wherein the cannabidiol, or a pharmaceutically acceptable salt thereof, and the cenobamate, or a pharmaceutically acceptable salt thereof, are administered simultaneously or sequentially.10. The method of any one of paragraphs 1 to 9, wherein the cannabidiol, or a pharmaceutically acceptable salt thereof, and the cenobamate, or a pharmaceutically acceptable salt thereof, are administered in separate dosage forms.11. The method of any one of paragraphs 1 to 10, wherein the method provides a synergistic therapeutic effect in the treatment of seizures as compared to the effect of cannabidiol or cenobamate when administered independently.12. The method of paragraph 11 , wherein the synergistic therapeutic effect is a reduction in the occurrence and / or severity of seizures.13. The method of paragraph 11 or 12, wherein the synergistic therapeutic effect comprises a pharmacodynamic synergistic effect.14. The method of any one of paragraphs 11 to 13, wherein the synergistic therapeutic effect is characterised as a Combination Index of less than 1 , such as less than 0.8.15. The method of any one of paragraphs 11 to 14, wherein the synergistic therapeutic effect is characterised as an Exposure Reduction for cannabidiol and / or cenobamate of greater than 1.16. The method of any one of paragraphs 1 to 15, wherein cannabidiol, or a pharmaceutically acceptable salt thereof, and cenobamate, or a pharmaceutically acceptable salt thereof, are administered to provide a fixed-exposure ratio for cannabidiokcenobamate in the subject of between about 1 :3 to about 3:1 , calculated based on b-EEso values of the individual compounds.17. The method of any one of paragraphs 1 to 16, wherein the amount of cannabidiol, or a pharmaceutically acceptable salt thereof, administered to the subject is from about 5 mg / kg / day to about 25 mg / kg / day and the amount of cenobamate, or a pharmaceutically acceptable salt thereof, administered to the subject is from about 12.5 mg / day to about 400 mg / day.18. The method of any one of paragraphs 1 to 17, wherein the amount of cannabidiol, or a pharmaceutically acceptable salt thereof, administered to the subject is up to 3-fold lower when cannabidiol, or a pharmaceutically acceptable salt thereof, is administered in combination with cenobamate, or a pharmaceutically acceptable salt thereof, than whencannabidiol, or a pharmaceutically acceptable salt thereof, is administered to the subject without cenobamate, or a pharmaceutically acceptable salt thereof. The method of any one of paragraphs 1 to 18, wherein the amount of cenobamate, or a pharmaceutically acceptable salt thereof, administered to the subject is up to 3-fold lower when cenobamate, or a pharmaceutically acceptable salt thereof, is administered in combination with cannabidiol, or a pharmaceutically acceptable salt thereof, than when cenobamate, or a pharmaceutically acceptable salt thereof, is administered to the subject without cannabidiol, or a pharmaceutically acceptable salt thereof. The method of any one of paragraphs 1 to 17, wherein both the amount of cannabidiol, or a pharmaceutically acceptable salt thereof, and the amount of cenobamate, or a pharmaceutically acceptable salt thereof, administered to the subject are up to 3-fold lower when administered in combination, than when either drug is administered without the other. The method of any one of paragraphs 1 to 18, wherein the amount of cannabidiol, or a pharmaceutically acceptable salt thereof, administered to the subject is: i) reduced by up to 4-fold, conveniently such as reduced by up to 3-fold, up to 2- fold, or up to 1.5-fold; or ii) reduced by up to 65%, conveniently such as reduced by up to 60%, up to 50%, up to 40%, or up to 30%; or iii) reduced by up to two thirds, conveniently such as reduced by up a third, or a half, in comparison to administration without cenobamate, or a pharmaceutically acceptable salt thereof. The method of any one of paragraphs 1 to 18, wherein the cannabidiol, or a pharmaceutically acceptable salt thereof, is administered at: i) a reduced maintenance dosage 2.5 to 8 mg / kg / day; or ii) a reduced maximum dosage of less than 25 mg / kg / day. The method of any one of paragraphs 1 to 18, wherein the amount of cenobamate, or a pharmaceutically acceptable salt thereof, administered to the subject is: i) reduced by up to 4-fold, conveniently such as up to 3-fold, up to 2-fold, or up to 1.5-fold; or ii) reduced by up to 65%, such as up to 60%, up to 50%, up to 40%, or up to 30%; or iii) reduced by up to two thirds, conveniently such as a third, or a half,in comparison to administration without cannabidiol, or a pharmaceutically acceptable salt thereof.24. The method of any one of paragraphs 1 to 18, wherein the cenobamate, or a pharmaceutically acceptable salt thereof, is administered at: i) a reduced maintenance dosage of 50 to 100 mg / day; or ii) a reduced maximum dosage of 100 to 387.5 mg / day.25. The method of any one of paragraphs 1 to 24, wherein the amount of cannabidiol, or a pharmaceutically acceptable salt thereof, administered to the subject is from about 2.5 mg / kg / day to about 25 mg / kg / day and the amount of cenobamate, or a pharmaceutically acceptable salt thereof, administered to the subject is from about 12.5 mg / day to about 400 mg / day.26. The method of any one of paragraphs 1 to 25, wherein cannabidiol, or a pharmaceutically acceptable salt thereof, is administered to the subject at a starting dose for a period of time followed by a maintenance dose and the maintenance dose is lower than 10 mg / kg / day.27. The method of any one of clams 1 to 26, wherein cannabidiol is administered to the subject once daily.28. A method of treating seizures in a subject in need thereof, wherein the method comprises the steps of: a. administering to the subject a starting dosage of cannabidiol, or a pharmaceutically acceptable salt thereof, for a first period of time; b. after the first period of time, increasing the dosage of cannabidiol, or a pharmaceutically acceptable salt thereof, to achieve a maintenance dosage for a second period of time; c. after the second period of time, reducing the maintenance dosage of cannabidiol, or a pharmaceutically acceptable salt thereof, by up to 4-fold for a third period of time; and d. after the third period of time, administering cenobamate, or a pharmaceutically acceptable salt thereof; wherein optionally steps c. and d. are carried out concurrently.29. A method of treating seizures in a subject in need thereof, wherein the method comprises the steps of: a. administering to the subject a starting dosage of cenobamate, or a pharmaceutically acceptable salt thereof, for a first period of time;b. after the first period of time, increasing the dosage of cenobamate, or a pharmaceutically acceptable salt thereof, to achieve a maintenance dosage for a second period of time; c. after the second period of time, reducing the maintenance dosage of cenobamate, or a pharmaceutically acceptable salt thereof, by up to 4-fold for a third period of time; and d. after the third period of time, administering cannabidiol, or a pharmaceutically acceptable salt thereof; wherein optionally steps c. and d. are carried out concurrently. A method of initiating treatment with cenobamate, or a pharmaceutically acceptable salt thereof, in a subject who is suffering from seizures and who is already being treated with a maintenance dose of cannabidiol, or a pharmaceutically acceptable salt thereof, the method comprising the steps of: a. administering a starting dosage of cenobamate, or a pharmaceutically acceptable salt thereof, to the subject for a first period; b. optionally, increasing the dosage of cenobamate, or a pharmaceutical acceptable salt thereof, following a cenobamate titration regimen for a cenobamate titration period; and c. administering a reduced maintenance dosage of cenobamate, or a pharmaceutically acceptable salt thereof, to the subject, wherein, the reduced maintenance dosage of cenobamate, or a pharmaceutically acceptable salt thereof, is reduced in comparison to treatment with cenobamate independently. A method of initiating treatment with cannabidiol, or a pharmaceutically acceptable salt thereof, in a subject who is suffering from seizures and who is already being treated with a maintenance dose of cenobamate, or a pharmaceutically acceptable salt thereof, the method comprising the steps of: a. administering a starting dosage of cannabidiol, or a pharmaceutically acceptable salt thereof, to the subject for a first period; b. optionally, increasing the dosage of cannabidiol, or a pharmaceutical acceptable salt thereof, following a cannabidiol titration regimen for a cannabidiol titration period; and c. administering a reduced maintenance dosage of cannabidiol, or a pharmaceutically acceptable salt thereof, to the subject,wherein the reduced maintenance dosage of cannabidiol, or a pharmaceutically acceptable salt thereof, is reduced in comparison to treatment with cannabidiol independently.32. A method of initiating treatment with cenobamate, or a pharmaceutically acceptable salt thereof, in a subject who is suffering from seizures and who is already being treated with cannabidiol, or a pharmaceutically acceptable salt thereof, the method comprising the steps of: a. reducing the dosage of cannabidiol, or a pharmaceutically acceptable salt thereof, being administered to the subject; b. administering a reduced maintenance dosage of cannabidiol, or a pharmaceutically acceptable salt thereof, to the subject; and c. administering a starting dosage of cenobamate, or a pharmaceutically acceptable salt thereof to the subject.33. A method of initiating treatment with cannabidiol, or a pharmaceutically acceptable salt thereof, in a subject who is suffering from seizures and who is already being treated with cenobamate, or a pharmaceutically acceptable salt thereof, the method comprising the steps of: a. reducing the dosage of cenobamate, or a pharmaceutically acceptable salt thereof, being administered to the subject; b. administering a reduced maintenance dosage of cenobamate, or a pharmaceutically acceptable salt thereof, to the subject; and c. administering a starting dosage of cannabidiol, or a pharmaceutically acceptable salt thereof to the subject.34. The method of any one of paragraphs 1 to 33, wherein the subject is a human.35. The method of any one of paragraphs 1 to 34, wherein the combination is well tolerated.36. The method of paragraph 35, wherein the method of treating seizures lacks (or provides a reduction in) CNS related adverse effects, such as somnolence and / or sedative and / or other muscle coordination related adverse effects.37. The method of paragraph 35, wherein the method of treating seizures provides treatment without CNS related adverse effects, such as somnolence and / or sedative and / or other muscle coordination related adverse effects.38. The method of paragraph 36 or 37, wherein the CNS related adverse effect is somnolence.39. The method of any one of paragraphs 36 to 38, wherein the subject being treated exhibits CNS related adverse effect free days (per 28 days) of at least 20 days, such as least 25 days, at least 26 days, at least 27 days, or 28 days.40. The method of paragraph 35, wherein the method of treating seizures provides treatment without an increase in CNS related adverse effects, such as somnolence and / or sedative and / or other muscle coordination related adverse effects, in comparison to treatment without cannabidiol.41. The method of paragraph 40, wherein the occurrence of CNS related adverse effects (per 28 days) is within 35%, such as within 20%, such as within 15%, or such as within 10%, of the occurrence in treatment without cannabidiol.42. The method of paragraph 35, wherein the method of treating seizures provides treatment without an increase in CNS related adverse effects, such as somnolence and / or sedative and / or other muscle coordination related adverse effects, in comparison to treatment without cenobamate.43. The method of paragraph 42, wherein the occurrence of CNS related adverse effects (per 28 days) is within 35%, such as within 20%, such as within 15%, or such as within 10%, of the occurrence in treatment without cenobamate.44. The method of paragraph 35, wherein the method of treating seizures provides a reduction in CNS-related adverse effects, such as somnolence and / or sedative and / or other muscle coordination related adverse effects, in comparison to treatment without cannabidiol.45. The method of paragraph 44, wherein the median percentage reduction in frequency (per 28 days) of CNS-related adverse effects is at least 10%, such as at least 20%, at least 50%, at least 75%, or at least 100%, in comparison to treatment without cannabidiol.46. The method of paragraph 35, wherein the method of treating seizures provides a reduction in CNS-related adverse effects, such as somnolence and / or sedative and / or other muscle coordination related adverse effects, in comparison to treatment without cenobamate.47. The method of paragraph 46, wherein the median percentage reduction in frequency (per 28 days) of CNS-related adverse effects is at least 10%, such as at least 20%, at least 50%, at least 75%, or at least 100%, in comparison to treatment without cenobamate.48. The method of any one of paragraphs 1 to 47, wherein the subject is a patient whose seizures do not respond to treatment with either cannabidiol or cenobamate (“non responder”), or whose seizures are inadequately controlled by treatment with either cannabidiol or cenobamate (“inadequate responder”).49. The method of paragraph 48, wherein the subject is a cannabidiol non-responder, wherein adverse side effects prevent the subject from achieving a therapeutic dose and / or achieving adequate seizure control with cannabidiol without cenobamate.50. The method of paragraph 49, wherein the adverse side effects are CNS related adverse effects, such as somnolence and / or sedative and / or other muscle coordination related adverse effects.51. The method of paragraph 48, wherein the subject shows inadequate response to cannabidiol, wherein adverse side effects prevent the subject from achieving a therapeutic dose and / or achieving adequate seizure control with cannabidiol without cenobamate.52. The method of paragraph 51, wherein the adverse side effects are CNS related adverse effects, such as somnolence and / or sedative and / or other muscle coordination related adverse effects.53. The method of paragraph 48, wherein the subject is a cenobamate non-responder, wherein adverse side effects prevent the subject from achieving a therapeutic dose and / or achieving adequate seizure control with cenobamate without cannabidiol.54. The method of paragraph 53, wherein the adverse side effects are CNS related adverse effects, such as somnolence and / or sedative and / or other muscle coordination related adverse effects.55. The method of paragraph 48, wherein the subject shows inadequate response to cenobamate, wherein adverse side effects prevent the subject from achieving a therapeutic dose and / or achieving adequate seizure control with cenobamate without cannabidiol.56. The method of paragraph 55, wherein the adverse side effects are CNS related adverse effects, such as somnolence and / or sedative and / or other muscle coordination related adverse effects.57. A pharmaceutical composition comprising cannabidiol, or a pharmaceutically acceptable salt thereof, for use in a method according to any one of paragraphs 1 to 56.58. A pharmaceutical composition comprising cenobamate, or a pharmaceutically acceptable salt thereof, for use in a method according to any one of paragraphs 1 to 56.59. A kit comprising a pharmaceutical composition comprising cannabidiol, or a pharmaceutically acceptable salt thereof, for oral administration and a pharmaceutical composition comprising cenobamate, or a pharmaceutically acceptable salt thereof, for oral administration, wherein said kit is for use in a combination therapy as defined in any one of paragraphs 1 to 56.WORKING EXAMPLES

[0305] Certain aspects and embodiments of the invention are illustrated by the following non-limiting examples.1 : Anticonvulsant studies with cannabidiol and cenobamate

[0306] The MES model [Luszczki et al, 2010] in male C57BI / 6J mice was employed to evaluate anticonvulsive properties of cannabidiol and cenobamate alone and, subsequently, any cannabidiokcenobamate pharmacodynamic interaction when given in combination.

[0307] The MES test is widely utilized pre-clinically to evaluate anticonvulsive properties of molecules and standard ASMs. This is a stringent model in which mice receive a predetermined high-level electrical stimulus of sufficient intensity to reliably produce tonic hindlimb extensor seizures in 100% of control animals. As such the maximal electroshock test provides a rigorous evaluation of anticonvulsive efficacy [Loscher et al, 1991; Swinyard et al, 1985],

[0308] Mice were pretreated with 10-100 mg / kg i.p. plant-derived, highly purified cannabidiol or 1-30 mg / kg i.p. cenobamate (Charles River Laboratories) before receiving a pre-validated fixed current intensity electrical stimulus via corneal stimulation (30 mA, 0.2 sec duration).

[0309] Antiseizure efficacy was determined by the absence of tonic hindlimb extension, indicative of generalized tonic clonic seizures. Exposures of cannabidiol, its active metabolite 7-hydroxy-cannabidiol, and cenobamate were quantified in plasma and brain (samples collected immediately after the seizure test) using liquid chromatography / tandem mass spectrometry (LC-MS / MS). The overall effect of [cannabidiol+7-hydroxy-cannabidiol] was estimated in brain after normalizing 7-hydroxy-cannabidiol potency to that of cannabidiol [Rana et al, 2023], Log(brain exposure)-probits (efficacy) plots were used for each ASM alone to derive effective brain exposures protecting 50% animals (b-EEso). Mice were then treated with three fixed ratios of cannabidiokcenobamate (1 :3, 1 :1 and 3:1) using Loewe’s equation of additivity that yield a theoretically derived additive effect (b-EEso+ADD) to perform the isobolographic analysis and quantitatively assess any additivity, antagonism or synergy [Luszczki et al 2009],

[0310] Cannabidiol and cenobamate each produced brain exposure-dependent anticonvulsive effects in the MES test (b-EEso: cannabidiol 14.89 pM and cenobamate 12.30 pM). Isobolographic analysis based on equi-effective b-EEsos revealed pharmacodynamic synergism between cannabidiokcenobamate at all three EESO+ADD ratios 1 :3, 1 :1 and 3:1 in the absence of any pharmacokinetic interactions. Pharmacodynamic synergy was also reflected by a Combination Index <1 (synergism) and an Exposure Reduction Index >1 (indicative of reduction of exposures in synergistic combination versus each single administration). Anticonvulsive effects were noted in the absence of any behavioural observations such as ataxia and reduced locomotion.

[0311] This study demonstrated a novel and surprising synergistic PD-DDI between cannabidiol and cenobamate in the mouse MES model of acute generalized seizures.Materials and MethodsTest Articles and Vehicle Controls:

[0312] Cannabidiol was provided by Jazz Pharmaceuticals. The cannabidiol was of botanical origin. The cannabidiol had a purity of >98.0% by HPLC-UV and contained less than 0.04% w / w THC.

[0313] Cenobamate was manufactured by Charles River. The cenobamate had a purity of >99% by HPLC-UV.

[0314] Valproic acid sodium salt (sodium valproate) was purchased from Sigma Aldrich (product number P4542). The sodium valproate had a purity of greater than 97.5% (by gas chromatography).

[0315] The Vehicle used in all cases was 1:1 :18 Ethanol: Kolliphor EL:0.9% physiological saline.Dose Formulation:

[0316] Cannabidiol: A cannabidiol stock solution (10 mg / mL) was prepared. Cannabidiol (100 mg) was weighed out and ethanol (500 pL) was added followed by Kolliphor EL (500 pL; warmed to 60°C). The mixture was stirred and vortexed until clear. 0.9% Physiological saline (9 mL) was added slowly to make up to volume. Serial dilution with vehicle was used prepare compound for dosing at appropriate concentration. A white, homogeneous suspension was obtained. The mixture was prepared immediately prior to dosing and continuously stirred until and during dosing.

[0317] Cenobamate: A cenobamate stock solution (3 mg / mL) was prepared. Cenobamate (21 mg) was weighed out and ethanol (350 pL) was added followed by Kolliphor EL (350 pL; warmed to 60°C). The mixture was stirred and vortexed until clear. 0.9% Physiological saline (6.3 mL) was added slowly to make up to volume. Serial dilution with vehicle was used prepare compound for dosing at appropriate concentration. A clear solution was obtained. The mixture was prepared immediately prior to dosing and continuously stirred until and during dosing.

[0318] Sodium valproate: A sodium valproate stock solution (25 mg / mL) was prepared. Sodium valproate 100 mg) was weighted out ethanol (200 pL) was added followed by Kolliphor EL (200 pL; warmed to 60°C). The mixture was stirred and vortexed until clear. 0.9% Physiological saline (3.6 mL) was added slowly to make up to volume. A clear solution was obtained. The mixture was prepared immediately prior to dosing.Study Animals:Table 1 : Study animalsStudy Procedures:

[0319] Naive mice were acclimatized to the procedure room in their home cages at least 7 days following arrival to the test facility, with food and water available ad libitum.

[0320] Animals [n=170, weight range 20-25 g (upon arrival) (Exp 1)] or [n=110, weight range 18.6-26 g (upon arrival) (Exp 2)] male C57BI / 6J mice from Charles River UK, approximately aged 6-7 weeks (upon arrival)] were housed in groups of 5, in standard caging with free access to food and water on a 12h / 12h light / dark cycle from arrival (lights on at 7:00AM).

[0321] The experimental parameters for Experiments 1 and 2 are set out in Table 2 and Table 3, below.

[0322] Animals were dosed (10 mL / kg) via intraperitoneal injection at 60 min for cannabidiol [Rana et al, 2023] and 30 min for cenobamate ptt, prior to MES and before plasma and brain sampling immediately post-MES test. Based on a mean distribution of body weight across groups, all animals were randomly assigned to vehicle 1 :1:18 (Ethanol: Kolliphor EL (Cremaphor): 0.9% saline), valproate (positive control) at 250 mg / kg, cannabidiol at [10, 30, 50, 70, and 100 mg / kg (Exp 1)] or [13.91, 27.86, and 41.77 mg / kg (Exp 2)], cenobamate at [1, 3, 5, 10, and 30 mg / kg (Exp 1)] or [2.47, 1.72 and 0.98 mg / kg (Exp 2)] and cannabidiokcenobamate at [13.91:2.47, 27.86:1.72, 41.77:0.98 mg / kg (Exp 2)].

[0323] Animals were observed throughout the study from the start of dosing. Any abnormal signs were recorded and reported. Mice were individually assessed for production of tonic hindlimb extensor seizure following a pre-determined high level (30 mA; 50 Hz) corneally delivered electroshock (0.2 second duration) of sufficient intensity to reliably produce tonic hind limb extensor seizures in 100% of control animals. The percentage of inhibition of seizure from the control group was determined.Table 2: Experimental parameters for Experiment 1Table 3: Experimental parameters for Experiment 2*reference (positive) controlSample Collection:

[0324] Each animal was humanely killed immediately after production of a convulsion or within 10 s following electroshock (whichever is earlier) by concussion of the brain from striking the cranium, followed by the confirmation of permanent cessation of the circulation from decapitation in accordance with The Humane Killing of Animals under Schedule 1 to the Animals (Scientific Procedures) Act 1986. Terminal blood and brain collection were performed following decapitation.

[0325] Blood was collected in EDTA tubes and centrifuged at 4°C for 10 min at 1500 x g. The resulting plasma was removed (200 L) and split into 2 aliquots stored in 0.5 mL Eppendorf tubes, containing 100 pL of ascorbic acid (100 mg / mL) for stabilisation. Brains were removed, washed in 0.9% physiological saline and halved. Left hemisphere was placed into separate 2 mL Precellys tubes and right hemisphere was placed into separate 5 mL Eppendorf tubes, weighed and frozen on cardice. Samples were stored at 80 °C.Data and StatisticsIsobolographic analysis:

[0326] The protective activities of cannabidiol and cenobamate administered alone were evaluated and expressed as effective doses (ED50; mg / kg based on dose administered) and effective exposures (EE50; pM based on bioanalysis of brain samples) where EX50 is defined as the dose or brain exposure required to protect 50% of mice from MES-induced tonic seizures. Cannabidiokcenobamate combinations were evaluated at three fixed ratios (1 :3, 1 :1 and 3:1) based on an EE50 derived from an assumption of linearly additive effects of EEs of the two drugs in combination (EESO+ADD).

[0327] For the three fixed-ratio cannabidiokcenobamate combinations (1 :3, 1 :1 and 3:1), calculations were based on Loewe’s equation of additivity [Andres-Mach et al, 2014; Loewe et al, 1953] as follows; x / EEso(cannabidiol) + y / EEso(cenobamate) = 1 ; where x = the exposure of cannabidiol and y= the exposure at which cenobamate, when co-administered with cannabidiol, should theoretically exert an additive 50% effect. Doses versus exposures for cannabidiol, 7-hydroxy-cannabidiol and cenobamate were also plotted. Subsequently, cannabidiol and cenobamate doses corresponding to 50% of respective EE50 were used for the cannabidiokcenobamate 1 :1 ratio. Similarly, dose proportions were calculated for the cannabidiol: cenobamate 1 :3 and 3:1 ratios based on theoretical additive EESO+ADD. In order to permit estimation of the cumulative effect of a given treatment plus its active metabolite, metabolite exposures were normalised to parent potency. For 7-hydroxy-cannabidiol its potency was normalised to parent, cannabidiol, by a 5-fold increase [Rana et al, 2023],Statistical Analysis:

[0328] All statistical tests were performed using GraphPad Prism v10.0 (GraphPad Software, SaDiego, CA, USA). Any differences between individual treatment groups and vehicle-treated controls were assessed using 2-tailed Fisher’s Exact Probability Test (p<0.05 considered significant). All exposure datasets (pM; n=10) were tested for normal distribution using the Shapiro-Wilk test, GraphPad Prism. In the presence of nonparametric datasets, median values were used for non-parametric analysis: Kruskall-Walland Dunn’s comparison tests; presented as box (median / interquartile range) and whisker (minimum and maximum) plots) to analyse statistically significant PK effects.

[0329] The percentage protection of animals against MES-induced seizure were plotted against doses of ASM alone (cannabidiol or cenobamate) from Exp 1 as log-probit linear regression analysis [Litchfield and Wilcoxon et al, 1949; Berenbaum et al, 2006; Tallarida et al, 2012; Cadart et al, 2002; Arambasic et al, 2014; and Finney et al, 1947] to derive ED50 and EE50. For log-probit analysis, it is standard practice to select four doses that exhibit effects between 16% to 84% to determine effective doses for subsequent isobolographic analysis [Luszczki et al, 2010; Luszczki et al, 2009; Andres-Mach et al, 2014; Zarnowska et al, 2017; Naderi et al, 2008; Kondrat-Wrobel et al, 2006; Luszczki et a,l 2006], However, in the present study, the five doses selected for each of cannabidiol and cenobamate, yieldedeffects <16% for one dose and two doses =100%. The lowest data point for cannabidiol was excluded to: (1) avoid skewed line-fit, which otherwise did not include the top data point, and underestimated the overall ED50 for cannabidiol, and (2) to keep consistent with use of four data points for the other ASMs. Top data point for cenobamate was excluded to avoid skewed fit, as 100% maximal effect was reached at the penultimate dose.

[0330] Loewe’s equation of additivity [Arambasic et al, 2014] was used to determine fractions of EE50 in the three cannabidiokcenobamate ratios 1 :3, 1 :1 and 3:1. Graphs were plotted in Prism, for cannabidiol and cenobamate to determine relationships versus these exposures to determine actual doses for the combination study (Exp 2). DDI using these three fixed dose-ratios of cannabidiol: cenobamate was assessed using CalcuSyn v2.11 (Biosoft). CalcuSyn determines the median-effect potency of drug alone (Dm) that inhibits the system by 50% and the coefficient m signifies the shape of the dose-effect relationship, where m=1 , >1 and <1 indicate hyperbolic, sigmoidal and flat sigmoidal dose-effect curves. The combination index (Cl) equation below quantitatively defines DDI as synergy (Cl < 1 ), additivity (Cl= 1 ) or antagonism (Cl > 1 ) [Chou et al, 2006 and Chou et al, 2010]where Di and D2 are doses of drugs 1 and 2, fais the fraction affected by D (percent inhibition / 100), Dmis the median-effect dose and Dxis the dose required to inhibit the system by x%. Additionally, CalcuSyn was also used to generate normalized isobolograms for nonconstant dose-ratio DDI and dose / exposure reduction index (D / ERI) for specific effects. D / ERI expresses dose / exposure reduction by folds of each drug in a synergistic combination at a given effect level compared to single administration [Chou et al., 2006 and Chou et al., 2010],ResultsPercentage Inhibition of Electroconvulsive Activity by Cannabidiol or Cenobamate

[0331] Cannabidiol and cenobamate each showed dose-dependent efficacy on the incidence of maximal electroshock seizures when compared to vehicle. Analysis revealed statistically significant (p<0.05) anticonvulsive effects for cannabidiol (70-100 mg / kg) and cenobamate (5-30 mg / kg) (Figure 1).Log-Probits and Effective Doses for 50% Efficacy (ED50)

[0332] Log(dose) versus probits of effects (anticonvulsive efficacy) plots were prepared (Figure 2), goodness of fit assessed (R2>0.9) and ED50 values derived for each ASM (cannabidiol: 55.87 and cenobamate: 3.03; mg / kg). The lowest data point for cannabidiol was excluded to: (1) avoid skewed line-fit, which otherwise did not include the top data point, and underestimated the overall EDsofor cannabidiol, and (2) to keep consistent with use offour data points for cenobamate. Top data point for cenobamate was excluded to avoid skewed fit, as 100% maximal effect was already reached at the penultimate dose.Log-Probits and Effective (Brain) Exposures for 50% Efficacy (b-EEso)

[0333] Log(median brain exposures)versus probits of effects(anticonvulsive efficacy) plots were prepared (Figure 3), goodness of fit assessed (R2>0.8) and b-EEso values derived for each ASM (cannabidiol: 14.89 and cenobamate: 12.30; / zM). The same data exclusion criteria were included, as justified above.Dose-Exposure Relationships

[0334] Dose-brain exposures and dose-plasma relationships for each of the ASMs: cannabidiol and cenobamate were linear (Figure 4; R2>0.9).Determination of cannabidiokcenobamate combination doses

[0335] All data points were used for this analysis for each ASM, since there was no need and / or justification to exclude any data points in context of dose-exposure relationships. Based on the b-EEso values for each ASM and using Loewe’s equation of additivity, the fixed combination ratios of (1 :3, 1 :1 and 3:1) for 2-drug-DDI was calculated: cannabidiokcenobamate - 1 :3 (3.72:9.23; pM), 1 :1 (7.45:6.15; pM) and 3:1 (11.17:3.08; pM).

[0336] Subsequently, dose-median brain exposure plot and resulting linear equations were used to calculate combination doses for the isobolographic analyses (Figure 5), as follows: cannabidiokcenobamate - 1 :3 (13.91 :2.47; mg / kg), 1 :1 (27.86:1.72; mg / kg) and 3:1 (41.77:0.98; mg / kg).Percentage Inhibition of Electroconvulsive Activity by cannabidiokcenobamate DDI

[0337] 2-drug combinations of cannabidiokcenobamate produced significant (*p<0.05) anticonvulsive effects for all three ratios tested (1 :1 , 1 :3 and 3:1), when compared with vehicle (Figure 6). Effects from cannabidiol or cenobamate alone groups were as expected and consistent to the low dose group effects in the previous study (Figure 1). Single doses were run to assess any PK changes with / out co-administration of ASMs.Isobolographic Analysis of cannabidiokcenobamate DDI

[0338] Isobolographic DDI analysis using net brain exposures against efficacy, revealed synergy at all cannabidiokcenobamate (b-EEso+ADD) 1 :3, 1 :1 and 3:1 ratios tested. All combination data points lie under the theoretical line of additivity in the isobologram and each combination index (Cl) value was indicative of synergy (Cl < 1 ) (Figure 7). Coadministration of cannabidiokcenobamate resulted in 1.3- to 26.0-fold reduction in netbrain exposures, revealing synergy at all three ratios (exposure reduction index; ERM) (Figure 7B).Pharmacokinetic effects during the cannabidiol:cenobamate isobolographic DDI

[0339] When overall brain exposures were compared with / out concomitant administration at cannabidiokcenobamate (b-EEso+ADo) 1 :3, 1 :1 and 3:1 ratios tested, no statistical differences were noted, revealing PD synergy independent of PK effects (Table 4 andFigure 8).Table 4: Pharmacokinetic effect during cannabidiol and cenobamate coadministration in the mouse MED model using overall brain Cmax exposure (median)Conclusions

[0340] Cannabidiol and cenobamate showed independent antiseizure effects in the mouse MES model in dose- and exposure- dependent manners. Furthermore, when concentrations of active components of molecules: cannabidiol and 7-hydroxy-cannabidiol; and cenobamate were assessed in the brain, (i.e. , the site of action), and b-EEsos were calculated for combination DDI analysis, the cannabidiol: cenobamate DDI was synergistic. Brain and plasma concentrations of all active components were unaltered when compared between coadministered animals versus single administration, pointing towards PD synergy, independent of PK interactions. Thus, treatment with a combination of cannabidiol and cenobamate may provide an improved therapeutic effect in comparison to treatment with either component alone.Example 2: Evaluation of the combination of cannabidiol and cenobamate on motor coordination using the accelerating rotarod model in C57BL / 6J mice

[0341] This study assesses the tolerability profile for the combination of cannabidiol and cenobamate using the mouse rotarod test. The accelerating rotarod test is used to assess motor coordination and balance in rodents. It is routinely used preclinically to evaluate possible sedative or muscle coordination side effects of a drug.Introduction and Objectives

[0342] Evaluation of anti-seizure medicine (ASM) combinations of cannabidiol and cenobamate on motor coordination using the accelerating rotarod in C57BL / 6J mice. The accelerating rotarod test is used here to assess motor coordination and balance in mouse that were administered with combinations of cannabidiol and cenobamate to evaluate possible sedative or muscle coordination side effects.MethodsExperimental Procedures

[0343] Animals were dosed i.p. 60 minutes prior to testing (Ptt) with either 13.91, 27.86, 41.77 mg / kg cannabidiol, or Vehicle at 10 mL / kg. Thirty minutes prior to testing animals were then dosed i.p. with diazepam (control) 4 mg / kg or cenobamate 2.47, 1.72, 0.98 mg / kg (see Table 5).Table 5: Summary of test materials, formulations and doses used in the studyDose formulation and analysis

[0344] Cannabidiol- Dosage Form: Colourless solution- Dose Route: i.p.- Doses Tested: 41.77, 27.86, & 13.91 mg / kg- Dose Volume: 10 mL / kg- Vehicle: 1 :1 :18 Ethanol: Kolliphor EL: Saline

[0345] Cenobamate- Dosage Form: Colourless solution- Dose Route: i.p.- Doses Tested: 2.47, 1.72 & 0.98 mg / kg- Dose Volume: 5 m L / kg- Vehicle: 1 :1 :18 Ethanol: Kolliphor EL: Saline

[0346] Diazepam- Dosage Form Clear solution- Dose Route i.p.- Doses T ested 4 mg / kg- Concentration 10 mL / kg- Manufacturer Sigma- Vehicle 1 :1 :18 Ethanol: Kolliphor EL: SalineT est SystemRotarod training

[0347] Four animals were placed on the Rotarod at a time, with a starting speed of 4 rpm, accelerating 1 rpm per 8s finishing at 40 rpm. Animals were encouraged to remain on the Rotarod for a maximum of 300s (capturing the animal’s attention by finger clicking). This was repeated 3 times. Animals that failed to get to 300s were excluded from the final trial the following day.Pre-dose baseline method

[0348] On the morning of the test, the mice which had met the criteria from Day 1, 3, 5, and 7 were subjected to a further pre-dose baseline assessment prior to drug treatment. If an animal had not reached the full 300s on the rotarod during this pre-dose session, it would have been excluded from the study.Rotarod trial

[0349] All dosed animals were placed on the Rotarod in sets of four at each time point. Latency to falling off the Rotarod, or maximum of 300s was recorded for each animal, the test was repeated three times and recorded each time. Animals were returned to the home cage once the test was completed.

[0350] Each lane of the rotarod is cleaned before the start of each trial on training and test days (including prior to first use on each day) with 70% ethanol.

[0351] Terminal blood was collected via cardiac puncture into a K2EDTA tube. Blood was then centrifuged at 4°C for 10 minutes. 100 pL of plasma was then split equally into two 0.5 mL Eppendorf tubes which were prefilled with 100 pL ascorbic acid (100 mg / mL) in a 1 :1 v / v ratio for stabilisation. Samples were stored at -80°C until shipment for bioanalysis.

[0352] Brain samples were collected from all animals. Each one was washed in saline, halved. The left hemisphere was placed into a 2 mL Precellys tube and the right hemisphere into a 5 mL Eppendorf tube. These were weighed and frozen on cardice. Samples were stored at -80°C until shipment as per the protocol.

[0353] Animals were humanely killed in accordance with The Humane Killing of Animals under Schedule 1 to the Animals (Scientific Procedures) Act 1986.

[0354] All mice were trained to walk on the accelerating rotarod for at least 3 training trials the day (Days 1, 3, 5 and 7) prior to drug testing (Days 2, 4, 6 and 8) (see Table 6).Table 6: Details of training, pre-dose baseline and post dose trials on the accelerating rotarod

[0355] All animals were trained in succession on the 1sttrial before commencing the 2ndtrial and so on. This was to prevent habituation and muscle fatigue. During the first 180s of trial 1 , animals were encouraged to stay on the apparatus and placed on the rotarod several times during this trial. For all trials (including training trials), latency that each mouse falls off the rotarod the first time were recorded.Study AnimalsTable 7: Details of Study AnimalsData and Statistics

[0356] The median latency to fall from the 3 post-dose trials were analyzed using a Kruskal Wallis test followed by Dunn’s multiple comparison analysis if the Kruskal Wallis test was significant (p<0.05).

[0357] Data was tested for normality using d’Agostino-Pearson and shown to not follow a normal distribution, therefore a non-parametric test was utilized. The median latency to fall from the 3 post-dose trials were analyzed using a Kruskal Wallis test followed by Dunn’s multiple comparison analysis if the Kruskal Wallis test was significant p<0.05 (GraphPad, Prism v9.2.0). Results

[0358] Latency to fall from the rod was significantly lower (mean / 105s) in diazepam treated animals. All other compound treated animals showed no motor adverse effects and stayed 300s on the rod.

[0359] No adverse effects were observed in the animals after administration of the test compounds. Diazepam group showed general motor depression but no obvious grimace scale signs.Conclusions

[0360] Evaluation of combinations of cannabidiol and cenobamate on motor coordination using the accelerating rotarod in C57BL / 6J mice (non-GLP) showed no impact on motor coordination and balance in mouse, thereby lack of any sedative or muscle coordination side effects.Example 3: A phase 1, open-label, fixed-sequence pharmacokinetic study to investigate the pharmacokinetic drug-drug interaction between cenobamate and cannabidiol (oral solution) in healthy adult participants.

[0361] This Phase 1 , open-label, fixed-sequence, bidirectional drug-drug interaction (DDI) study evaluated the effects of repeated doses of cenobamate (CNB) on the PK of cannabidiol oral solution (CBD-OS) and the effect of repeated doses of cannabidiol on the PK of cenobamate in healthy adult participants. Approximately 20 participants were included, with 17 completing the study.

[0362] This study evaluated the potential bidirectional pharmacokinetic DDI, that is the effect of CBD-OS on CNB PK and vice versa upon steady-state, concomitant dosing of CBD-OS and CNB.Objectives and Endpoints

[0363] Table 8 describes the objectives and endpoints of the study.Table 8: Study objectives and endpointsAbbreviations: 7-COOH-CBD = 7-carboxy-cannabidiol; 7-OH-CBD = 7-hydroxy-cannabidiol; AUCo-i2h = area under the concentration-time curve from time zero to 12 hours postdose; AUCo-24h = area under the concentration time curve from time zero to 24 hours post-dose; BID = twice a day; CBD = cannabidiol; Cmax= maximum plasma concentration; CNB = cenobamate (Xcopri); C-SSRS = Columbia-Suicide Severity Rating Scale; CYP = cytochrome P450; ECG = electrocardiogram; OS = oral solution; PK = pharmacokinetic(s); QD = once daily; SS = steady state; TEAE = treatment-emergent adverse event.Overview of Study Design

[0364] This was a Phase 1, open-label, fixed-sequence, bidirectional PK DDI study in healthy adult participants. The study evaluated the effect of repeated administration of CNB on the steady-state PK of CBD and the effect of repeated administration of CBD-OS on the steady-state PK of CNB. Twenty participants were entered into the study to ensure that approximately 12 completed the study and were evaluable for PK.

[0365] The study comprised 4 periods: Screening (up to 28 days), CBD-OS dosing (5 days) with washout (7 days), CNB titration up to 200 mg (Days 13 to 93) and coadministration of CBD-OS with 200 mg CNB (Days 94 to 98). Over successive 14-day intervals, CNB was titrated from 12.5 mg once daily, followed by 25, 50, 100, and 150 mg once daily; 200 mg once daily CNB was administered for 11 days before coadministration with CBD-OS. Key assessments included PK sampling and safety evaluations at prespecified visits. The study start date was when the first participant signed informed consent and study end date was the date of the last scheduled assessment of the last participant.Selection of Study PopulationInclusion / Exclusion Criteria

[0366] The study population included healthy adult participants between 18 to 55 years of age, inclusive, with a body weight of at least 50 kg and a BMI within the range of 18.5 to 30.0 kg / m2(inclusive). Participants were healthy as determined by no clinically significant findings from medical history, PE, 12-lead ECG, vital sign measurements, and clinical laboratory tests.

[0367] Women were required to be of non-childbearing potential.Study Intervention

[0368] There was a single treatment arm in this study and all participants received the same study interventions. The study interventions in this study are described in Table 9. CBD-OS was dosed by weight (7.5 mg / kg BID). Participant weight on Day -1 was used for calculating dose on Days 1 to 5. If on Day 93 a participant’s weight had not changed by > 10% from Day -1, the participants Day -1 weight was used for weight-based dose calculations. If the participant’s weight changed > 10% on Day 93, Day 93 weight was used for weight-based dose calculations.Table 9: Study Interventions Administered

[0369] Participants were admitted for baseline assessments, then received CBD-OS 7.5 mg / kg BID on Days 1 to 4 and a single morning dose on Day 5, with all doses administered 30 minutes after initiation of a standard-calorie meal. Following a 7-day washout, CNB titration commenced at 12.5 mg daily on Day 13 and was escalated to 200 mg daily per dosing guidance. After receiving the first dose of CNB in each 2-week titration period, participants remained in the CRU for 3 days to assess safety prior to being checked out to complete dosing at home. On the last day of each titration period, the participants were checked in to the CRU for safety assessments and to prepare for the next dose in the titration. During the 200 mg CNB titration and coadministration with CBD-OS, participants remained in the CRU for the duration of the treatment period. On Days 94 to 98, participants received CBD-OS 7.5 mg / kg BID with CNB 200 mg once daily. Pharmacokinetic and safety assessments were conducted throughout the study.

[0370] Each participant took part in the study from the time they signed the ICF through the end of study procedures / contact. Each participant was enrolled for approximately 20 weeks.

[0371] Study interventions were taken for 13 weeks (91 days).Sample Analysis and Validation

[0372] Determination of CBD (and the metabolites 7-OH-CBD and 7-COOH-CBD) in plasma (EDTA) was performed using validated methods consisting of liquid-liquid extraction and analyzed using liquid chromatography / mass spectrometry. The bioanalytical method measured both CBD and the 7-OH-CBD metabolite in human matrix over the range of 1.00 to 1000 ng / mL and the 7-COOH-CBD metabolite over the range of 10.0 to 10,000 ng / mL.

[0373] Determination of CNB and its metabolite (CNB glucuronide) in plasma (EDTA) was performed using validated methods consisting of plasma protein precipitation and analyzed using liquid chromatography / mass spectrometry. The bioanalytical method measured CNB in human matrix over 50 ng / mL to 50,000 ng / mL, and metabolite (CNB glucuronide) over 2 ng / mL to 2000 ng / mL.Study ParticipantsDisposition of Participants

[0374] A total of 49 participants were enrolled, with 20 in the treated group and 29 classified as screen failures. All treated participants were included in the Safety and PK Analysis Sets. Seventeen (85.0%) participants completed the study, while 3 (15.0%) participants discontinued early due to TEAEs (2 [10.0%] participants) or positive urine drug screen on Day 40 (1 [5.0%] participant). Among screen failures, the most common reason was eligibility not met (25 [86.2%] participants), and 4 (13.8%) participants met eligibility criteria but were not needed.Analysis Sets

[0375] A total of 49 participants were included in the Enrolled Analysis Set, 29 of these were screen failed. There were 20 participants in the Safety Analysis Set and the PK Analysis Set. None of the 20 participants were excluded from any analysis set.Demographic and Other Baseline Characteristics

[0376] The participants were predominantly male (85.0%) and White (60.0%), with 40.0% identifying as Hispanic or Latino. Mean (SD) age was 33.8 (10.28) years, mean weight was 80.07 (11.316) kg, and mean BMI was 26.24 (2.619) kg / m2.Prior and Concomitant Therapy

[0377] There were no prior medications or procedures within 14 days or 5 half-lives of check-in of this study.

[0378] Four participants received concomitant medications other than acetaminophen, which was allowed at doses of < 2 grams / day for up to 3 consecutive days. One participant received polymyxin b / trimethoprim drops for a TEAE of conjunctivitis viral, 1 participant received epinephrine / lidocaine hydrochloride for a TEAE of skin mass (excised), 1 participant received 0.9% sodium chloride for a TEAE of diarrhea, and 1 participant received dextromethorphan hydrobromide / guaifensesin / paracetamol / pseudoephedrine hydrochloride for a TEAE of upper respiratory tract infection.Exposure and Study Intervention ComplianceExposure

[0379] Seventeen of 20 participants took all doses of study intervention as expected based on the protocol. Three of 20 participants discontinued the study prior to receiving all doses. One participant received their last dose of CBD-OS alone on Day 5 and did not receive any doses of CNB. This participant discontinued the study due to a TEAE. Two participants received all doses of CBD-OS alone and their last doses of 25 mg CNB on Day 40. One of these participants discontinued due to a TEAE and the other participant was withdrawn after a positive drug screen.Compliance With Intervention

[0380] CBD-OS study intervention was administered in the clinic by the investigator or designee and the date and time of each dose was recorded in the source documents.

[0381] Cenobamate was administered in the clinic by the investigator or designee and the date and time of each dose was recorded in the source documents, and also dispensed for participant self-administration at home.

[0382] Compliance for at-home dosing of CNB was assessed at each clinic visit by direct questioning, home telephone check-ins (conducted while participants were home dosing), review of participant diaries, and reconciling the number of CNB tablets dispensed and returned. All participants completing the study were compliant with study intervention.Evaluation of response to study interventionSafety Summary

[0383] There were no deaths or SAEs reported in this study.

[0384] Fifteen (75.0%) participants overall reported at least 1 TEAE. Treatment-emergent AEs leading to discontinuation from the study were reported in 2 (10.0%) participants overall (Table 10), 1 participant with moderate rash maculo-papular from the CBD-OS treatment period and 1 participant with mild dermatitis from the CNB treatment period.

[0385] Across treatment periods, TEAEs occurred in 10 (50.0%) participants in the CBD-OS treatment period (Days 1 to 5) and washout period, 12 (63.2%) participants in the CNB treatment period (Days 13 to 93), and 4 (23.5%) participants in the CBD-OS + CNB treatment period (Days 94 to 98) through to the follow-up visits.

[0386] The majority of TEAEs were mild and reported across all treatment periods (7 [35.0%] participants in the CBD-OS treatment period and washout period, 8 [42.1%] participants in the CNB treatment period, and 4 [23.5%] participants in the CBD-OS + CNB treatment period through to the follow-up visits), while moderate TEAEs were less frequent (3 [15.0%] participants in the CBD-OS treatment period and washout period and 4 [21.1%] participants in the CNB treatment period). There were no severe TEAEs reported (Table 10).

[0387] There were no trends of clinical concern in laboratory parameters and abnormal laboratory findings reported in individual participants did not impact participant safety or study outcomes.

[0388] No clinically meaningful findings were observed in the vital sign measurements or ECG measurements in this study. No concerns were identified on the C-SSRS in this study. Seven of 20 participants overall showed clinically significant changes on physical examination, all of which were captured as TEAEs.Table 10: Overall Summary of Treatment-Emergent Adverse Events (Safety Analysis Set)Abbreviations: % = number of participants (n) as a percentage of number of participants (N) per treatment period; N = number of participants exposed per treatment period; n = number of participants who experienced the TEAE; SAE = serious adverse event; TEAE = treatment-emergent adverse event.Note: For TEAEs by intensity, participants with multiple events were counted under the category of their most intense event; and where multiple TEAEs were reported for the same participant across treatment periods, they appear in more than 1 column, but are counted only once in the overall column.Discontinuations and / or Dose Modifications Due to Adverse Events

[0389] There were 2 participants who discontinued the study due to TEAEs. One participant experienced a moderate intensity TEAE of rash maculo-papular during washout on Day 10 that was determined to be related to treatment (CBD-OS). The last dose of CBD- OS was on Day 5. The TEAE was 7 days 22 hours in duration. Another participant experienced a mild intensity dermatitis on Day 33 that was determined to be not related to treatment (CNB). The TEAE was approximately 8 days in duration and resolved after study intervention was withdrawn.Evaluation Clinical Laboratory Tests

[0390] Clinical laboratory abnormalities were distributed across CBD-OS, CNB, and CBD- OS + CNB treatment periods, with no clear pattern of increased frequency in any specific arm. Abnormalities included changes in ALT, GGT, serum creatinine, and creatine kinase for clinical chemistry and hemoglobin and hematocrit for hematology analysis. These abnormalities were not associated with clinical symptoms or adverse outcomes. None of the findings were deemed clinically significant by the investigators.

[0391] Mean serum creatinine values were noted to be marginally increased from baseline while the participants were on CBD-OS +CNB. The maximum mean change from baseline was 0.126 mg / dL on Day 99. As expected, this was reflected in a slight decrease in themean eGFR on those days. A slight rise in creatinine has been observed in other CBD studies and mean creatinine values were trending downwards by the Follow-up Visits. No such trend was noted with urea.

[0392] A slight but noticeable elevation of mean GGT values reaching a maximum mean of 43.6 U / L (maximum mean change from baseline was 22.2 ll / L) on Day 96 started while participants were on CNB, but began to show a downward trend by the Follow-up Visits.

[0393] In summary, these laboratory abnormalities were not clinically meaningful or were known effects of the study interventions (Epidiolex, 2025 and Xcopri, 2024) and did not impact participant safety or study outcomes. No new safety signals were identified for CBD- OS or CNB when administered alone or in combination.

[0394] Positive drug screens were found in some participants. It should be noted that all but 1 of these positive drug screens were for cannabinoids and occurred after these participants were dosed with CBD-OS. One participant screened positive for methamphetamines on Day 40 and was discontinued from the study.Other Safety Evaluations

[0395] No clinically meaningful findings were observed in the vital sign measurements or ECG measurements in this study.

[0396] Seven of 20 participants overall showed clinically significant changes on physical examination, all of which were captured as TEAEs. Clinically significant physical examination findings included dermatitis in 1 participant and maculopapular rash in 1 participant which led to discontinuation of each participant from the study; conjunctival findings in 2 participants; musculoskeletal tenderness in 1 participant; abrasions, tenderness, swelling, and ecchymosis in 1 participant; and cystic lesion on scrotum in 1 participant.

[0397] No concerns were identified on the C-SSRS in this study.PharmacokineticsPlasma Concentrations of Cannabidiol and Cenobamate

[0398] Based on the pre-dose plasma concentration of CBD on Days 3, 4, and 5, CBD appeared to reach steady-state exposures by Day 5. Cenobamate exposures increased with each successive up titration, and appeared to reach steady state at 200 mg dose by Day 93 (see Figure 9 and Figure 10).

[0399] Note: On Day 5, participants received 7.5 mg / kg CBD-OS morning dose only. On Day 98, participants received 7.5 mg / kg CBD-OS twice a day + 200 mg CNB once daily in the morning. On Day 93, participants received 200 mg CNB once daily in the morning. On Day 98, participants received 7.5 mg / kg CBD-OS twice a day + 200 mg CNB once daily in the morning. Two participants discontinued the study during the CNB titration period on Day 40.Pharmacokinetic Parameters of Cannabidiol and Cenobamate and Metabolites

[0400] For CBD and its metabolites (7-OH-CBD and 7-COOH-CBD), exposures AUCo-i2h, AUCo-iast, and Cmax) at 7.5 mg / kg BID for the reference treatment were within those previously observed with CBD-OS administration at 7.5mg / kg BID dosage (Table 11). Compared with CBD-OS alone, coadministration with CNB was associated with mean and geomean AUCo-i2h, AUCo-iast, and Cmax values that were similar for CBD parent, while reduced for its metabolites 7-OH-CBD and 7-COOH-CBD. Median Tmax values were similar between treatments for CBD, while for 7-COOH-CBD and 7-OH-CBD, median Tmax was slightly shorter with CBD-OS + CNB. Coefficients of variation indicated moderate to high interparticipant variability across all parameters and analytes (Table 11).

[0401] The mean (%CV) metabolite-parent ratios (MRCmax and MRAUCo-iast) were lower in the CBD-OS + CNB treatment period for both metabolites. For 7-COOH-CBD, MRCmax was 18.6 (62.9%) in the CBD-OS only treatment period and 6.51 (57.3%) in the CBD-OS + CNB treatment period, whereas, MRAUCo-iastwas 34.8 (56.1%) in the CBD-OS only treatment period and 12.3 (47.8%) in the CBD-OS + CNB treatment period. For 7-OH-CBD, MRCmax was 0.533 (48.3%) in the CBD-OS only treatment period and 0.230 (40.4%) in the CBD-OS + CNB treatment period, whereas, MRAUCo-iastwas 0.620 (48.3%) in the CBD-OS only treatment period and 0.294 (40.2%) in the CBD-OS + CNB treatment period.Table 11 : Summary of CBD and its Metabolites Pharmacokinetic Parameters (PK Analysis Set)Abbreviations: max = maximum; min = minimum; N = number of participants per treatment period;Note: Parameters were estimated for Day 5 (steady state CBD-OS at 7.5 mg / kg twice a day alone) and for Day 98 (steady state CBD-OS at 7.5 mg / kg twice a day in the presence of steady state CNB at 200 mg once daily).

[0402] Geometric mean (Geo %CV) CNB exposures (AUCo-24h, AUCo-iast, and Cmax) at 200 mg once daily for the reference treatment (Table 12) were within previously observed exposures of CNB at this dose (Vernillet, 2020). Exposure to CNB, (AUCo-24h, AUCo-iast, and Cmax), was similar when coadministered with CBD-OS compared with CNB alone, with slightly higher exposures observed for CNB glucuronide. Median Tmax for CNB was unchanged with coadministration, while a prolonged Tmax was observed for CNB glucuronide in the presence of CBD-OS. Coefficients of variation indicated low interparticipant variability across all parameters and analytes (Table 12).

[0403] The mean (%CV) metabolite-parent ratios (MRCmax and MRAUCo-iast) were higher in the CBD-OS + CNB treatment period for CNB glucuronide. For CNB glucuronide, MRCmax was 0.0676 (13.9 %) in the CNB only treatment period and 0.0925 (16.3%) in the CBD-OS + CNB treatment period, whereas, MRAUCo-iastwas 0.0713 (14.4%) in the CNB only treatment period and 0.0936 (15.4%) in the CBD-OS + CNB treatment period.Table 12: Summary of CNB and its Metabolite Pharmacokinetic Parameters (PK Analysis Set)Abbreviations: max = maximum; min = minimum; N = number of participants per treatment period; n = number of participants in category.an = 17.Note: Parameters were estimated for Day 93 (steady state CNB at 200 mg once daily alone) and for Day 98 (steady state CNB at 200 mg once daily in the presence of steady state CBD-OS at 7.5 mg / kg twice a day); and Two participants discontinued the study during the CNB titration period on Day 40.Statistical Analysis of Pharmacokinetics of Cannabidiol and CenobamateAnalysis of the Effect of Steady- State Cenobamate on Steady-State Cannabidiol

[0404] The GLSM ratios (90% Cis) for CBD Cmax and AUCo-i2h were contained within the 80% to 125% bioequivalence range, while those for 7-COOH-CBD and 7-OH-CBD were below this range for both Cmax and AUCo-i2h, where point estimates were reduced by approximately 65% for 7-COOH-CBD, and reduced by approximately 55% for 7-OH-CBD. Pharmacokinetic data for 20 participants were included for reference treatment and PK data for 17 participants were included for the test treatment as 3 participants discontinued treatment prior to initiation of the test treatment (Table 13 and Figure 11). Table 13: Statistical Analysis of Drug-Drug Interaction (CNB on CBD and its Metabolites) (PK Analysis Set) Treatment Comparison (Test Versus Reference): CBD-OS + CNB Versus CBD-OS AloneAbbreviations: Note: The Cmaxand AUCo-i2h analyses were performed on In-transformed parameters using a linear mixed effects model with treatment as a fixed effect and participant as a random effect; and the dose level for CBD-OS was 7.5 mg / kg twice a day. The dose level for CNB was 200 mg once daily.Analysis of the Effect of Steady- State CBD-OS on Steady-State Cenobamate

[0405] The GLSM ratios (90% Cis) of CNB Cmax and AUCo-24h following coadministration of CBD-OS + CNB compared with CNB alone were contained within the 80% to 125% bioequivalence range, whereas the GLSM ratios (90% Cis) for CNB glucuronide Cmax and AUCo-24h slightly exceeded the upper bound of this range at approximately 40% higher (Table 14 and Figure 12).Table 14: Statistical Analysis of Drug-Drug Interaction (CBD-OS on CNB and its Metabolite) (PK Analysis Set) Treatment Comparison (Test Versus Reference): CBD- OS + CNB Versus CNB AloneNote: The Cmaxand AUCo-24h analyses were performed on In-transformed parameters using a linear mixed effects model with treatment as a fixed effect and participant as a random effect; and The dose level for CBD-OS was 7.5 mg / kg BID. The dose level for CNB was 200 mg once daily.Conclusions

[0406] Coadministration of CNB with CBD-OS resulted in no change in exposure to CBD but reduced exposure to both CBD metabolites (7-OH-CBD and 7-COOH-CBD).

[0407] Coadministration of CBD-OS with CNB resulted in similar exposure (Cmax and AUCo-24h) to CNB compared with CNB alone. Exposure (Cmax and AUCo-24h) to the metabolite CNB glucuronide was slightly increased in the presence of CBD-OS.

[0408] Coadministration of multiple doses (7.5 mg / kg BID) CBD-OS and 200 mg once daily CNB was well tolerated by the participants in this study.Example 4: A Phase 1b, Multicenter, Open-Label, Single-arm Study to Evaluate the Efficacy and Safety of Cannabidiol Oral Solution (CBD-OS) in Participants Aged 12 to 75 Years for the Treatment of Focal-Onset SeizuresBrief Summary

[0409] This study will enrol participants with Focal-Onset Seizures (FOS). Focal-onset seizures, or focal seizures (formerly known as partial seizures), are a common type of seizure characterized by excessive abnormal electrical activity originating in one or more specific regions of the brain.

[0410] The study will assess the efficacy of CBD-OS as an adjunctive treatment in reducing the frequency of focal seizures compared to baseline as well as the effect of CBD- OS on “beyond seizure” endpoints in early line and refractory participants with FOS. This study will also examine PK, safety, and potential predictors or mediators of treatment response.

[0411] The broad age range (12 to 75 years of age) for participants in this study was selected to ensure that the study population is representative of the FOS population.

[0412] Participants in the study will be currently treated with at least 1 , but no more than 4, anti-seizure medicines on a stable regimen. The concomitant anti-seizure medicines may include cenobamate, providing the participant has been taking cenobamate for less than 4 months (including the titration period) prior to Screening (Visit 1). Any medication or vaccine (including additional ASMs such as cenobamate, over-the-counter or prescription medicines, vitamins, and / or herbal supplements) that the participant is receiving at the time of enrolment or receives during the study will be recorded.

[0413] This study will assess the efficacy of CBD-OS as an adjunctive treatment in reducing the frequency of focal seizures compared to baseline as well as the effect of CBD- OS on “beyond seizure” endpoints in early line and refractory participants with FOS. This study will also examine PK, safety, and potential predictors or mediators of treatment response.Objectives and EndpointsTable 15: Objectives and EndpointsNote: Countable focal seizures include focal aware seizures with motor component, focal unaware seizures, secondarily generalized seizures.Overall Study Design

[0414] The study is a Phase 1b, multicenter, open-label study to examine the efficacy and safety of CBD-OS as adjunctive therapy in reducing seizures and beyond seizure endpoints in participants aged 12 to 75 years, inclusive, with early-line and refractory FOS.Main Study

[0415] Participants will have focal epilepsy, according to the I LAE Classification of Epilepsy, 2017; participants must be currently treated with at least 1 , but no more than 4 ASMs on a stable regimen prior to Screening (Visit 1) and have no planned changes to treatment for the duration of the study.

[0416] Each participant will participate in the study from the time the ICF is signed through the end of study procedures / contact. Each participant will be enrolled for up to 27 weeks.

[0417] In this study, assessments should be consistently completed by either the participant or caregiver. If the investigator determines that a caregiver is needed to complete the assessments, it is important that the same caregiver completes the assessments at each time point. For the purposes of this study, a caregiver is defined asan individual who attends to the participant’s daily needs, and who is able to attest to the participant’s symptoms and behavior via eDiary assessments.

[0418] Participants will proceed through the following study periods while undergoing study assessments.• Screening Visit (Visit 1): At the Screening Visit, participants (or their parent[s] / LAR) will sign the IGF. Participants will be considered enrolled after the IGF is signed and will subsequently be screened for study eligibility and begin the 6-week baseline period. Participants and / or caregivers will also be trained in how to record information in the eDiary. o Baseline Period (6 weeks): The purpose of the Baseline Period is to collect information on the frequency and severity of seizures in the eDiary.• Baseline Visit (Visit 2): Participants will complete additional assessments and be rechecked for study eligibility followed by administration of study intervention.• Open-label Treatment Period (16 weeks): All participants will be assigned to openlabel treatment with CBD-OS as follows: o Titration Period (4 weeks): Site staff will first verify information collected during the 6-week Baseline Period and confirm the participant’s eligibility. Eligible participants will be provided with sufficient study intervention CBD- OS) to achieve their optimal maximum dose during the 4-week titration period. Site staff will instruct the participant / caregiver on how to dose and titrate the study intervention. Site staff will also verify that study intervention is correctly administered. o Dose Optimization Treatment Period (12 weeks): Participants will be treated with a target CBD-OS maintenance dosage of 20 mg / kg / day following dose titration, with an option to increase up to 25 mg / kg / day based on observed efficacy and safety, if deemed clinically appropriate. Increases in CBD-OS dose are only permitted up to Week 12 (Visit 8). However, decreases in CBD-OS dosage due to any safety / tolerability concerns are permitted. Participants will have an EOT Visit following 16 weeks of treatment with CBD-OS.• Taper Period (10 days): Participants should be gradually withdrawn from treatment over a 10-day taper period and complete an End of Taper Visit. The Taper Period may be skipped per the physician’s clinical discretion, if the physician does not believe a taper is in the participant’s best interest. However, abrupt discontinuation is not recommended. The End of Taper Visit should be completed regardless of participation in the Taper Period.• Safety Follow-up Visit (phone call): Participants will have a Safety Follow-up Visit telephone call 28 days after the last dose of CBD-OS is administered.

[0419] If a participant decides to withdraw from the study intervention or study (as applicable), the EOT or E / D Visit should be scheduled to occur as soon as possible after. After the EOT or E / D Visit, the participant should gradually be withdrawn from treatment over a 10-day taper period and complete an End of Taper Visit, followed by a Safety Follow-up Visit (phone call) 28 days after their last CBD-OS dose, as specified in the Schedule of Activities.Table 16: Study DesignJustification for Dose

[0420] The starting dose of CBD-OS will be administered as per the approved local product label, but consistently with food (Epidiolex USPI, 2024). Participants will take CBD-OS BID. Consistent dosing of CBD-OS with respect to meals is recommended to maintain consistent CBD plasma exposure.

[0421] Study intervention will be initiated at a dosage of 2.5 mg / kg BID (5 mg / kg / day) and increased stepwise during the 4-week Titration Period. Starting at Week 4, CBD-OS dosage will subsequently be increased to 10 mg / kg BID (20 mg / kg / day) for at least 1 week. A flexible titration scheme will subsequently be implemented during the Treatment Period to enable optimization of study intervention dosage. Participants will titrate to a dosage of 20 mg / kg / day following dose titration, with an option to increase up to 25 mg / kg / day based on observed efficacy and safety, if deemed clinically appropriate. No dosage increases are allowed during the last 4 weeks of the treatment period. However, decreases in CBD-OS dosage due to any safety / tolerability concerns are permitted.End of Study Definition

[0422] A participant is considered to have completed the study if they have completed all phases of the study. The end of the study is defined as the date of the last visit of the last participant in the study.Study PopulationInclusion Criteria

[0423] Participants are eligible to be included in the main study only if all of the following criteria apply:Medical Conditions and Concomitant Medication / Therapy1. Participant has a documented diagnosis of focal epilepsy according to the I LAE Classification of Epilepsy, 2017, characterized by focal seizure types with typical interictal / ictal EEG findings (eg, focal sharp waves or slowing). Imaging may reveal focal structural abnormalities, though normal imaging is possible in genetic cases. Focal epilepsy may be unifocal, multifocal, or hemispheric.2. Participant is currently treated with at least 1 , but no more than 4, ASMs on a stable regimen.3. If the participant is on a dietary treatment of epilepsy, the regimen must be stable (at least 3 months prior to Screening [Visit 1]) and no changes to treatment are planned for the duration of the study.4. All medications or interventions for epilepsy must have been stable for at least 28 days prior to Screening (Visit 1) with no planned changes to the regimen for the duration of the study.5. If fitted with neurostimulation devices for epilepsy (eg, VNS / RNS / DBS), implantation must have occurred at least 6 months prior to Screening (Visit 1) with no planned changes to the settings for the duration of the study. Participants with an implanted neurostimulation device may not participate in the substudy.6. Participant is willing to keep lifestyle factors expected to affect seizures stable for the duration of the study.Sex and Contraceptive / Barrier Requirements7. Contraceptive use by male and female participants should be consistent with CTFG guidelines and any applicable local regulations regarding the methods of contraception for those participating in clinical studies. - Will not be pregnant or lactating and have a confirmed negative highly sensitive serum pregnancy test at Screening (Visit 1).Male Participants:Fertile male participants with WOCBP partners must be willing to use a male barrier method of contraception in addition to a second method of acceptable contraception used by their WOCBP partners, from the time of Screening (Visit 1) until 3 months after the safety follow-up visit, as detailed in the protocol.WOCBP:- Will not be pregnant or lactating and have a confirmed negative highly sensitive serum pregnancy test at Screening (Visit 1).- Must also have a confirmed negative highly sensitive serum / urine pregnancy test prior to receiving their first dose of study intervention.- Must be willing to use a highly effective method of contraception, including abstinence, from the time of signing the ICF until 1 month after the safety follow-up visit, as detailed in the protocol.Informed Consent / Assent8. Participant or participant’s caregiver s according to local laws) is / are willing and able to give signed informed consent / assent for participating in the study, including compliance with the requirements and restrictions listed in the ICF and protocol.9. Participant’s caregiver s is / are willing to allow the responsible authorities to be notified of participation in the study, if mandated by local law.Other Inclusion Criteria10. Participant is aged 12 to 75 years old, inclusive, at Screening.11. Participant has had an MRI in the past 10 years that ruled out a progressive cause of epilepsy.At the end of the 6-week Baseline Period, participants must also meet the following criteria:12. Experienced at least 3 countable focal seizures during the 6-week Baseline Period without a focal seizure-free interval of greater than 25 days. At least 1 focal seizure must occur in each half of the Baseline Period. Additionally, participant has a history of at least 2 focal seizures within the 12 weeks prior to Screening (Visit 1). Countable focal seizures include: focal aware seizures with motor component, focal unaware seizures, secondarily generalized seizures.13. Participant / caregiver completes at least 90% of seizure diary entries during the 6-week Baseline Period (ie, minimum of 38 days of diary entries) with no more than 3 consecutive days of missing entries.Exclusion Criteria

[0424] Participants are excluded from the study if any of the following criteria apply:Medical Conditions1. Has a concurrent, confirmed diagnosis of non-epileptic seizures or events that can confound the assessment of the efficacy measures, in the opinion of the investigator.2. Has clinically significant unstable medical condition(s), other than epilepsy.3. Has an illness in the 28 days prior to Screening (Visit 1), other than epilepsy, which in the opinion of the investigator could affect seizure frequency.4. Has history of status epilepticus in the 3 months prior to Screening (Visit 1).5. History of suicidal behavior, current suicidal risk as determined from history, or presence of active suicidal ideation as indicated by a positive response to Item 4 or Item 5 on the C-SSRS or is considered at risk of suicide or self-harm based on the clinical judgement of the investigator following interview with the participant and / or caregiver.6. Has known or suspected hypersensitivity to cannabinoids or any of the excipients of the study intervention, such as sesame oil.7. Any known or suspected history of alcohol or substance use disorder.8. Has, in the opinion of the investigator, clinically significant abnormalities in the ECG measured at Screening or prior to Screening (Visit 1), or any concurrent cardiovascular conditions which will interfere with the ability to read their ECGs.9. Significantly impaired hepatic function at screening or prior to dosing, defined as any of the following (can only be confirmed once laboratory results are available):- Serum ALT or AST > 5 x ULN.Serum TBL > 1 .5 x ULN or INR > 1 .5 (Note: for participants diagnosed with Gilbert’s disease BL > . x LN and / or direct bilirubin > 1 x ULN are exclusionary).Serum L or S > x LN with the presence of fatigue, nausea, vomiting, right upper quadrant pain or tenderness, fever, rash and / or eosinophilia (> 5%).- Any elevated ALT, AST, TBL, or INR at screening should be discussed with the medical monitor (to confirm clinical significance in determining eligibility) prior to Screening (Visit 1) and the medical monitor may allow for a confirmatory re-draw prior to Baseline (Visit 2).10. Has clinically significant impaired renal function at Screening (Visit 1), as evidence by an eGFR (CKD-EPI) less than 30 mL / min.11 . Has any other significant disease or disorder which, in the opinion of the investigator, may either put the participant at risk because of participation in the study, may influence the result of the study, or may affect the participant’s ability to take part in the study.12. An active CNS infection, demyelinating disease, degenerative neurologic disease, or any CNS disease deemed to be progressive during the course of the study that may confound the interpretation of the study results (including autoimmune encephalitis).Prior and Concomitant Medication / Therapy13. Is currently treated with Epidiolex or received treatment with Epidiolex within 28 days prior to Screening (Visit 1).14. Has experienced a lack of efficacy and / or poor tolerability to an adequate treatment regimen of Epidiolex based on medical history and the clinical judgement of the investigator. Participants who discontinued treatment for reasons other than safety, tolerability or lack of efficacy and previously received Epidiolex for 28 days or more prior to Screening (Visit 1) are eligible for the study.15. Has undergone general anesthesia in the 28 days prior to screening or prior to Screening (Visit 1) or has planned / scheduled general anesthesia during the treatment period.16. Has undergone surgery for epilepsy in the 6 months prior to Screening (Visit 1) or planned to undergo surgery for epilepsy during the study.17. Has been taking felbamate for less than 12 months prior to Screening (Visit 1). Participants who are stable on felbamate for 12 months or greater are eligible for inclusion.18. Has been taking cenobamate for less than 4 months (including the titration period) prior to Screening (Visit 1).19. 19. Is currently being treated with or had previously (within 3 months prior to Screening [Visit 1]) received intravenous immunoglobulin treatment or plasma exchange for the treatment of seizures.20. Is currently being treated with a medication considered to be a strong inducer of CYP3A4 and / or CYP2C19 that cannot be discontinued at least 14 days or 5 half-lives (whichever is longer) before starting study intervention or is planning to use such medication at any time during the study.Prior / Concurrent Clinical Study Experience21. Has participated in a clinical study involving administration of an investigational medicinal product (new chemical entity) or medical device (eg, VNS) within 28 days prior to Screening (Visit 1).22. Has previously been enrolled in (excluding re-screens [Section 5.3]), completed, or withdrawn from this study.Other Drugs or Substances23. Is currently using a drug of abuse or current non-prescribed use of any prescription drug.24. Is currently using or has used recreational or medicinal cannabis, cannabinoid / CBD based medications, products, or supplements (botanical or synthetic) within 28 days prior to Screening (Visit 1) and / or is unwilling to abstain for the duration of the study.25. Is currently consuming, and unwilling to stop consumption, or planning to consume tonic water on a regular basis throughout the study.Other Exclusion Criteria26. Is unwilling or unable to comply with all study requirements, including accurate eDiary completion.27. Has travel planned outside their country of residence during the study, unless the participant has confirmation that the study medication is permitted in the destination country, and all stops along the way.28. Presence of only nonmotor simple partial seizures or primary generalized epilepsies.29. Presence or previous history of LGS.Meals and Dietary Restrictions

[0425] Participants / caregivers will be trained to administer CBD-OS orally, or via gastric or nasogastric tubes BID (eg, morning and evening), preferably at the same time each day and consistently with food. Dosing should be consistent from Day 2 onward, since the Day 1 dose administered at the site will most likely not be at the participant’s normal AM or PM dose time.Screen Failures

[0426] Screen failures are defined as participants who consent to participate in the clinical study but are not subsequently assigned treatment with CBD-OS. A minimal set of screen failure information is required to ensure transparent reporting of screen failure participants, to meet the CONSORT publishing requirements, and to respond to queries from regulatory authorities. Minimal information includes demography, screen failure details, eligibility criteria, and any SAEs.

[0427] Participants who do not meet the criteria for participation in this study (ie, screen failure), or who could not be enrolled within the screening / baseline window for logistical reasons, may be re-screened once at the discretion of the investigator or designee. For all re-screens, all screening procedures, including informed consent / assent, must be repeated. Sites should discuss planned re-screens with the medical monitor prior to re-screening. Rescreened participants should be assigned a new participant number for every screening / rescreening event.Study Intervention / Treatment AdministeredTable 17: Study Intervention(s) AdminsteredI ntervention / T reatment

[0428] Participants will receive their first study intervention dose under medical supervision on Day 1. Participants / caregivers will be trained to administer CBD-OS orally, or via gastric or nasogastric tubes BID (eg, morning and evening), preferably at the same time each day and consistently with food.

[0429] The date and time of the dose administered under medical supervision will be recorded in the source documents, and the eCRF. In general, study intervention start and stop dates, including dates for intervention delays and / or dose adjustments should also be recorded in the eCRF.

[0430] After site staff have verified that the study intervention is being administered correctly, the participant or caregiver may administer subsequent doses without medical supervision. Participants / caregivers will be provided with clear instructions for the dose escalation and taper dosing periods of the study.

[0431] Treatment compliance with study intervention will be assessed at each visit by direct questioning. In addition, caregivers or participants should return all study intervention bottles (either unused product or empty bottles) at each visit, either directly to the study site or via mail courier (refer to the Pharmacy Manual). Compliance will be documented in the source documents. Deviation(s) from the initial prescribed dosage regimen should be recorded in the eCRF.

[0432] A record of the quantity of CBD-OS dispensed to and administered by each participant must be maintained and reconciled with study intervention and compliance records. Any discrepancies will be discussed with the participant or caregiver and documented accordingly within the participant’s source documents.Dose Modification

[0433] All dose modifications will be captured in EDC including the reason for the change. Doses of CBD-OS will be administered as adjunctive therapy to current ASM(s) using the titration scheme to enable optimization of study intervention dosage, as follows:• CBD-OS will be initiated at a dosage of 2.5 mg / kg BID (5 mg / kg / day) for 1 week (Week 1). o CBD-OS dosage will then be increased to 5 mg / kg BID (10 mg / kg / day) for 1 week (Week 2). o Then dosage will be increased to 7.5 mg / kg BID (15 mg / kg / day) for 1 week (Week 3).• Starting at Week 4, CBD-OS dosage will be increased to 10 mg / kg BID (20 mg / kg / day) for at least 1 week.Starting at Week 5, Investigators will have the following options:o Maintain CBD-OS dosage at 20 mg / kg / day o Increase CBD-OS dosage to 25 mg / kg / day if further efficacy is desired and there are no safety / tolerability concerns (in consultation with the medical monitor) o Decrease CBD-OS dosage in a stepwise fashion to a minimum dosage of 15 mg / kg / day, if there are safety / tolerability concerns.• Increases in CBD-OS dosage up to 25 mg / kg / day are only permitted up to Week 12 (Visit 8). To achieve a stable CBD-OS dosing period, no CBD-OS dosage increases are allowed for a minimum of 4 weeks prior to the end of the treatment period.• However, decreases in CBD-OS dosage due to any safety / tolerability concerns are permitted.• Reasons for any dosage adjustments throughout the study will be documented.• In the case of one or more missed doses, the missed doses should not be compensated. Dosing should be resumed at the existing treatment schedule.

[0434] Investigators may decrease the dose at any time if a participant experiences intolerance.• If an unacceptable AE develops at any time during the Titration Period, dosing should initially be suspended or amended, at the investigator’s discretion, until the event has resolved.• During the Treatment Period, participants should continue their stable dosing regimen. If the participant is no longer able to tolerate the stable dose, or if an AE occurs, the investigator may consider temporarily or permanently reducing the dosage for the remainder of the Treatment Period.• Participants discontinuing the study intervention should complete a 10-day taper period (10% of the final dose per day for 10 days) unless continued dosing is not possible due to an AE or other safety or tolerability considerations. Refer to the SoA for details.Concomitant Therapy

[0435] Any medication or vaccine (including additional ASMs such as cenobamate, over- the-counter or prescription medicines, vitamins, and / or herbal supplements) that the participant is receiving at the time of enrollment or receives during the study must be recorded with the following:• Reason for use• Dates of administration including start and end dates• Dosage information including dose and frequency

[0436] The medical monitor should be contacted if there are any questions regarding concomitant or prior therapy. All medications for epilepsy must have been stable at least 4 weeks prior to Screening, and certain medications, procedures, and therapies are prohibited for the duration of the study; additional details are provided in the inclusion and exclusion criteria.

[0437] Cannabidiol oral solution could potentially alter the metabolism of other medications that are administered concurrently (including ASMs), and pharmacological interactions with other concurrently administered medications could occur.

[0438] Modifications to concomitant medications should be avoided during the study. Where required for participant safety, adjustments of concomitant ASMs or addition of new ASMs may be permitted. These changes must be recorded in the eCRF or another electronic device as appropriate, and the medical monitor must be informed. Concomitant ASM dose reductions are permitted on clinical grounds (eg, due to AEs or transaminase elevations not meeting withdrawal criteria) following discussion with the medical monitor.

[0439] Medications that are prohibited during the study include felbamate (initiation within 12 months of Screening or during study), cenobamate (initiation within 4 months [including the titration period] of Screening or during the study), strong inducers of CYP3A4 and / or CYP2C19, recreational / medicinal cannabis, and botanical or synthetic cannabinoid-based medications, products, or supplements.Pharmacokinetics

[0440] Pharmacokinetic samples will be collected during the study. Pharmacokinetic samples will not be collected from participants who have discontinued study intervention prior to the PK visit. Plasma samples will be collected for measurement of plasma concentrations of CBD and its major metabolites as specified in the Schedule of Activities.

[0441] Two PK samples will be collected at each PK visit as follows:• 1 PK sample at predose• 1 PK sample between 2.5 to 5 hours postdose

[0442] The maximum amount of blood taken for PK analysis will be approximately 2 mL per time point. A maximum of 6 samples may be collected at additional time points during the study if warranted and agreed upon by the investigator and the sponsor. Instructions for the collection and handling of biological samples will be provided by the sponsor. The actual date and time (24-hour clock time) of each sample will be recorded.

[0443] Participants (or caregivers) will record the date, time of dose, and the date, time of meal type (eg, high fat meal [dairy or meat], standard meal [fruit or vegetable], or other [if not fitting into one of the categories above]) for all meals consumed by the participant within 24 hours prior to PK collection in the eDiary.

[0444] Analysis of all PK samples will be conducted at the bioanalytical laboratory and additional details are provided in the laboratory manual.

[0445] For participants on other ASMs, the plasma samples for measuring CBD and its metabolites may also be used to measure levels of those ASMs.Pharmacodynamics

[0446] Pharmacodynamic parameters are not evaluated in this study.Efficacy Endpoints

[0447] Countable focal seizure frequency, including percent change from baseline and the proportion of participants who achieve > 50%, > 75% and 100% reduction from baseline, will primarily be summarized over the dose optimization treatment period. Additional summaries will be provided for the full treatment period, the titration period, and other divisions of the treatment period (including a stable dose or maintenance period) to be defined in the SAP. Summaries over the same periods will also be provided for total seizure frequency, focal to bilateral tonic-clonic seizure frequency, and total seizure-free days per 28 days including change from baseline.References

[0448] A number of publications are cited above in order to more fully describe and disclose the invention and the state of the art to which the invention pertains. Full citations for these references are provided below. The contents of each of these references is incorporated herein.

[0449] Devinsky et al., “Epilepsy”, Nature Reviews Disease Primers, 2018, 3, article number 18024.

[0450] Fiest et al., “Prevalence and incidence of epilepsy: a systematic review and metaanalysis of international studies”, Neurology, 2017, 88, 296-303.

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[0452] Fisher et al., “Operational classification of seizure types by the I LAE: Position paper of the I LAE Commission for Classification and Terminology” Epilepsia, 2017, 58(4), 522-530.

[0453] Wirrell et al., “Methodology for classification and definition of epilepsy syndromes with list of syndromes: Report of the I LAE Task Force on Nosology and Definitions” Epilepsia, 2022, 63, 1333-1348.

[0454] Zuberi et al., “I LAE classification and definition of epilepsy syndromes with onset in neonates and infants: Position statement by the I LAE Task Force on Nosology and Definitions” Epilepsia, 2022, 63, 1349-1397.

[0455] Specchio et al., “I LAE classification and definition of epilepsy syndromes with onset in childhood: Position statement by the I LAE Task Force on Nosology and Definitions” Epilepsia, 2022, 63, 1398-1442.

[0456] Riney et al., “I LAE classification and definition of epilepsy syndromes with onset at a variable age: Position statement by the I LAE Task Force on Nosology and Definitions” Epilepsia, 2022, 63, 1443-1474.

[0457] Hirsch et al., “ILAE definition of Idiopathic Generalized Epilepsy Syndromes: Position statement by the ILAE Task Force on Nosology and Definitions” Epilepsia, 2022, 63, 1475-1499.

[0458] Gong, X., et al. “Synthesis of CBD and Its Derivatives Bearing Various C4'-Side Chains with a Late-Stage Diversification Method”, J. Org. Chem., 2020, 85, 4, 2704-2715.

[0459] Rana RR, Rajasekaran K, Knappertz V et al. Pharmacodynamic synergism contributes to the antiseizure action of cannabidiol and clobazam. Exp Neurol. 2023; 360: 114286.

[0460] Luszczki JL, Trojnar MK, Ratnaraj N, et al. Interactions of stiripentol with clobazam and valproate in the mouse maximal electroshock-induced seizure model. Epilepsy Research 2010; 90: 188-198.

[0461] Luszczki JL, Antkiewicz-Michauluk L and Czuczwar SJ. Isobolographic analysis of interactions between 1-methyl-1,2,3,4-tetrahydroisoquinoline and four conventional antiepileptic drugs in the mouse maximal electroshock-induced seizure model. EurJ Pharmacol. 2009; 602: 298.

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[0475] Zarnowska I, Luszczki JL, Zarnowski T et al. Proconvulsant effects of the ketogenic diet in electroshock-induced seizures in mice. Metabolic Brain Disorder 2017; 32: 351.

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[0478] Luszczki JL and Czuczwar SJ. Biphasic characterisatic of interactions between stiripentol and carbamazepine in the mouse maximal electroshock-induced seizure model: a three-dimensional isobolographic analysis. Naunyn-Schmiedeberg’s Archives of Pharmacology 2006; 374: 51.

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Claims

CLAIMS1 . Cannabidiol, or a pharmaceutically acceptable salt thereof, for use in a method of treating seizures in a subject in need of treatment, wherein the method comprises administering to the subject a therapeutically effective amount of cannabidiol, or a pharmaceutically acceptable salt thereof, in combination with a therapeutically effective amount of cenobamate, or a pharmaceutically acceptable salt thereof.

2. Cenobamate, or a pharmaceutically acceptable salt thereof, for use in a method of treating seizures in a subject in need of treatment, wherein the method comprises administering to the subject a therapeutically effective amount of cenobamate, or a pharmaceutically acceptable salt thereof, in combination with a therapeutically effective amount of cannabidiol, or a pharmaceutically acceptable salt thereof.

3. Cannabidiol or cenobamate for use according to claim 1 or 2, wherein the seizures are focal onset seizures, generalised onset seizures, seizures with unknown onset, or a combination of any of these seizures, optionally wherein the seizures are a combination of focal onset seizures and generalised onset seizures.

4. Cannabidiol or cenobamate for use according to claim 1 or 2, wherein the seizures are selected from absence seizures, atypical absence seizures, atonic seizures, clonic seizures, tonic seizures, tonic-clonic seizures, febrile seizures, focal to bilateral tonic clonic seizures, gelastic and dacrystic seizures, myoclonic seizures, myoclonic-tonic-clonic seizures, myoclonic-atonic seizures and epileptic (or infantile) spasms.

5. Cannabidiol or cenobamate for use according to any one of claims 1 to 4, wherein the seizures are associated with epilepsy; optionally wherein the epilepsy is an epileptic syndrome selected from syndromes with onset in neonates and infancy, syndromes with onset in childhood, syndromes with onset at a variable age, and idiopathic generalised epilepsy syndromes (IGEs).

6. Cannabidiol or cenobamate for use according to claim 5, wherein the epilepsy is characterised as a refractory epilepsy.

7. Cannabidiol or cenobamate for use according to any one of claims 1 to 6, wherein the cannabidiol, or a pharmaceutically acceptable salt thereof, and the cenobamate, or a pharmaceutically acceptable salt thereof, are administered simultaneously or sequentially.

8. Cannabidiol or cenobamate for use according to any one of claims 1 to 7, wherein the cannabidiol, or a pharmaceutically acceptable salt thereof, and the cenobamate, or a pharmaceutically acceptable salt thereof, are administered in separate dosage forms.

9. Cannabidiol or cenobamate for use according to any one of claims 1 to 8, wherein the method provides a synergistic therapeutic effect in the treatment of seizures in comparison to the effect of cannabidiol or cenobamate when administered independently; optionally wherein the synergistic therapeutic effect is a reduction in the occurrence and / or severity of seizures.

10. Cannabidiol or cenobamate for use according to claim 9, wherein the synergistic therapeutic effect comprises a pharmacodynamic synergistic effect.11 . Cannabidiol or cenobamate for use according to claim 9 or 10, wherein: i) the synergistic therapeutic effect is characterised by a Combination Index of less than 1 , such as less than 0.8; and / or ii) the synergistic therapeutic effect is characterised by an Exposure Reduction for cannabidiol and / or cenobamate of greater than 1 .

12. Cannabidiol or cenobamate for use according to any one of claims 1 to 11 , wherein cannabidiol, or a pharmaceutically acceptable salt thereof, and cenobamate, or a pharmaceutically acceptable salt thereof, are administered to provide a fixed-exposure ratio for cannabidiokcenobamate in the subject of between about 1 :3 to about 3:1 , calculated based on b-EEso values of the individual compounds.

13. Cannabidiol or cenobamate for use according to any one of claims 1 to 12, wherein the amount of cannabidiol, or a pharmaceutically acceptable salt thereof, administered to the subject is from about 5 mg / kg / day to about 25 mg / kg / day and the amount of cenobamate, or a pharmaceutically acceptable salt thereof, administered to the subject is from about 12.5 mg / day to about 400 mg / day.

14. Cannabidiol or cenobamate for use according to any one of claims 1 to 13, wherein the amount of cannabidiol, or a pharmaceutically acceptable salt thereof, administered to the subject is: i) reduced by up to 4-fold ; or ii) reduced by up to 65%; or iii) reduced by up to two thirds,in comparison to administration without cenobamate, or a pharmaceutically acceptable salt thereof.

15. Cannabidiol or cenobamate for use according to any one of claims 1 to 13, wherein the cannabidiol, or a pharmaceutically acceptable salt thereof, is administered at: i) a reduced maintenance dosage 2.5 to 8 mg / kg / day; or ii) a reduced maximum dosage of less than 25 mg / kg / day.

16. Cannabidiol or cenobamate for use according to any one of claims 1 to 13, wherein the amount of cenobamate, or a pharmaceutically acceptable salt thereof, administered to the subject is: i) reduced by up to 4-fold; or ii) reduced by up to 65%; or iii) reduced by up to two thirds, in comparison to administration without cannabidiol, or a pharmaceutically acceptable salt thereof.

17. Cannabidiol or cenobamate for use according to any one of claims 1 to 13, wherein the cenobamate, or a pharmaceutically acceptable salt thereof, is administered at: i) a reduced maintenance dosage of 50 to 100 mg / day; or ii) a reduced maximum dosage of 100 to 387.5 mg / day.

18. Cannabidiol or cenobamate for use according to any one of claims 1 to 14, wherein the amount of cannabidiol, or a pharmaceutically acceptable salt thereof, administered to the subject is from about 2.5 mg / kg / day to about 25 mg / kg / day and the amount of cenobamate, or a pharmaceutically acceptable salt thereof, administered to the subject is from about 12.5 mg / day to about 400 mg / day.

19. Cannabidiol of any one of clams 1 to 18, wherein cannabidiol is administered to the subject once daily.

20. Cannabidiol, or a pharmaceutically acceptable salt thereof, for use in a method of treating seizures in a subject in need thereof, wherein the method comprises the steps of: a. administering to the subject a starting dosage of cannabidiol, or a pharmaceutically acceptable salt thereof, for a first period of time;b. after the first period of time, increasing the dosage of cannabidiol, or a pharmaceutically acceptable salt thereof, to achieve a maintenance dosage for a second period of time; c. after the second period of time, reducing the maintenance dosage of cannabidiol, or a pharmaceutically acceptable salt thereof, by up to 4-fold for a third period of time; and d. after the third period of time, administering cenobamate, or a pharmaceutically acceptable salt thereof; wherein optionally steps c. and d. are carried out concurrently.

21. Cenobamate, or a pharmaceutically acceptable salt thereof, for use in a method of treating seizures in a subject in need thereof, wherein the method comprises the steps of: a. administering to the subject a starting dosage of cenobamate, or a pharmaceutically acceptable salt thereof, for a first period of time; b. after the first period of time, increasing the dosage of cenobamate, or a pharmaceutically acceptable salt thereof, to achieve a maintenance dosage for a second period of time; c. after the second period of time, reducing the maintenance dosage of cenobamate, or a pharmaceutically acceptable salt thereof, by up to 4-fold for a third period of time; and d. after the third period of time, administering cannabidiol, or a pharmaceutically acceptable salt thereof; wherein optionally steps c. and d. are carried out concurrently.

22. Cannabidiol, or a pharmaceutically acceptable salt thereof, for use in a method of initiating treatment with cenobamate, or a pharmaceutically acceptable salt thereof, in a subject who is suffering from seizures and who is already being treated with cannabidiol, or a pharmaceutically acceptable salt thereof, the method comprising the steps of: a. administering a starting dosage of cenobamate, or a pharmaceutically acceptable salt thereof, to the subject for a first period; b. optionally, increasing the dosage of cenobamate, or a pharmaceutical acceptable salt thereof, following a cenobamate titration regimen for a cenobamate titration period; andc. administering a reduced maintenance dosage of cenobamate, or a pharmaceutically acceptable salt thereof, to the subject, wherein, the reduced maintenance dosage of cenobamate, or a pharmaceutically acceptable salt thereof, is reduced in comparison to treatment with cenobamate independently.

23. Cenobamate, or a pharmaceutically acceptable salt thereof, for use in a method of initiating treatment with cannabidiol, or a pharmaceutically acceptable salt thereof, in a subject who is suffering from seizures and who is already being treated with cenobamate, or a pharmaceutically acceptable salt thereof, the method comprising the steps of: a. administering a starting dosage of cannabidiol, or a pharmaceutically acceptable salt thereof, to the subject for a first period; b. optionally, increasing the dosage of cannabidiol, or a pharmaceutical acceptable salt thereof, following a cannabidiol titration regimen for a cannabidiol titration period; and c. administering a reduced maintenance dosage of cannabidiol, or a pharmaceutically acceptable salt thereof, to the subject, wherein the reduced maintenance dosage of cannabidiol, or a pharmaceutically acceptable salt thereof, is reduced in comparison to treatment with cannabidiol independently.

24. Cannabidiol, or a pharmaceutically acceptable salt thereof, for use in a method of initiating treatment with cenobamate, or a pharmaceutically acceptable salt thereof, in a subject who is suffering from seizures and who is already being treated with cannabidiol, or a pharmaceutically acceptable salt thereof, the method comprising the steps of: a. reducing the dosage of cannabidiol, or a pharmaceutically acceptable salt thereof, being administered to the subject; b. administering a reduced maintenance dosage of cannabidiol, or a pharmaceutically acceptable salt thereof, to the subject; and c. administering a starting dosage of cenobamate, or a pharmaceutically acceptable salt thereof to the subject.

25. Cenobamate, or a pharmaceutically acceptable salt thereof, for use in a method of initiating treatment with cannabidiol, or a pharmaceutically acceptable salt thereof, in asubject who is suffering from seizures and who is already being treated with cenobamate, or a pharmaceutically acceptable salt thereof, the method comprising the steps of: a. reducing the dosage of cenobamate, or a pharmaceutically acceptable salt thereof, being administered to the subject; b. administering a reduced maintenance dosage of cenobamate, or a pharmaceutically acceptable salt thereof, to the subject; and c. administering a starting dosage of cannabidiol, or a pharmaceutically acceptable salt thereof to the subject.

26. Cannabidiol or cenobamate for use according to any one of claims 1 to 25, wherein the subject is a human.

27. The method of any one of claims 1 to 26, wherein the combination is well tolerated.

28. The method of claim 27, wherein the method of treating seizures lacks (or provides a reduction in) CNS related adverse effects, such as somnolence and / or sedative and / or other muscle coordination related adverse effects.

29. The method of claim 27, wherein the method of treating seizures provides treatment without CNS related adverse effects, such as somnolence and / or sedative and / or other muscle coordination related adverse effects.

30. The method of claim 28 or 29, wherein the CNS related adverse effect is somnolence.31 . The method of any one of claims 28 to 30, wherein the subject being treated exhibits CNS related adverse effect free days (per 28 days) of at least 20 days, such as least 25 days, at least 26 days, at least 27 days, or 28 days.

32. The method of claim 27, wherein the method of treating seizures provides treatment without an increase in CNS related adverse effects, such as somnolence and / or sedative and / or other muscle coordination related adverse effects, in comparison to treatment without cannabidiol.

33. The method of claim 32, wherein the occurrence of CNS related adverse effects (per 28 days) is within 35%, such as within 20%, such as within 15%, or such as within 10%, of the occurrence in treatment without cannabidiol.

34. The method of claim 27, wherein the method of treating seizures provides treatment without an increase in CNS related adverse effects, such as somnolence and / or sedative and / or other muscle coordination related adverse effects, in comparison to treatment without cenobamate.

35. The method of claim 34, wherein the occurrence of CNS related adverse effects (per 28 days) is within 35%, such as within 20%, such as within 15%, or such as within 10%, of the occurrence in treatment without cenobamate.

36. The method of claim 27, wherein the method of treating seizures provides a reduction in CNS-related adverse effects, such as somnolence and / or sedative and / or other muscle coordination related adverse effects, in comparison to treatment without cannabidiol.

37. The method of claim 36, wherein the median percentage reduction in frequency (per 28 days) of CNS-related adverse effects is at least 10%, such as at least 20%, at least 50%, at least 75%, or at least 100%, in comparison to treatment without cannabidiol.

38. The method of claim 27, wherein the method of treating seizures provides a reduction in CNS-related adverse effects, such as somnolence and / or sedative and / or other muscle coordination related adverse effects, in comparison to treatment without cenobamate.

39. The method of claim 38, wherein the median percentage reduction in frequency (per 28 days) of CNS-related adverse effects is at least 10%, such as at least 20%, at least 50%, at least 75%, or at least 100%, in comparison to treatment without cenobamate.

40. The method of any one of claims 1 to 39, wherein the subject is a patient whose seizures do not respond to treatment with either cannabidiol or cenobamate (“non responder”), or whose seizures are inadequately controlled by treatment with either cannabidiol or cenobamate (“inadequate responder”).

41. The method of claim 40, wherein the subject is a cannabidiol non-responder, wherein adverse side effects prevent the subject from achieving a therapeutic dose and / or achieving adequate seizure control with cannabidiol without cenobamate.

42. The method of claim 41 , wherein the adverse side effects are CNS related adverse effects, such as somnolence and / or sedative and / or other muscle coordination related adverse effects.

43. The method of claim 40, wherein the subject shows inadequate response to cannabidiol, wherein adverse side effects prevent the subject from achieving a therapeutic dose and / or achieving adequate seizure control with cannabidiol without cenobamate.

44. The method of claim 43, wherein the adverse side effects are CNS related adverse effects, such as somnolence and / or sedative and / or other muscle coordination related adverse effects.

45. The method of claim 40, wherein the subject is a cenobamate non-responder, wherein adverse side effects prevent the subject from achieving a therapeutic dose and / or achieving adequate seizure control with cenobamate without cannabidiol.

46. The method of claim 45, wherein the adverse side effects are CNS related adverse effects, such as somnolence and / or sedative and / or other muscle coordination related adverse effects.

47. The method of claim 40, wherein the subject shows inadequate response to cenobamate, wherein adverse side effects prevent the subject from achieving a therapeutic dose and / or achieving adequate seizure control with cenobamate without cannabidiol.

48. The method of claim 47, wherein the adverse side effects are CNS related adverse effects, such as somnolence and / or sedative and / or other muscle coordination related adverse effects.

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