Synthetic transdermal cannabidiol for the treatment of focal epilepsy in adults

Abstract

To provide a method of reducing seizure frequency in a subject having epilepsy.SOLUTION: Provided is a method of reducing seizure frequency in a subject having epilepsy by transdermally administering an effective amount of cannabidiol (CBD) to the subject.SELECTED DRAWING: Figure 1

Description

[Technical field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS This application claims the benefit of and priority to U.S. Provisional Patent Application Publication No. 62 / 560,446, filed September 19, 2017, No. 62 / 593,575, filed December 1, 2017, No. 62 / 613,160, filed January 3, 2018, No. 62 / 652,995, filed April 5, 2018, and No. 62 / 660,198, filed April 19, 2018, the entire contents of each of which are incorporated herein by reference in their entirety.

[0002] The present disclosure relates to a method of reducing seizure frequency in a subject suffering from epilepsy by transdermally administering to the subject an effective amount of cannabidiol (CBD), whereby seizure frequency is reduced. [Background technology]

[0003] Cannabinoids are a class of compounds found in the Cannabis plant. The two main cannabinoids contained in Cannabis are cannabidiol, or CBD, and Δ9-tetrahydrocannabinol, or THC. CBD lacks the psychostimulant effects of THC. Studies have shown that CBD can be used to treat disorders such as epilepsy, arthritis, and cancer.

[0004] Epilepsy is a disease characterized by a persistent predisposition to seizures and the neurobiological, cognitive, psychiatric, and social consequences of the condition. An epileptic seizure is a transient onset of signs and / or symptoms due to abnormal, excessive, or synchronized neuronal activity in the brain. Seizures in epilepsy may be associated with genetic disorders or brain damage, such as trauma or stroke, but most often the cause is unknown. There are more than 200,000 cases of epilepsy in the United States annually.

[0005] Generalized epilepsy affects both hemispheres of the brain from the beginning. Focal epilepsy (formerly known as partial epilepsy) is a seizure that affects only one hemisphere or lobe of the brain from the beginning. Symptoms of focal epilepsy vary depending on which hemisphere or lobe of the brain the seizure is occurring in. Summary of the Invention

[0006] The present disclosure relates to a method of reducing seizure frequency in a subject suffering from epilepsy, comprising transdermally administering to the subject an effective amount of cannabidiol (CBD), wherein the seizure frequency is reduced.

[0007] The seizure frequency can be reduced by 25%. In some embodiments, the seizure frequency can be reduced by 30%. The seizure frequency can be reduced by 50%. The seizure frequency can be reduced by 65%. The reduction in seizure frequency can be the reduction from baseline seizure frequency to administration of an effective amount of CBD. In some embodiments, the reduction in seizure frequency is measured by reduction in weekly seizures. In some embodiments, the reduction in seizure frequency is measured by seizure frequency per 28-day cycle. In some embodiments, the reduction in seizure frequency is measured by monthly seizure frequency.

[0008] In some embodiments, focal onset seizures (formerly known as partial onset seizures) are reduced in adults. Adults are subjects 18 years of age or older. In some embodiments, focal aware seizures (formerly known as simple partial seizures) are reduced. Focal impaired awareness seizures (formerly known as complex partial seizures) can be reduced. Focal impaired awareness with generalized tonic-clonic seizures (formerly known as complex partial with generalized tonic-clonic seizures) can be reduced.

[0009] The subject may have a high seizure frequency. The epilepsy may be drug-resistant epilepsy (formerly known as refractory epilepsy).

[0010] In some embodiments, the method also includes administering at least one antiepileptic drug selected from the group consisting of levetiracetam, carbamazepine, topiramate, lamotrigine, lacosamide, clonazepam, valproate, phenytoin, eslicarbazepine, clobazam, and oxcarbazepine. The antiepileptic drug may be, for example, an anticonvulsant. The CBD transdermal gel can be used with at least one antiepileptic drug as an adjunctive therapy. In some embodiments, the CBD transdermal gel can be used with two or three antiepileptic drugs as an adjunctive therapy. The CBD transdermal gel can also be used as a monotherapy.

[0011] In some embodiments, the CBD is (-)-CBD. The CBD may be synthetic CBD. The CBD may be pure CBD.

[0012] An effective amount of CBD may be about 195 mg to about 780 mg total daily. CBD can be administered in a single daily dose. In some embodiments, CBD is administered in two daily doses.

[0013] In some embodiments, the effective amount of CBD is 195 mg in divided daily doses. The effective amount of CBD may be 390 mg in divided daily doses. In some embodiments, the effective amount of CBD is 585 mg in divided daily doses. The effective amount of CBD may be 780 mg in divided daily doses.

[0014] An effective amount of CBD may be provided in a 97.5 mg single-use sachet. In some embodiments, an effective amount of CBD may be provided in a 195 mg single-use sachet. An effective amount of CBD may be provided in a 390 mg single-use sachet.

[0015] The CBD is formulated as a gel. In some embodiments, the CBD is formulated as an enhanced permeability gel. The gel can contain 4.2% (w / w) CBD or 7.5% (w / w) CBD.

[0016] In some embodiments, the transdermal preparation may be a cream, salve, or ointment. The CBD may be delivered by a bandage, pad, or patch.

[0017] The transdermal administration of an effective amount of CBD can reduce the intensity of at least one adverse event compared to oral administration of CBD. The at least one adverse event can be somnolence, psychostimulant effects, liver function, gastrointestinal-related adverse events, diarrhea, loss of appetite, fatigue, fever, vomiting, lethargy, upper respiratory tract infection, convulsions, or a combination thereof. In some embodiments, the transdermal administration of an effective amount of CBD reduces the intensity of at least one adverse event by about 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, or 95% compared to oral administration of CBD.

[0018] In some embodiments, the subject is an adult, ie, 18 years of age or older.

[0019] In some embodiments, the reduction in seizure frequency occurs after 3 months. The reduction in seizure frequency can occur after 12 weeks. In some embodiments, the reduction in seizure frequency occurs after 6 months. The reduction in seizure frequency can occur after 24 weeks.

[0020] The present disclosure relates to a method of reducing seizure frequency in a subject suffering from epilepsy. The method includes transdermally administering a first effective amount of cannabidiol (CBD) to the subject for a period of time, whereby seizure frequency is reduced. The method also includes transdermally administering a second effective amount of CBD to the subject after a period of time, whereby the second effective amount of CBD is less than the first effective amount of CBD, whereby the reduced seizure frequency is maintained.

[0021] The period may be 12 weeks. The period may be 24 weeks. [Brief description of the drawings]

[0022] [Figure 1] 1 is a graph showing the median percentage reduction in monthly attack rates (efficacy population) with embodiments of the present technology. [Diagram 2] 1 is a graph showing the median percentage reduction in seizure rate for patients with focal aware seizures (Type B) according to embodiments of the present technology. [Diagram 3] 13 is a graph showing the median percentage reduction in seizure rate for patients with focal impaired awareness seizures (Type C) according to an embodiment of the present technology. [Figure 4] 1 is a graph showing the median percentage reduction in seizure rate for patients with focal impairment of awareness with generalized tonic-clonic seizures (Type D) according to embodiments of the present technology. [Diagram 5] 1 is a graph showing the mean percentage change in seizure rate after 12 weeks (STAR ​​1) and after 3 and 6 months (STAR ​​2) according to an embodiment of the present technology. [Figure 6] 13 is a graph showing median SF28 over time up to each three-month interval according to an embodiment of the present technology. [Figure 7] 13 is a graph showing median SF28 over time out to each 3-month interval out to 6 months in STAR2 according to an embodiment of the present technology. [Figure 8] 13 is a graph showing median SF28 over time for patients with no change in AED in accordance with an embodiment of the present technology. [Figure 9] 1 is a graph showing the median % change in seizure rate after 3, 6, 9, and 12 months for all patients treated with CBD transdermal gel in STAR2, according to an embodiment of the present technology. [Figure 10] 1 is a graph showing the median change (%) in seizure rate after 3, 6, 9, and 12 months for patients treated with placebo or CBD transdermal gel (195 mg and 390 mg) in STAR1 according to an embodiment of the present technology. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0023] As used herein, the term "treating" or "treatment" refers to the alleviation, amelioration, alleviation or relief of at least one symptom of a condition, disease or injury in a subject, such as a human, or the improvement in an identifiable measurement associated with the condition, disease or disorder.

[0024] As used herein, the term "clinical efficacy" refers to the ability to produce a desired effect in humans as demonstrated through U.S. Food and Drug Administration (FDA) clinical trials.

[0025] As used herein, "cannabidiol" or "CBD" refers to cannabidiol, cannabidiol prodrugs, and pharma- ceutically acceptable derivatives of cannabidiol, including pharma- ceutically acceptable salts of cannabidiol, cannabidiol prodrugs, and cannabidiol derivatives. CBD includes 2-[3-methyl-6-(1-methylethenyl)-2-cyclohexen-1-yl]-5-pentyl-1,3-benzenediol, as well as its pharma- ceutically acceptable salts, solvates, metabolites (e.g., skin metabolites), and metabolic precursors. The synthesis of CBD is described, for example, in Petilka et al., Helv. Chim. Acta, 52:1102 (1969), and Mechoulam et al., J. Am. Chem. Soc., 87:3273 (1965), which are hereby incorporated by reference.

[0026] As used herein, the term "high seizure frequency" refers to a seizure frequency per 28 days (SF28) of 15 or greater.

[0027] As used herein, the term "drug-resistant epilepsy" refers to epilepsy in which drugs have not adequately treated the seizures. Drug-resistant epilepsy is the failure of sufficient trials of two tolerated, appropriately selected and used antiepileptic drug schedules (whether as monotherapy or in combination) to achieve a sustained seizure-free state.

[0028] As used herein, the term "focal onset seizures" (previously known as "partial seizures") refers to seizures that initially affect only one hemisphere or lobe of the brain.

[0029] As used herein, the term "focal impaired awareness seizures" (previously known as "complex partial seizures") refers to seizures that primarily affect one hemisphere or lobe of the brain, resulting in impaired awareness.

[0030] As used herein, "focal impairment of awareness with generalized tonic-clonic seizures" refers to focal impairment of awareness seizures having tonic (rigidity) and clonic (rhythmic nystagmus) features.

[0031] The term "adjunctive therapy" refers to the administration of a therapy to a subject already receiving an existing or separate administration, but does not necessarily mean that the therapy is given or provided at the same time or by the same route. For example, CBD may be administered in addition to or adjunctively to an existing oral drug therapy.

[0032] As used herein, the term "transdermally administering" refers to contacting the CBD with the skin of a patient or subject under conditions effective for the CBD to penetrate the skin.

[0033] "Seizure frequency per 28-day period" or "SF28" is calculated using the following formula: SF28 = (total number of seizures in D days) × (28 / D) It is calculated by where D is the total number of days for which seizure information was collected for the specified time interval.

[0034] Reduction from baseline in seizure frequency (RedSF) during the maintenance period was: RedSF = SF28(baseline)-SF28(maintenance) It is defined as:

[0035] Baseline refers to the period during which CBD gel is not administered, and the number of seizures during this period is counted. In other words, the baseline period is the period during which the patient is on a regular AED and seizure frequency is acquired. The baseline period can be, for example, 8 weeks. The subject may have a high seizure frequency during the baseline period. Maintenance refers to the period during which CBD transdermal gel is administered, and the number of seizures during this period is counted. The maintenance period can be, for example, 12 weeks, 3 months, 6 months, 9 months, 12 months, 15 months, 18 months, or 20 months.

[0036] The percentage reduction from baseline in seizure frequency during the maintenance period was: %RedSF = 100 × [SF28(baseline)-SF28(maintenance) / SF28(baseline) It is defined as:

[0037] Patients will be defined as 50% responders for a given treatment period if their %RedSF is 50% or greater.

[0038] In some embodiments, seizure frequency is calculated per 7-day period to provide a weekly seizure frequency value. The weekly seizure frequency can be reduced by 25%, 30%, 50% or 65%. The reduction in seizure frequency can be a reduction from baseline seizure frequency to the administration of an effective amount of CBD.

[0039] The present disclosure relates to a method of reducing seizure frequency in a subject suffering from epilepsy, comprising transdermally administering to the subject an effective amount of cannabidiol (CBD), wherein the seizure frequency is reduced.

[0040] CBD is the main non-psychotropic cannabinoid found in Cannabis, with low affinity for CB1 and CB2 receptors. CBD produces multiple effects, including blocking the equilibrative nucleoside transporter, the orphan G protein receptor GPR-55, and the transient receptor potential ankyrin type 1 channel, which modulate the intracellular effects of calcium. CBD's effects on these targets, each known to play a role in neuronal excitability, are the scientific basis for its antiepileptic potential. The expectation of a wide margin of safety in humans is based on the results of well-controlled studies in which CBD has been well tolerated across several modes of administration.

[0041] Treatment of epilepsy in human patients generally includes antiepileptic and anticonvulsant drugs. Studies have been conducted that CBD can effectively treat Lennox-Gastaut and Dravet syndromes (a type of epilepsy syndrome), but the research has focused on orally delivered cannabidiol (CBD) for children with epilepsy.

[0042] Transdermal delivery of cannabinoids, such as CBD, has advantages over oral administration because the drug can be absorbed directly into the bloodstream through the skin. This avoids first-pass liver metabolism, potentially allowing lower dosage levels of active pharmaceutical ingredients with higher bioavailability (about 25%) and improved safety profile. Transdermal delivery also avoids the gastrointestinal (GI) tract, reducing the chance of potential degradation of CBD to THC by stomach acid, which may be associated with GI-related adverse events and undesirable psychostimulant and euphoric effects. Moreover, oral CBD provides low (about 6%) and variable bioavailability. Transdermal delivery of CBD can avoid or reduce somnolence adverse events that are typically present with oral administration of CBD. Transdermal delivery of CBD can also avoid psychostimulant and / or euphoric effects and / or GI-related adverse events that are typically present with oral administration of CBD. Transdermal delivery of CBD can avoid liver function adverse events that are typically present with oral administration of CBD. In some embodiments, administering an effective amount of CBD transdermally reduces the intensity of at least one adverse event by about 15% to about 95% compared to oral administration of CBD.

[0043] A clear transdermal gel was developed to provide consistent and controlled CBD delivery in twice-daily (approximately every 12 hours) administration. 4.2% (w / w) or 7.5% (w / w) CBD can be used. CBD can be in gel form and can be manufactured pharmaceutical as a clear, enhanced permeability gel designed to provide controlled drug delivery transdermally in once or twice-daily administration. The CBD gel can be applied by the patient or a medical professional to the patient's arms, back, legs, or any combination thereof.

[0044] Zero-order delivery from transdermal application of CBD is lower than oral or buccal routes of delivery. maxBecause CBD transdermal gels can provide a high dose, the use of CBD transdermal gels can result in relatively low systemic exposure, well below the safety thresholds in humans that have been established for more gradual dosing via oral, inhaled, and injectable formulations.

[0045] It was expected that there would be zero-order kinetics between oral and transdermal administration, but this was not the case. Without being bound by theory, a two-compartment model with two absorption rates (one faster with a lag time and one slower without a lag time) was prepared together, where a transdermal application of CBD gel is applied to the skin, then absorbed through the skin to the application site, enters the bloodstream, and enters adipose tissue all throughout the subject's body (e.g., liver) and site of action (e.g., brain). This model was unexpected and novel, but it supports the progression from once-daily dosing to twice-daily dosing once a steady-state level is reached. In addition, ultimately, subjects can reduce dosing by half once a steady state is reached. In addition, the induction period for CBD transdermal gel is about 12-24 weeks, which may be due to the novel and unexpected model of transdermal administration.

[0046] Since CBD is essentially water insoluble, ethanol and propylene glycol can be used as solubilizers, and diethylene glycol monoethyl ether can be used as a permeability enhancer. The alcohol content of the CBD transdermal gel is approximately 54% (w / w).

[0047] The CBD gel may include diluents and carriers, as well as other conventional excipients, such as wetting agents, preservatives, and suspending and dispersing agents.

[0048] The CBD gel may include a solubilizing agent, a penetration enhancer, a solubilizer, an antioxidant, a bulking agent, a thickening agent, and / or a pH adjusting agent. The composition of the CBD gel may be, for example, a. cannabidiol present in an amount of about 0.1% to about 20% (w / w) of the composition, b. a lower alcohol having 1 to 6 carbon atoms present in an amount of about 15% to about 95% (w / w) of the composition, c. a first penetration enhancer present in an amount of about 0.1% to about 20% (w / w) of the composition, and d. a sufficient amount of water in the composition to total 100% (w / w). Other formulations of CBD gels can be found in WO 2010 / 127033, the entire contents of which are incorporated herein by reference. EXAMPLES

[0049] This study evaluates the safety and efficacy of CBD transdermal gel as an adjunctive therapy for the treatment of adult focal epilepsy. CBD transdermal gel is a clear, highly permeable gel designed to provide controlled drug delivery transdermally in once or twice daily dosing. A 4.2% (w / w) CBD gel was evaluated in this study.

[0050] method STAR1 (Synthetic Transdermal Cannabidiol for the Treatment of Epilepsy) was a randomized, double-blind, placebo-controlled Phase 2 study evaluating cannabidiol administered BID (twice daily) for 12 weeks (maintenance phase) in adults with focal epilepsy. Following an 8-week baseline (baseline phase), patients were randomized 1:1:1 to receive 390 mg CBD daily in divided doses (e.g., 195 mg twice daily), 195 mg CBD daily in divided doses (e.g., 97.5 mg twice daily), or placebo. Divided daily doses were given every 12 hours (± 2 hours). CBD transdermal gel and placebo were rubbed into both left and right shoulders and / or both upper arms until the area was dry. The primary endpoint was the change in seizure frequency over the treatment period relative to baseline. The primary endpoint is based on the reduction in seizure frequency per 28 days (SF28) comparing the baseline phase with the maintenance phase.

[0051] At the end of the 12 weeks, patients could choose to enroll in the ongoing STAR2 18-month (amended to 24-month) open-label extension study evaluating 390 mg CBD transdermal gel in adult patients with focal epilepsy. Data following 9 months of total exposure to CBD transdermal gel are presented below (3 months of treatment in STAR1 and 6 months of treatment in STAR2).

[0052] Demographics and baseline characteristics Patients (N=188) were randomized to STAR1. Mean age was 39 (range 18-71) years. At baseline, patients were taking a mean of 2.5 antiepileptic drugs (AEDs) with a median monthly seizure frequency of 10.6 (range 3-330). By group, median monthly seizure frequency at baseline was 10.5 for placebo, 14.0 for the divided-dose group from a daily dose of 195 mg, and 10.14 for the divided-dose group from a daily dose of 390 mg.

[0053] Of 188 randomized patients, 186 were analyzed for efficacy, with 174 completing the 12-week STAR1 study. 171 patients (98% of STAR1 completers) continued into STAR2. Patients were taking a wide range of AEDs, with a median of 3.0 AEDs. Use of clobazam was excluded in both STAR1 and STAR2 because of a known interaction between clobazam and CBD.

[0054] Effectiveness With reference to Figure 1, after 12 weeks of blinded treatment, the median reduction in focal onset seizures was 18.42% (n=62) for 195 mg / day CBD transdermal gel, 14.03% (n=61) for 390 mg / day CBD transdermal gel, and 8.70% (n=63) for placebo. There was no statistically significant difference in efficacy between 195 mg / day (p=0.431), 390 mg / day (p=0.846), and placebo. Secondary endpoints showed no statistically significant differences between 195 mg / day, 390 mg / day, and placebo. The 50% responder rates were similar across treatment groups: placebo=23.8%, 195 mg / day=21% (p=0.414), and 390 mg / day=16.4% (p=0.21).

[0055] With reference to Figures 2 and 3, it can be seen that there was no statistically significant difference in efficacy between 195 mg / day, 390 mg / day and placebo for focal awareness (type B) or focal awareness impaired (type C) seizures. What was unexpected and surprising was that for patients with focal awareness impaired seizures with generalized tonic-clonic seizures, there was a near statistically significant difference in efficacy between 195 mg / day (p=0.071) and placebo. It was also unexpected and surprising that the lower dose of CBD transdermal gel resulted in greater efficacy for patients with focal awareness impaired seizures with generalized tonic-clonic seizures.

[0056] With reference to Figure 4, the results from focal consciousness impairment seizures with generalized tonic-clonic seizures were interesting, with a 60% median reduction (p=0.071) observed in the 195mg / day treatment group compared to a 22.2% median reduction (p=0.308) for the 390mg / day group and a 0.41% median reduction for the placebo group. It was unexpected that the lower dose of CBD transdermal gel resulted in a greater median reduction in focal consciousness impairment seizures with generalized tonic-clonic seizures.

[0057] The lack of separation between CBD transdermal gel and placebo in STAR1 may have been due in part to the 15 (24%) placebo-treated patients who achieved at least a 50% reduction in focal seizures; 13 of these 15 patients had relatively low baseline seizure rates (<15 focal seizures per month). Table 1 shows that the majority (>50%) of placebo "good" responders were female.

[0058] [Table 1]

[0059] In addition, placebo responders were more likely to be taking topiramate than the broader population. Table 2 shows the AEDs used in "good responders" and the overall patient population.

[0060] [Table 2]

[0061] In STAR1, patients with frequent seizures (defined as a baseline seizure frequency of 15 or more per month) taking either 195 mg / day or 390 mg / day of CBD transdermal gel experienced a greater percentage reduction in seizures compared to patients with frequent seizures taking a placebo.

[0062] 171 patients were enrolled in STAR2.

[0063] Post-hoc analyses showed that by month 3 in STAR2, patients taking CBD transdermal gel in STAR1 and STAR2 (6 months total of CBD transdermal gel) had a greater reduction in seizure frequency compared to patients taking only CBD transdermal gel for 3 months in STAR2 (i.e., patients taking placebo in STAR1). See Table 3.

[0064] [Table 3]

[0065] In addition, using CBD transdermal gel for 9 months provides better benefits. Efficacy is maintained with continued treatment. Patients who took placebo in STAR1 and completed 6 months in STAR2 had less seizure reduction than patients taking CBD transdermal gel (195mg or 390mg) during STAR1. See Table 4.

[0066] [Table 4]

[0067] Continued exposure to CBD transdermal gel in STAR2 (all patients taking 390 mg / day) resulted in clinically meaningful reductions in seizures. Patients receiving CBD transdermal gel for 6 months (3 months during STAR1 and 3 months during STAR2) had a median reduction in seizures from baseline of more than 30%. Patients receiving CBD transdermal gel for 9 months (3 months during STAR1 and 6 months during STAR2) had a median reduction in seizures from baseline of more than 65% (195 mg / day in STAR1 and 390 mg / day in STAR2) and more than 48% (390 mg / day in STAR1 and STAR2). The results are summarized in Table 4 and Figure 5 above.

[0068] Seizure control was assessed as a function of duration of CBD transdermal gel regardless of initial randomization group or dose. Longer exposure to CBD transdermal gel resulted in greater improvements in seizure frequency, with median percentage changes in seizures ranging from -16.3% at 3 months (n=170) to -27.3% at 6 months (n=148), -50.2% at 9 months (n=98), and -58.0% at 12 months (n=70).

[0069] As shown in Table 5, patients who received CBD transdermal gel for 6 months responded best.

[0070] [Table 5]

[0071] These results are also seen in Figure 6, which shows the median SF28 over time out to each three-month interval. As can be seen from Figure 6, the two non-placebo groups maintained their improvement with longer exposure. Figure 7 shows the median SF28 over time out to each three-month interval out to six months in STAR2. A sustained improvement or reduction in seizure frequency is seen for the two non-placebo groups.

[0072] Figure 8 shows the median SF28 over time for patients who did not have any AED changes. The graph in Figure 8 shows that the more cumulative the CBD transdermal gel, the greater the effectiveness of the statistically significant results.

[0073] Post-hoc analysis showed that placebo responders were more likely to be female, and non-responders had the highest CBD plasma concentrations at 390 mg / day (although this was highly variable). Table 6 shows the percentage reduction from baseline placebo to treatment (SF28) in seizure rate by demographics.

[0074] [Table 6]

[0075] The analysis also showed that patients aged 26-40 years responded best, with the youngest and oldest patients nominally worsening. Table 7 shows the percentage reduction from baseline placebo to treatment (SF28) in seizure rate by age.

[0076] [Table 7]

[0077] The analysis further showed that only men at the 195 mg / day dose responded positively, whereas women at both doses responded poorly. Table 8 shows the percentage reduction from baseline placebo to treatment (SF28) in seizure rate by gender.

[0078] [Table 8]

[0079] In STAR1, the adverse event rate for CBD transdermal gel 195 mg / day was 49.2%, the adverse event rate for CBD transdermal gel 390 mg / day was 51.6%, and the adverse event rate for placebo was 41.3%. The most common adverse events were upper respiratory tract infections (viral and bacterial) (16%), headache (11%), fatigue (7%), and fissures (5%). The two treatment-emergent adverse events that occurred in more than 5% of CBD transdermal gel patients and more frequently than placebo were fatigue (5.6% for CBD transdermal gel, 1.6% for placebo) and headache (5.6% for CBD transdermal gel, 3.2% for placebo). CBD plasma levels were dose-proportional, but there was no correlation between plasma levels and efficacy.

[0080] Median plasma concentrations at the 4-week dose in 25% responders at weeks 4 to 8 were lower than in non-responders, but the differences were nominal. There was no difference in median 8-week concentrations between responders and non-responders between weeks 8 and 12. max Imitation C max(PopPK model), but both were true C max The intersubject pharmacokinetic variability of CBD transdermal gel is within the range expected for a transdermal product.

[0081] A small number of patients in STAR2 had their background AEDs elevated. The improvement in seizure frequency observed in STAR2 was not due to these changes in background AEDs. This can be seen by a comparison of Figure 8, which shows the response among patients who did not have it, and the AED change with Figure 7, which includes all patients. As can be seen, these two figures are very similar.

[0082] safety CBD transdermal gel was very well tolerated, with incidence of adverse events comparable to placebo and no clinically significant differences between active treatment groups. The safety profile of CBD transdermal gel was consistent with data from phase 1 and phase 2 clinical trials. There were no clinically significant changes in ECG or laboratory results in patients taking CBD transdermal gel. In addition, CBD transdermal gel was well tolerated by the skin, with minimal skin erythema.

[0083] Summary of findings A clinically meaningful response to CBD transdermal gel correlated with continued treatment with CBD transdermal gel, as measured by focal seizure reduction from the baseline period in STAR1. Patients who received CBD transdermal gel (195 mg / day for 3 months during STAR1 and 390 mg / day for 6 months in STAR2) for a total of 9 months achieved a median seizure reduction of 65%. Patients who received CBD transdermal gel (390 mg / day for 3 months in STAR1 and 6 months in STAR2) achieved a median seizure reduction of 48% from baseline. In addition, CBD transdermal gel was shown to be very well tolerated after 9 months of exposure.

[0084] It was found that the correlation between continuation of treatment with CBD transdermal gel and reduction in focal seizures from baseline in STAR1 continued through Month 12. Figure 9 shows the median change in seizure rate (%) at 3, 6, 9, and 12 months for all patients treated with CBD transdermal gel in STAR2. Figure 10 shows the median change in seizure rate (%) at 3, 6, 9, and 12 months for patients treated with placebo CBD transdermal gel (195 mg and 390 mg) in STAR1. As can be seen in Figures 9 and 10, longer exposure to CBD transdermal gel resulted in greater improvement in seizure frequency in all CBD transdermal gel patients (Figure 9), including when examined by the originally randomized CBD dose in STAR1 (Figure 10).

[0085] The data demonstrate that focal seizures in adults can be effectively treated with transdermal gel delivery of medicinal cannabidiol. In this patient population, continued treatment with CBD transdermal gel was shown to significantly reduce seizure rates compared to baseline. Importantly, baseline seizure frequency appears to be an important indicator of response. The data demonstrate that CBD transdermal gel may have an effect on focal seizures in adults suffering from drug-resistant epilepsy. The potential for a CBD-based treatment with optimal tolerability profile would be significant for these patients.

[0086] Modification of the STAR2 trial The protocol for the STAR2 clinical trial has been modified to allow for titration of different doses of CBD transdermal gel based on observed results. The new protocol allows physicians to prescribe CBD transdermal gel at 195mg / day, 390mg / day, 585mg / day, or 780mg / day. The modified protocol allows physicians to titrate the dose of CBD transdermal gel up or down.

[0087] In the modified STAR2 trial, all patients will start with 195 mg of CBD transdermal gel every 12 hours (± 2 hours) (390 mg / day), and after the first month the option is to either increase or decrease the dose of CBD transdermal gel. This dose can be increased to 292.5 mg every 12 hours (± 2 hours) (585 mg / day). After one month at the 585 mg / day dose, the dose can be increased again to 390 mg every 12 hours (± 2 hours) (780 mg / day).

[0088] After one month, the CBD transdermal gel dosage can be reduced to 97.5 mg every 12 hours (± 2 hours) (195 mg / day). For patients taking a daily dose of 195 mg, there is the option to back the dose up to 390 mg / day, up to a maximum of 585 mg / day.

[0089] With each dose, the dose of CBD transdermal gel will increase or decrease, but patients will stay for a month to reach a plateau before changing the dose again.

Claims

1. 1. A pharmaceutical composition containing cannabidiol (CBD) for use in a method of reducing seizure frequency in a subject suffering from epilepsy, the epilepsy being characterized by focal impaired awareness seizures accompanied by generalized tonic-clonic seizures, the method comprising transdermally administering to the subject an effective amount of cannabidiol (CBD), whereby seizure frequency is reduced.

2. 2. The pharmaceutical composition of claim 1, wherein seizure frequency is reduced by 30%.

3. 2. The pharmaceutical composition of claim 1, wherein seizure frequency is reduced by 50%.

4. The pharmaceutical composition of claim 1 , wherein the subject has a high seizure frequency.

5. 2. The pharmaceutical composition of claim 1, wherein the epilepsy is drug-resistant epilepsy.

6. 10. The pharmaceutical composition of claim 1, wherein the method further comprises administering at least one antiepileptic drug selected from the group consisting of levetiracetam, carbamazepine, topiramate, lamotrigine, lacosamide, clonazepam, valproate, clobazam, phenytoin, eslicarbazepine, and oxcarbazepine.

7. 2. The pharmaceutical composition of claim 1, wherein the CBD is (-)-CBD.

8. 2. The pharmaceutical composition of claim 1, wherein the effective amount of CBD is between 195 mg and 390 mg total daily.

9. 2. The pharmaceutical composition of claim 1, wherein the effective amount of CBD is 195 mg per day divided into doses.

10. 2. The pharmaceutical composition of claim 1, wherein the effective amount of CBD is 390 mg per day divided into doses.

11. 2. The pharmaceutical composition of claim 1, wherein the effective amount of CBD is provided in a 97.5 mg single-use sachet.

12. 2. The pharmaceutical composition of claim 1, wherein the effective amount of CBD is provided in a 195 mg single-use sachet.

13. 10. The pharmaceutical composition of claim 1, wherein the CBD is formulated as a gel.

14. 10. The pharmaceutical composition of claim 1, wherein the CBD is formulated as an enhanced permeability gel.

15. 10. The pharmaceutical composition of claim 1, wherein the CBD is administered in a single daily dose.

16. 10. The pharmaceutical composition of claim 1, wherein the CBD is administered in two daily doses.

17. 2. The pharmaceutical composition of claim 1, wherein the CBD is synthetic CBD.

18. 2. The pharmaceutical composition of claim 1, wherein the CBD is pure CBD.

19. The pharmaceutical composition of claim 1 , wherein the subject is an adult.

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