CBD Shows Continued Safety Profile, Seizure Reductions in Open-Label Extension

Anup D. Patel, MD, the section chief of pediatric neurology at Nationwide Childrens Hospital and an associate professor of clinical pediatrics and neurology at The Ohio State University College of Medicine

Anup D. Patel, MD

New data from a long-term, open-label extension trial of cannabidiol (CBD; Epidiolex, GW Pharmaceuticals) in patients with Lennox-Gastuat Syndrome (LGS) has shown that the therapy remains well-tolerated, with a similar adverse event (AE) profile to what was seen in the core studies of the therapy.

Presented at the American Epilepsy Society’s annual meeting in New Orleans, Louisiana, the data revealed maintained reductions in drop and total seizure frequency through 72 weeks of exposure. As well, a high proportion of patients and caregivers noted an improvement in the overall condition of the patients.

“What was great was that we saw a similar [adverse] effect profile to what we saw in our randomized, double-blind, placebo-controlled trials, but we didn’t learn anything new,” Anup D. Patel, MD, the section chief of pediatric neurology at Nationwide Children’s Hospital and an associate professor of clinical pediatrics and neurology at The Ohio State University College of Medicine told NeurologyLive. “There was nothing new or emergent that came up later on in treatment for these patients.”

These results suggest a long-term benefit of the treatment and a durability of effect in patients with LGS. Approved by the FDA for the treatment of both LGS and Dravet Syndrome in June 2018, CBD was previously evaluated in 2 phase 3 trials, GWPCARE3 (NCT02224560) and GWPCARE4 (NCT02224690). These data were acquired in the open-label extension of these trials, which included 368 patients from the original trials.

In the original trials, patients received CBD in a 100-mg/mL oral solution for up to 3 years. In this extension, they received an initial titration to 20 mg/kg/d given in 2 divided doses, which could then be increased or decreased at the investigator’s discretion. The mean dose was 23 mg/kg/d (range, 21 to 25 mg/kg/d).

The primary end point was safety with secondary end points of drop seizure and total seizure frequency, and Subject/Caregiver Global Impression of Change (S/CGIC). At both weeks 24 and 48, approximately 88% of patients and/or caregivers reported an improvement in overall condition on the S/CGIC.

“From an efficacy standpoint, that was also maintained across the different time points,” Patel said. “Which, therefore, means that we don’t see a drop-off in how well it could potentially work for patients who already started it. Once they stay on it and have a response, we continue to see that response over the different time points.”

At baseline, the median number of drop seizures were 80 and the median number of total seizures over a 28-day period was 168. The median percentage reductions in drop and total seizures, which were assessed at 12-week visit windows, were maintained through 72 weeks. Drop seizures were reduced by 48% to 70% over the full extension period. Total seizures were reduced by 48% to 63%. Last observation carried forward analyses showed similar findings, with reductions in drop seizures ranging from 48% to 55% and total seizure reductions ranging from 48% to 51%.

“If you look at our final time point, between 61 and 72 weeks, 12% of the patients were seizure free,” Patel explained, “which is traditionally a higher rate of seizure-freedom than you would normally expect in a similar trial.”

The therapy remained generally well tolerated, with 94% of patients experiencing an AE. A number of AEs occurred at a rate of ≥10%, with the most common being diarrhea (32%), convulsion (27%), somnolence (26%), pyrexia (25%), vomiting (22%), decreased appetite (21%), upper respiratory tract infection (18%), nasopharyngitis (12%), weight decrease (11%), and cough (10%).

In total, serious AEs were reported in 33% of patients, and 11% discontinued as a result of an AE. Forty-seven patients (13%) had elevations in liver transaminases which was greater than 3 times the upper limit of normal, though none met Hy’s law criteria for severe liver injury. Of these patients, 35 (74%) were taking concomitant valproic acid.

REFERENCE:

1. Patel A, Gil-Nagel A, Chin R, et al. Long-term safety and efficacy of add-on cannabidiol (CBD) treatment in patients with Lennox-Gastaut Syndrome (LGS) in an open-label extension (OLE) trial (GWPCARE5). Presented at: American Epilepsy Society Annual Meeting; New Orleans, Louisiana; November 30 to December 4, 2018. aesnet.org/meetings_events/annual_meeting_abstracts/view/500065.