Epidiolex Has Safe, Consistent Profile Over Long-Term in Tuberous Sclerosis Complex

Elizabeth Thiele, MD, PhD

An interim analysis of the phase 3 GWPCARE6 open-label extension trial (NCT02544750) of GW Pharmaceuticals’ cannabidiol (CBD; Epidiolex) demonstrated the therapy’s well-tolerated profile in patients with tuberous sclerosis complex (TSC) across a long-term treatment period.

The research, led by Elizabeth Thiele, MD, PhD, director of pediatric epilepsy and the Herscot Center for Tuberous Sclerosis Complex at Massachusetts General Hospital, and professor of neurology, Harvard Medical School, showed reductions in seizures were maintained through 48 weeks with a high proportion of patients reporting global improvement. Findings of the study were accepted for presentation at the American Academy of Neurology (AAN) 2020 Annual Meeting.

A range of 53% to 61% of patients experienced seizure response rates of ≥50% and 29% to 45% of patients had response rates of ≥75% for seizure reduction. Seizure reduction rates of 100% were documented in 6% to 11% of patients across the 12-week visit windows.

Data also showed a 68% median reduction in seizure frequency over the 48 weeks with treatment with CBD. Improvements on the Subject/Caregiver Global Impression of Change (S/CGIC) measure were reported by 87% of patients and caregivers at Week 26. Ratings of “much” or “very much” improved were reported in 53% of the cohort.

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When compared with placebo, 36% of patients who received 25-mg CBD and 40% in the 50-mg group experienced a ≥50% reduction in seizures. Additionally, 48% of patients in both treatment groups reported a significantly greater reduction in total seizure frequency compared with 27% of those in the placebo group (P = .0013 and P = .0018, respectively).

GWPCARE6 was a double-blind, randomized, placebo-controlled study that demonstrated the efficacy of CBD with an acceptable safety profile for the treatment of patients with seizures associated with TSC across a 16-week stretch. The open-label extension included 199 of the 201 patients who completed the randomized controlled trial. Of those, 59% were male with a mean age of 13 years (range 1—57) and had a baseline median seizure frequency of 28 days and 57 seizures. Patients in the open-label extension had a starting dose of 25 mg/kg/day with titration up to 50 mg/kg/day. Primary end points of the study were the long-term safety of CBD, while percentage of reduction in seizures (countable focal or generalized), responder rates, and S/GIC measures all were among secondary end points.

Among the 199 patients included, the mean modal dose was 27 mg/kg/day. Ultimately, 20% (n = 39) of the patients withdrew from the open-label extension.

Thiele and colleagues also noted that elevated alanine aminotransferase (ALT)/ raised aspartate aminotransferase (AST) more than 3 times the upper limit of normal were reported in 8.5% (n = 17), with 12 of those patients on concomitant valproate.

Adverse events (AEs) were documented in 93% of patients, with 15% experiencing a serious AE, and 6% discontinuing due to AEs. The most common AEs, occurring in >20% of patients, were diarrhea, seizure, and decreased appetite, which were observed in 42%, 22%, and 20%, respectively. There was 1 death in the study deemed unrelated to treatment.

Epidiolex was previously approved by the FDA in June 2018 for the treatment of seizures associated with Dravet syndrome and Lennox-Gastaut syndrome (LGS) in patients aged 2 and older. In February, GW Pharmaceuticals submitted a supplemental new drug application for CBD oral solution to expand its indication to include seizures associated with TSC. That application was acceptd for review in April 2020, with an assigned PDUFA date of July 31, 2020.

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REFERENCE

Thiele E, Bebin EM, Filloux F, et al. Long-term safety and efficacy of cannabidiol (CBD) for the treatment of seizures in patients with tuberous sclerosis complex (TSC) in an open-label extension (OLE) trial (GWPCARE6). Neurology. 2020;94(15 Suppl): 0677.