April 19, 2018
UPDATED April 20, 2018 // A US Food and Drug Administration (FDA) advisory committee has voted unanimously to support approval of a purified formulation of cannabidiol (Epidiolex, GW Pharmaceuticals) as an adjunctive treatment for Lennox-Gastaut syndrome (LGS) and Dravet syndrome (DS) in patients 2 years of age or older.
Although there are medications already on the market that include synthetic cannabinoid chemicals, if approved, this would be the first pharmaceutical formulation of a plant-based cannabinoid that maintains the mechanism of action of the chemical but without the "high" associated with marijuana, according to the manufacturer.
The Peripheral and Central Nervous System Drugs Advisory Committee had almost no concerns about the safety or effectiveness of Epidiolex, and congratulated the FDA, the manufacturer, and patients and families for having presented solid evidence.
"This is clearly a breakthrough drug for an awful disease," said panelist John Mendelson, MD, a senior research scientist at the Friends Research Institute, San Francisco, California.
"It's an honor to be part of a meeting that's making an important decision based on science and public input rather than a political discussion," said panel member Mark W. Green, MD, FAAN, professor of neurology, anesthesiology, and rehabilitation medicine, Icahn School of Medicine at Mt. Sinai, New York City.
"This is a historic moment," said Michael Privitera, MD, director of the epilepsy center at the University of Cincinnati, Ohio, who was an investigator for one of the pivotal studies. Privitera said he paid his own way to the meeting and receives no money from GW Pharmaceuticals. "We don't really understand how it stops seizures, but it's different than any other drug we've seen," he said, adding that it was rigorously studied.
"This will be more reliable than the dispensary marijuana that's available in many states," Privitera added.
The FDA usually follows its panels' advice. Billy Dunn, MD, director of the FDA's Division of Neurology Products, said the agency is "reviewing [Epidiolex] on an expedited timeline." 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.
No Risk for Abuse
Even though Epidiolex is derived from marijuana (Cannabis sativa), it does not have properties conducive to abuse, said the FDA reviewers. That is crucial, because currently, Epidiolex is considered to be a Schedule I drug by the Drug Enforcement Administration (DEA). If the FDA approves Epidiolex, it will make a recommendation to the DEA that the drug be rescheduled.
If Epidiolex is rescheduled, GW Pharmaceuticals expects to make it available to physicians as soon as possible — most likely during the second half of this year — company CEO Justin Gover told Medscape Medical News. The company is proposing an initial target dose of 10 mg/kg daily, with dose adjustments up to 20 mg/kg, based on clinical response and tolerability.
One of the company's pivotal safety and efficacy trials in patients with LGS was published online January 24 in the Lancet. Data from that trial and two other pivotal studies were presented at the advisory panel meeting.
The primary endpoint — percentage reduction in drop seizures in LGS patients and percentage reduction in convulsive seizures in DS patients — was statistically significant for patients who received 14 weeks of treatment.
In study 1423, 171 LGS patients (average age, 15 years) were randomly assigned to receive either Epidiolex 20 mg/kg daily or placebo, in addition to existing therapies.
At baseline, the patients had been experiencing a median of 74 drop seizures per month. Drop seizures were defined as atonic, tonic, or tonic-clonic seizures that involved the entire body, trunk, or head and that led to or could have led to a fall or injury or the patient's slumping in a chair or hitting his or her head on a surface.
Patients taking Epidiolex experienced a significantly greater median reduction in drop seizures compared to those taking placebo (44% vs 22%; P = .0135).
In another LGS study (study 1414), 76 patients taking 10 mg/kg daily experienced a statistically significant 37% reduction in drop seizures, compared to a drop of 17% for the 76 patients taking placebo (P < .01).
Patients in both LGS studies also experienced a reduction of total seizures from 36% to 41%. Caregivers were the given Subject/Caregiver Global Impression of Change scale and were asked to give their impression of whether the patients had gotten worse, had experiened no change, or had improved. Of those caregivers of patients who took the 10 mg/kg dose, 66% said they saw improvement.
For DS, the dose studied was 20 mg/kg. Patients taking that dose experienced a 39% reduction in convulsive seizures during 14 weeks of treatment. Sixty-two percent of caregivers said they had seen an improvement.
Elevated Liver Enzymes
The company also presented safety data from the phase 3 trials, the open-label extension trial, and the compassionate use program, totalling 1651 patients and about 1200 patient-years.
Eighty-eight percent of patients in the controlled studies experienced some adverse event; the most common were somnolence, decreased appetite, and diarrhea. About 14% of patients in the controlled trials experienced a serious adverse event.
Twenty deaths were reported; one occurred in the controlled studies, and 19 occurred in the open-label or compassionate use programs. None were linked to Epidiolex, said the FDA staff.
The FDA said that the patients taking Epidiolex discontinued treatment because of adverse events more often than those taking placebo — 9.3% vs 1.3%.
One area of concern for both the FDA and the advisory panel was what appeared to be transient increases in transaminase levels, seen in 8% of patients taking 10 mg/kg and 16% of those taking 20 mg/kg. Serious events due to the elevations in liver enzyme levels occurred in 3% to 4% of patients.
FDA reviewer Lara Dimick-Santos, MD, of the Division of Gastroenetrology and Inborn Errors Products, Center for Drug Evaluation and Research, noted that in 37 patients, alanine transaminase (ALT) levels were elevated at least five times greater than the upper limit of normal. Seventeen patients recovered without stopping or just before stopping Epidiolex.
Dimick-Santos concluded that there is a causal association between increased ALT levels and use of Epidiolex. Concomitant use of valproic acid seemed to be the most common risk factor. She noted that no patients with underlying liver dysfunction at baseline have been studied, and it is unknown whether chronic liver injury could occur with long-term use of Epidiolex.
The advisory committee said it believed elevated liver enzyme levels could be managed through proper labeling and monitoring.