Dr Elizabeth ThieleElizabeth Thiele, MD, PhD
The US Food and Drug Administration’s (FDA) Peripheral and Central Nervous System Drugs Advisory Committee has announced a unanimous recommendation to support the approval of a cannabidiol oral solution (Epidiolex, GW Pharmaceuticals) for the adjunctive treatment of seizures associated with Lennox-Gastaut syndrome (LGS) and Dravet syndrome in patients aged 2 years and older.

The decision came in at 13-0 in favor of approval, based on the efficacy and safety data from a trio of randomized, double-blind, placebo-controlled trials. Two 14-week trials—CARE 3 and CARE 4—including patients with LGS, and a single 14-week trial including patients with Dravet syndrome, CARE 1.1 Additional safety data from a 3-week dosing study of patients with Dravet syndrome were also included.

If granted the go-ahead, it would mark the first approved formulation of purified, plant-based cannabidiol oral solution, adding a new class of anti-epileptic treatments, as well as the first-time approval for Dravet syndrome. The therapy currently has a Prescription Drug User Fee Act (PDUFA) action date of June 27, 2018.

“As a physician who treats LGS and Dravet syndrome, I know that patients and their families usually face significant difficulties getting seizures under control using existing therapies,” Elizabeth Thiele, MD, PhD, director of pediatric epilepsy, Massachusetts General Hospital, professor of neurology, Harvard Medical School, primary investigator for one of GW’s and Greenwich’s studies in LGS patients, said in a statement.2 “The results from these studies suggest that this pharmaceutical formulation of cannabidiol may provide hope for a new treatment option that may be effective for some patients.”

The CARE 3 study included 225 patients randomized 1:1:1 to either cannabidiol, in doses of 10 mg/kg/day (n = 73) or 20 mg/kg/day (n = 76), or placebo (n = 76). The therapy was started at 2.5 mg/kg/day and increased by 2.5 mg/kg/day for 7 or 11 days to the final dose. The findings revealed that the change from baseline in drop seizure frequency was -41.9% (interquartile range [IQR], -72.4 to -1.3; P = .0047) and -37.2% (IQR, -63.8 to -5.6; P = .0016) for the 20 and 10 mg/kg/day groups, respectively. In comparison, the placebo group observed a -17.2% change (IQR, -37.1 to 0.9).

Total median seizure frequency was also reduced by -38.4% (P = .0091) for the 20 mg/kg/day and by -36.4% (P = .0015) for the 10 mg/kg/day, compared to -18.5% for placebo.

When assessing for the secondary endpoint of ≥50% reduction in convulsive seizures from baseline, the cannabidiol groups both displayed larger proportions—39.5% of the 20 mg/kg/day (odds ratio [OR], P = .0006) and 35.6% (OR, 3.3; P = .003), respectively—of patients achieving that mark, compared to placebo (14.5%).

In CARE 4, similar results were observed. In total, 171 patients with LGS were randomized 1:1 to either cannabidiol 20 mg/kg/day (n = 86) or placebo (n = 85). The cannabidiol group experienced a mean difference in drop seizure frequency reduction of -17.2% (95% CI, -30.3 to -4.1; P = .0135). Ultimately, the treatment group experienced a -43.9% (IQR, -69.6 to -1.9) reduction compared to a -21.8% (IQR, -45.7 to 1.7) reduction with the placebo group. The proportion of patients with ≥50% reduction was 44.2% for the cannabidiol group and 23.5% for the placebo group (OR, 2.6; P = .0043). Additionally, total seizure frequency was reduced by 44.2% for the cannabidiol group compared to 23.5% with placebo (P = .0005).

In CARE 1, a total of 120 children and adolescents with Dravet syndrome were randomized 1:1 to either cannabidiol 20 mg/kg/day (n = 61) or placebo (n = 59).3 The total convulsive seizure frequency was reduced by -38.9% (IQR, -69.5 to -4.8) for the cannabidiol group and -13.3% (IQR, -52.5 to 20.2) for the placebo group, for a mean difference of -22.8% (95% CI, -41.1 to -5.4; P = .0123).

The secondary endpoint of ≥50 reduction from baseline in convulsive seizures was also in favor of the therapy, with 42.6% (n = 26) of patients in the treatment group achieving that mark, compared to 27.1% (n = 16) of the placebo-administered patients (OR, 2.0; 95% CI, 0.93 to 4.30; P = .0784).

The therapy previously received a Fast Track designation from the FDA in June 2014.
REFERENCES
1. FDA Briefing Document: Peripheral and Central Nervous System Drugs Advisory Committee Meeting. FDA website. fda.gov/downloads/AdvisoryCommittees/CommitteesMeetingMaterials/Drugs/PeripheralandCentralNervousSystemDrugsAdvisoryCommittee/UCM604736.pdf. Published April 19, 2018. Accessed April 19, 2018.
2. GW Pharmaceuticals and U.S. Subsidiary Greenwich Biosciences
Announces the Unanimous Positive Result of FDA Advisory Committee Meeting for First Plant-Based Pharmaceutical Cannabidiol Treatment for Seizures in Patients with Two Rare, Severe Forms of Epilepsy [press release]. London, England: GW Pharmaceuticals Investor Relations; April 19, 2018. globenewswire.com/news-release/2018/04/19/1482047/0/en/GW-Pharmaceuticals-and-U-S-Subsidiary-Greenwich-Biosciences-Announces-the-Unanimous-Positive-Result-of-FDA-Advisory-Committee-Meeting-for-First-Plant-Based-Pharmaceutical-Cannabidi.html. Accessed April 19, 2018.
3. Cross HJ, Devinsky O, Marsh E, et. al. Cannabidiol (CBD) reduces convulsive seizure frequency in Dravet syndrome: results of a multi-center, randomized, controlled trial (GWPCARE1). Neurology. 2017;88(16)
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