A purified formulation of cannabidiol (Epidiolex, GW Pharmaceuticals) is safe and effective as adjunctive treatment for drop seizures in patients with Lennox-Gastaut syndrome (LGS), new research shows.
Epidiolex, given at a dose of 10 mg/kg or 20 mg/kg per day, led to a significantly greater reduction in the frequency of drop seizures than did placebo, investigators report.
“Significant results” in favor of Epidiolex were also seen in secondary outcome measures of at least a 50% reduction in the frequency of drop seizures, the reduction in the frequency of all seizures, and improvement in overall condition.
With this study, “we have confirmed and extended our scientific evidence for the role of a highly purified cannabidiol in this disorder,” Orrin Devinsky, MD, professor of neurology, neurosurgery, and psychiatry at NYU School of Medicine in New York City, told Medscape Medical News. The study also established that Epidiolex is effective and has a favorable safety profile at both doses studied, said Devinsky.
The study was published online May 17 in the New England Journal of Medicine.
Landmark Study
LGS is a rare, severe form of epilepsy characterized by frequent drop seizures and severe cognitive impairment. Six medications are approved to treat seizures in patients with the syndrome, but disabling seizures occur in most patients despite these treatments.
Epidiolex has been studied in several studies of patients with LGS and Dravet syndrome, with promising results.
The current study enrolled 225 patients (mean age around 15 years) with LGS across 30 international sites in a randomized, double-blind, placebo-controlled trial to assess the efficacy and safety of two doses of Epidiolex added to conventional antiepileptic medication: 76 received 20 mg/kg/day Epidiolex, 73 received 10 mg/kg/day Epidiolex, and 76 received placebo.
All medications were divided into two doses per day for 14 weeks. Seizure frequency was monitored beginning 4 weeks before baseline and then tracked throughout the 14-week study period and for 4 weeks after the study period.
During the 4-week baseline period, the median number of drop seizures was 85 in all groups combined. The median reduction from baseline in drop-seizure frequency per 28 days during the treatment period was 41.9% in the 20-mg Epidiolex group, 37.2% in the 10-mg group, and 17.2% in the placebo group.
The estimated median difference in reduction between the 20-mg group and the placebo group was 21.6 percentage points (95% confidence interval [CI], 6.7 – 34.8 percentage points; P = .005) and the estimated median difference in reduction between the 10-mg group and the placebo group was 19.2 percentage points (95% CI, 7.7 – 31.2 percentage points; P = .002).
During treatment, 30 patients (39%) in the 20-mg group, 26 (36%) in the 10-mg group, and 11 (14%) in the placebo group had at least a 50% reduction from baseline in drop-seizure frequency. The odds ratio (OR) for 20 mg vs placebo was 3.85 (95% CI, 1.75 – 8.47; P < .001) and the OR for 10 mg vs placebo was 3.27 (95% CI, 1.47 – 7.26; P = .003).
Adjunctive Epidiolex also reduced the frequency of all seizures, by a median of 38.4% in the 20-mg group and 36.4% in the 10-mg group vs 18.5% in the placebo group.
Adverse events were reported in 94% of patients in the 20-mg Epidiolex group, 84% in the 10-mg group, and 72% of patients in the placebo group. Most were judged by investigators to be mild to moderate in severity.
The most common adverse events in the Epidiolex groups were somnolence, decreased appetite, and diarrhea. These events occurred more frequently in the higher-dose group. Six patients in the 20-mg group and 1 in the 10-mg group stopped the drug because of adverse events. Fourteen patients who received Epidiolex (9%) had elevated liver aminotransferase concentrations.
“This landmark study provides data and evidence that Epidiolex can be an effective and safe treatment for seizures seen in patients with Lennox Gastaut Syndrome, a very difficult to control epilepsy syndrome,” co-first author Anup Patel, MD, chief of neurology at Nationwide Children’s Hospital in Columbus, Ohio, said in a statement.
A study published last year found a 39% drop in seizure frequency in patients with Dravet syndrome, as reported by Medscape Medical News.
“A Good Option”
“Epidiolex is a useful adjunctive therapy for LGS and Dravet syndrome,” Sanjeev Kothare, MBBS, chief of the Division of Pediatric Neurology at Northwell Health in New York City, told Medscape Medical News.
“Patients with Dravet and LGS often have refractory epilepsy, which is difficult to control, and new treatments are needed for these patients. We have used various antiepileptic drugs, vagus nerve stimulation, and ketogenic diet, but in spite of that patients can still have continuing seizures,” said Kothare, who is also professor of neurology and pediatrics at the Donald and Barbara Zucker School of Medicine at Hofstra/Northwell.
“Epidiolex acts through a different mechanism of action so it makes better sense, and its efficacy has been shown in the 40% to 50% range — more in Dravet, a little lesser in LGS — and it is fairly safe,” said Kothare. “We do see some GI [gastrointestinal] side effects and liver function abnormalities, but it is a good option.”
Last month, a US Food and Drug Administration (FDA) advisory panel unanimously voted to recommend approval of Epidiolex as an adjunctive treatment for LGS and Dravet syndrome in patients 2 years of age and older. The agency is due to make a decision by June 27. Epidiolex is also being reviewed by the European Medicines Agency, which accepted the company’s application in February.
The study was supported by GW Pharmaceuticals, which operates in the United States as Greenwich Biosciences. Devinsky received research funding from GW Pharmaceuticals but no salary support outside of a one-time consulting fee for participating in the FDA advisory panel. He holds equity interests in Pairnomix, Receptor Life Sciences Rx, Tilray, Rettco, and Tevard. A complete list of author disclosures is available with the full text of the article at NEJM.org. Kothare has served as a monitor for efficacy and safety in clinical trials involving Epidiolex.
N Engl J Med. Published online May 16, 2018. Abstract
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