By Pegah Afra, MD

Associate Professor of Neurology, Weill Cornell Medical College; Associate Attending Neurologist; New York-Presbyterian Hospital; Adjunct Associate Professor, University of Utah

SYNOPSIS: Cannabidiol used as an add-on therapy for intractable focal seizures in patients with tuberous sclerosis complex was efficacious. Cannabidiol also had an acceptable adverse event profile, but frequently induced transient elevation of liver enzymes.

SOURCE: Theile EA, Bebin EM, Bhathal H, et al. Add-on cannabidiol treatment for drug-resistant seizures in tuberous sclerosis complex: A placebo-controlled randomized clinical trial. JAMA Neurol 2020; Dec 21:e204607. doi:10.1001/jamaneurol.2020.4607. [Online ahead of print].

The efficacy of purified cannabidiol (CBD) derived from Cannabis sativa L. has been demonstrated in Lennox-Gastaut syndrome (LGS) and Dravet syndrome (conditions associated with generalized seizures).^1-4 This study investigated the safety and efficacy of CBD in treating focal seizures associated with tuberous sclerosis complex (TSC), an autosomal dominant disorder caused by sequence variations in the TSC1 and/or TSC2 genes, encoding hamartin and tuberin, which are linked to the mammalian target of rapamycin (mTOR) kinase signaling pathway.⁵

TSC is characterized by cortical tubers, white matter heterotopias, subependymal nodules, and subependymal giant cell astrocytomas (SEGAs) in the brain. Epilepsy is the most common neurological manifestation, seen in 85% of patients with TSC, with 60% of patients having intractable medication-resistant epilepsy.⁶

This was a Phase III, international, double-blind, parallel-group, randomized clinical trial of purified CBD derived from Cannabis sativa L. (100 mg/mL oral solution). The study design consisted of four weeks of baseline period (during which baseline seizure frequency was obtained) followed by 16 weeks of treatment period. The treatment period consisted of four weeks of titration period (during which study drug was escalated) and 12 weeks of maintenance period (during which participants received a stable dosage of study drug). Following the 16-week treatment period, there was a 10-day taper period, followed by four weeks of a safety followup period.

For the purpose of the study, the authors defined TSC-associated seizures as focal motor seizures without impairment of awareness (IOA), focal seizures with IOA, focal seizures evolving to bilateral motor seizures, and generalized seizures (tonic-clonic, tonic, clonic, or atonic). TSC-associated seizures did not include absence, myoclonic, or focal sensory seizures, or infantile/epileptic spasms.

Eligibility criteria included definite diagnosis of TSC, medication-resistant epilepsy, taking at least one antiseizure medication (ASM), and eight TSC-associated seizures during the baseline period (four weeks), with at least one seizure occurring in three of the four weeks. Exclusion criteria consisted of a history of nonepileptic seizures, clinically significant illness other than epilepsy, epilepsy surgery in the six months before screening, felbamate use for less than one year before screening, and use of oral mTOR inhibitors (everolimus and sirolimus). Patients were randomized to three groups: CBD25 (receiving 25 mg/kg/day), CBD50 (receiving 50 mg/kg/day), and placebo.

The primary endpoint was the change from baseline in the number of TSC-associated seizures during the 16 weeks of the treatment period. There were several secondary outcomes, including the proportion of patients who had at least 50% reduction from baseline in primary endpoint seizures and total seizures (i.e., all types of seizures), and change from baseline overall condition as reported by the participant or parent.

Between April 6, 2016, and Oct. 4, 2018, 255 patients were assessed at 46 sites, and 224 patients were randomized to the three groups. All patients had intractable seizures with CBD being, on average, the eighth instituted medication. The reduction from baseline in the type of seizures considered the primary endpoint was 48.6% (95% confidence interval [CI]) in the CBD25 group, 47.5% (95% CI) in the CBD50 group, and 30.1% (95% CI) in the placebo group. The secondary outcome of 50% reduction from baseline in primary endpoint seizures was 36% of the CBD25 group, 40% of the CBD50 group, and 22% of the placebo group.

Overall, 16.9% of patients taking CBD had a 75% reduction in seizure frequency vs. none in the placebo group. One patient in the CBD25 group was seizure-free during the entire treatment period, and four patients in the CBD25 group and two patients in the CBD50 group, but none in the placebo group, were seizure-free during the maintenance period. Improvement from baseline in overall condition was reported in 69% of the CBD25 group, 62% of the CBD50 group, and 39% of the placebo group.

The most common adverse events (AE) were diarrhea, somnolence, decreased appetite, and elevation in liver transaminase levels. In patients taking CBD with clobazam, somnolence, rash, and pneumonia occurred more frequently. The most common AEs leading to discontinuation were rash, alanine transaminase (ALT) elevation, somnolence, and urticaria.

Serious AEs (elevated liver enzymes) were reported in 21% of the CBD25 group, 14% of the CBD50 group, and 3% of the placebo group. No deaths were reported. Serum aminotransferase elevations greater than three times the upper limit of normal range occurred in 28 patients (18.9% of CBD25 and 12% of CBD 50, but none in the placebo group). Twenty-two of 28 were taking concomitant valproate. Most elevations resolved within 30 days of starting treatment, either spontaneously or following treatment discontinuation or after CBD or ASM dosage reduction.

COMMENTARY

From a standpoint of safety, the CBD profile in TSC is consistent with LGS and Dravet studies.^1-4 The most common AEs included somnolence and sedation (especially in the presence of clobazam),
as well as CBD-associated risk of transaminase elevation and drug-induced liver injury (specifically when used with valproate [VPA]). There was a difference between the CBD25 and CBD50 groups, with higher AEs and serious AEs in the CBD50 group. The most frequent AE leading to withdrawal was CBD-associated transaminase elevation, which was more pronounced in those with baseline elevations of ALT, taking concomitant VPA, and/or CBD50. All patients with drug-induced liver injury recovered. It was concluded that CBD had an acceptable safety profile.

Regarding efficacy, this study confirms the efficacy of CBD as add-on therapy of primarily focal seizures associated with TSC. This is in line with known efficacy of CBD as add-on therapy for generalized seizures of LGS and Dravet syndrome.^1-4 There was no difference in efficacy between CBD25 and CBD50. There is a drug-drug interaction between CBD and clobazam, resulting in increased exposure to active metabolites of each drug.

REFERENCES

1. Devinsky O, Cross JH, Laux L, et al. Trial of cannabidiol for drug-resistant seizures in the Dravet syndrome. N Engl J Med 2017;376:2011-2020.
2. Devinsky O, Patel AD, Cross JH, et al. Effect of cannabidiol on drop seizures in the Lennox-Gastaut syndrome. N Engl J Med 2018;378:1888-1897.
3. Thiele EA, Marsh ED, French JA, et al. Cannabidiol in patients with seizures associated with Lennox-Gastaut syndrome (GWPCARE4): A randomised, double-blind, placebo-controlled phase 3 trial. Lancet 2018;391:1085-1096.
4. Miller I, Scheffer IE, Gunning B, et al. Dose-ranging effect of adjunctive oral cannabidiol vs placebo on convulsive seizure frequency in Dravet syndrome: A randomized clinical trial. JAMA Neurol 2020;77:613-621.
5. Curatolo P, Bombardieri R, Jozwiak S. Tuberous sclerosis. Lancet 2008;372:657-668.
6. Chu-Shore CJ, Major P, Camposano S, et al. The natural history of epilepsy in tuberous sclerosis complex. Epilepsia 2010;51:1236-1241.