Regulatory Decision Summary for Epidiolex

This New Drug Submission was filed to obtain market authorization for Epidiolex (cannabidiol oral solution) for the treatment of seizures associated with Lennox-Gastaut syndrome (LGS), Dravet syndrome (DS), or tuberous sclerosis complex (TSC).

The safety and efficacy of Epidiolex for the treatment of seizures associated the Lennox-Gastraut syndrome (LGS), Dravet syndrome (DS), and tuberous sclerosis complex (TSC) was supported by a total of 5 pivotal studies across the 3 indications.

The first pivotal trial in patients with LGS, Study GWPCARE4, was a randomised, double-blind, placebo-controlled trial that compared Epidiolex 20 milligrams per kilogram per day (mg/kg/day) in 86 patients to placebo in 85 patients, aged 2 to 45 years old inadequately controlled on at least one anti-epileptic drugs (AED), with or without vagal nerve stimulation and/or ketogenic diet. This study demonstrated a statistically significant median percent change of monthly seizure reduction of -44% compared to placebo with -22% with a p-value of 0.01 when used with concomitant AED such as valproic acid, clobazam, lamotrigine and rufinamide. The second pivotal trial, Study GWPCARE3, was also a randomised, double-blind, placebo-controlled trial that compared two doses of Epidiolex (10 mg/kg/day [73 patients] and 20 mg/kg/day [76 patients]) to placebo in 76 patients aged 2-47 years old inadequately controlled on at least one AED, with or without vagal nerve stimulation and/or ketogenic diet. This study demonstrated that both doses were statistically significant in the reduction of monthly seizure compared to placebo with a median percentage change of -37% and -42% compared to placebo with -17% with p-values of less than 0.01 for both doses when used with concomitant AED. Both trials had a 4-week baseline period, during which patients were required to have a minimum of 8 drop seizures (greater than or equal to 2 drop seizures per week). The baseline period was followed by a 2-week titration period and a 12-week maintenance period.

The first pivotal trial in patients with DS, Study GWPCARE1 Part B, was a randomised, placebo-controlled, double-blind study that compared Epidiolex 20 mg/kg/day in 61 patients to placebo in 59 patients aged 2-18 years old who were inadequately controlled with at least 1 concomitant AED with or without vagal nerve stimulation or ketogenic diet. There was a 4-week baseline period, patients were required to have at least 4 convulsive seizures (tonic-clonic, tonic, clonic, or atonic seizures) while on stable AED therapy. The baseline period was followed by a 2-week titration period and a 12-week maintenance period. This study demonstrated a statistically significant median percent change in monthly seizure reduction compared to placebo (-39% compared to -13%, respectively) when used with concomitant AED such as valproic acid, clobazam, stiripentol and other AED, with a p-value of 0.01.

The second pivotal trial in DS, Study GWPCARE2, was a randomised, placebo-controlled, double-blind trial comparing two doses of Epidiolex (10 mg/kg/day [64 patients] and 20 mg/kg/day [69 patients]) to placebo (65 patients) aged 2-18 years old inadequately controlled with at least one concomitant AED, with or without vagal nerve stimulation or ketogenic diet. This study had a 4-week baseline period, followed by a 2-week titration period and a 12-week maintenance period. This study demonstrated a statistically significant median percent change of monthly seizure reduction compared to placebo (-49%, -46% and -27%, respectively) when used with concomitant AED with p-values of 0.01 and 0.03, respectively.

The single pivotal trial, Study GWPCARE6, in patient with TSC was a randomised, placebo-controlled, double-blind study comparing two different doses (25 mg/kg/day [75 patients], as well as a dose which was not included in the final dosing recommendations) compared to placebo (76 patients) in patients aged 1-56 years old inadequately controlled with at least one concomitant AED, with or without vagal nerve stimulation or ketogenic diet. This study had a 4-week baseline period, followed by a 4-week titration period and a 12-week maintenance period. The 25 mg/kg/day dose demonstrated a statistically significant percent change in monthly seizure reduction from baseline compared to placebo (-49% compared to -27%, respectively), with a p-value of 0.0009 when Epidiolex was used with concomitant AED.

Safety was assessed in the pivotal trials as well as in a pooled data set. The most common adverse events (AEs) associated with Epidiolex use included liver transaminase elevations, somnolence (sedation, lethargy, and fatigue), rash and hypersensitivity, pneumonia (and other infection), gastrointestinal symptomatology (diarrhea, vomiting, decreased appetite, and weight loss), hematologic effects (anemia), and increase of creatinine levels. Class effects of anti-epileptic drugs such as suicidality and caution with withdrawal of therapy due to risk of seizure exacerbation were included in the Product Monograph (PM).

The majority of liver transaminase elevation AEs resolved in most patients with time, dose reduction, or discontinuation of Epidiolex or other AED. No patient met the criteria for Hy’s Law drug-induced liver injury. Use of concomitant valproic acid and/or, to a lesser extent, clobazam therapy increased the risk of liver transaminase elevation occurrence. As baseline liver transaminase elevations increases the risk of further liver transaminase elevations, patients with transaminase elevations greater than three times the upper limit of normal (ULN) and concurrent elevations of bilirubin greater than two times the ULN have a contraindication to use Epidiolex. In general, alanine transaminase elevations occurred more commonly than aspartate transaminase elevations. Liver transaminase elevations were a cause for discontinuation of Epidiolex therapy. The PM includes warnings and precautions, and recommendations for monitoring of liver function, as well as discontinuation instructions of Epidiolex therapy in case of transaminase elevations. The monitoring instructions are to be restarted within one month following changes in Epidiolex dosing or in medications that are known to impact the liver. Intensive monitoring is recommended when valproate acid is a concomitant medication or if patients have elevated liver transaminases at baseline that do not meet the contraindication criteria.

Somnolence is an AE associated with Epidiolex use and is higher when concomitantly used with clobazam. Somnolence was commonly reported early in treatment but was also observed at later stages of treatment. Central nervous system depressants including alcohol can potentiate the somnolence and sedation effect. Due to this somnolence and sedation effect, prescribers should monitor patients and advise patients not to drive or operate machinery until they have gained sufficient experience on treatment in order to gauge whether it adversely affects their ability to drive or operate machinery. As with all AEDs, Epidiolex should be withdrawn gradually, because of the risk of seizure and status epilepticus increase with withdrawal of therapy.

Gastro-intestinal AEs were also common, including diarrhea, decreased appetite, weight loss and vomiting. Further, pneumonia and urinary tract infection were among infections that were associated with the use of Epidiolex.

Epidiolex has also been associated with rash and hypersensitivity. These rashes have been reported to be often self-limiting and resolve during treatment. Hypersensitivity has been infrequently reported and is a contraindication to the use of Epidiolex in the PM. Additionally, Epidiolex has been associated with effects on hemoglobin parameters and elevation of creatinine. Anemia has also been reported as an adverse in the clinical trials.

There was a lack of safety data on use in patients under 2 years of age, particularly potential effect on growth, development, cognition, and long-term use of Epidiolex as an anti-epileptic drug. The safety and efficacy of Epidiolex in patients 65 years of age and older have not been studied as the clinical studies of Epidiolex did not include this patients population. It is not known whether geriatric patients would respond differently than younger adult patients. Dose selection should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy.

The chemistry and manufacturing information submitted for Epidiolex has demonstrated that the drug substance and drug product can be consistently manufactured to meet the approved specifications.

The comparative bioavailability data was reviewed and results of the study showed that the administration of Epidiolex with either high-fat, high-calorie or low-fat, low-calorie meals resulted in significant increases in exposure compared to the fasted state. The administration of Epidiolex with whole milk or alcohol also increased exposure, to a lesser degree. Given the increases in exposure under all conditions studied, the Dosage and Administration section of the PM was revised to specify that dose administration should take place under consistent conditions to ensure predictable exposure and efficacy.

Following review and requested revisions, the final labelling and PM were considered to be acceptable.

A Risk Management Plan (RMP) was submitted and reviewed by the Marketed Health Products Directorate and was considered acceptable

Overall, the benefit-harm-uncertainty profile was favourable for Epidiolex in patients aged 2 and over used as adjunctive treatment with other AEDs for the treatment of seizures in LGS, DS and TSC outweigh the risks associated with therapy. Risks are mitigated by monitoring recommendations and Warning and Precautions contained in the labelling of the Canadian Product Monograph, as well as routine post-market surveillance. Therefore, a Notice of Compliance pursuant to section C.08.004 of the Food and Drug Regulations was recommended.

For further details about Epidiolex, please refer to the Product Monograph, approved by Health Canada and available through the Drug Product Database.