PHILADELPHIA – A pharmaceutical-grade formulation of orally administered cannabidiol, a cannabis derivative, showed “very positive and promising” safety and efficacy during in an open-label, multicenter, compassionate-use U.S. program that has so far enrolled 313 children and young adults with severe and “extremely” treatment-refractory epilepsy.
In the 261 patients followed on treatment for at least 12 weeks at a total of 16 U.S. centers, patients had a median 49% reduction in their baseline number of monthly convulsant seizures, Dr. Orrin Devinsky said while presenting in a late-breaker poster at the annual meeting of the American Epilepsy Society.
In addition, 47% of these patients had at least a 50% cut in their baseline number of monthly convulsant seizures. And during the final 4 weeks on treatment (weeks 9-12 on treatment), 9% of all patients and 13% of the 44 patients with Dravet syndrome were completely seizure free, reported Dr. Devinsky, professor of neurology and director of the Comprehensive Epilepsy Center at New York University.
Dr. Orrin Devinsky
“In these extremely treatment-refractory patients, these numbers [of seizure-free patients] were much greater than I would have predicted,” Dr. Devinsky said during a press conference. Although he cautioned that a more definitive assessment of the drug’s safety and efficacy will need to await reports of results from four phase III, randomized, placebo-controlled trials that are expected in 2016, “this drug will likely be effective for some patients,” he predicted. “I’m very encouraged by these results.”
The safety analysis, done using data from all 313 patients including those who had not yet received the drug for 12 weeks, showed a “generally well-tolerated” profile, with 4% of patients stopping treatment because of adverse events, 5% experiencing a serious adverse event considered treatment related, and 12% of patients withdrawing because of lack of efficacy.
In a second poster presented at the meeting, investigators at the University of California, San Francisco, one of the other centers involved in this series, reported results for 25 of these patients who they followed on continuous treatment for up to 12 months. In this subgroup, 10 patients (40%) had at least a 50% reduction in their baseline number of convulsant seizures at 12 months, and 1 patient, with Dravet syndrome, was seizure free. During 12 months of follow-up, 12 of the 25 patients discontinued treatment because of lack of efficacy, reported Dr. Michael S. Oldham, a member of the San Francisco group who is now a pediatric neurologist at the University of Louisville (Ky.).
Dr. Michael S. Oldham
Speaking at the same press conference, Dr. Oldham echoed Dr. Devinsky’s assessment of these uncontrolled findings using this cannabidiol formulation. “This was a significantly drug-resistant population, so the fact that we saw at least 50% seizure reductions [in about a third of patients] was remarkable,” he said. “It was exciting to see the results sustained to 12 months with no added adverse events” beyond those seen after 3 months on treatment, Dr. Oldham said in an interview.
Cannabidiol is the most abundant nonpsychoactive cannabinoid contained in cannabis, and the formulation tested in this series contains 99% cannabidiol dissolved in oil. It is being developed by GW Pharmaceuticals under the brand name Epidiolex.
The reported series enrolled patients with various types of juvenile-onset epilepsies, the most common of which was Dravet syndrome. The series also included 40 patients (15%) with Lennox-Gastaut syndrome, and 19% had epilepsy of unknown cause. The enrolled patients averaged 12 years old, ranging from 4 months to 41 years old. At entry enrolled patients averaged 139 convulsant seizures and a median of 31 convulsant seizures every 28 days. The seizure tally focused on convulsant seizures because they are the easiest to reliably identify, Dr. Devinsky noted. The enrolled patients were concurrently on an average of three other antiepileptic drugs. Patients received a gradually escalated dosage until they reached their maximally tolerated dosage or a maximum of 50 mg/kg/day.
The four phase III trials expected to have results reported in 2016 include two that have enrolled patients with Dravet syndrome and two that have enrolled patients with Lennox-Gastaut syndrome. If the tested cannabidiol formulation continues to show good safety and efficacy in those studies and enters the U.S. market, its use will likely gradually expand, first to patients with other severe and drug-refractory forms of epilepsy and then, as experience further grows, to use in less drug-refractory patients, Dr. Devinsky predicted. Both Dr. Devinsky and Dr. Oldham noted that they have heard from several parents who are eager to put their children with milder forms of epilepsy on this formulation, but Dr. Devinsky cautioned that it is much too soon in the drug’s development to consider taking that step.