BALTIMORE -- Adjunctive cannabidiol, or CBD, (Epidiolex) met its primary endpoint of reducing seizures in patients with tuberous sclerosis complex (TSC), a rare and severe form of childhood-onset epilepsy, a phase III pivotal trial showed here.

Seizure frequency dropped from baseline by 49% with daily doses of CBD at 25 mg/kg per day (P=0.0009) and by 48% with CBD at 50 mg/kg per day (P=0.0018), versus 27% with placebo, reported Elizabeth Thiele, MD, PhD, of the Massachusetts General Hospital in Boston, and co-authors at the American Epilepsy Society annual meeting.

"Our findings suggest this formulation of purified CBD offers patients with TSC a new treatment option for their very difficult-to-manage seizures," Thiele said in a statement.

Epidiolex is a pharmaceutical formulation of a highly purified oral solution form of CBD, a component of the cannabis plant that does not cause the high associated with tetrahydrocannabinol (THC). Drug maker GW Pharmaceuticals won FDA approval for Epidiolex to treat two other rare epilepsies, Dravet syndrome and Lennox-Gastaut syndrome, in 2018.

The majority (80% to 90%) of people with TSC -- a condition that causes benign tumors to form throughout the body -- also have seizures. TSC is a leading cause of genetic epilepsy and more than 60% of patients do not achieve seizure control with standard treatment.

In this study, Thiele and colleagues randomized 224 patients with a confirmed diagnosis of treatment-resistant TSC into three arms: CBD at 25 mg/kg per day (CBD25), CBD at 50 mg/kg per day (CBD50), or placebo, added to the patient's current anti-epileptic drug treatment. Participants were ages 1 to 57 years and had a median age of 11.

Patients were taking a median of three anti-epileptic drugs and previously had tried and discontinued a median of four other drugs. The most common concomitant medications in the trial were valproate (Depakote) at 45%, vigabatrin (Sabril) at 33%, levetiracetam (Keppra) at 29%, and clobazam (Onfi) at 27%.

At baseline, monthly TSC-associated seizure frequency was 56 for the CBD25 group, 61 for CBD50, and 54 for placebo. The primary endpoint was percent change from baseline in TSC-associated focal and generalized seizure frequency for CBD versus placebo over the treatment period of 16 weeks -- a 4-week titration, followed by 12-week maintenance at the target dose.

In addition to meeting the primary endpoint, more patients taking CBD25 (36%) and CBD50 (40%) experienced a greater than 50% reduction in seizures than placebo (22%). Caregivers reported improvements in the patient's overall condition in 69% of patients on CBD25, 62% on CBD50, and 39% on placebo.

Overall 93% of patients on CBD25, 100% on CBD50, and 95% on placebo had an adverse event; most were mild or moderate. The most common events were diarrhea, decreased appetite, and somnolence.

Alanine aminotransferase/aspartate aminotransferase (ALT/AST) increases that were more than three times upper normal limits occurred in 13% of the CBD25 group, 25% in the CBD50 group, and none of the placebo group. Of the patients reporting elevations, 70% of patients in CBD25 and 83% on CBD50 were taking concomitant valproate.

"I think this study highlights that purified oral CBD may help a wide range of epilepsy syndromes and seizure types," observed Daniel Friedman, MD, of NYU Langone Comprehensive Epilepsy Center in New York City, who was not involved with the trial. "Randomized controlled trials have demonstrated efficacy in Dravet syndrome, Lennox Gastaut Syndrome, and now tuberous sclerosis," he said.

"Open-label prospective studies have suggested it may be an effective treatment for other epilepsy syndromes and etiologies," Friedman told MedPage Today. "This suggests that the mechanisms of CBD's anti-seizure activity do not depend on epilepsy etiology and this drug may help other types of more common intractable epilepsies."

The TSC trial "also confirms that there is likely a dose ceiling for CBD near 20 or 25 mg/kg a day and raising doses higher than this is unlikely to add benefit, but will increase the risk of side effects," he added.

This study marks the fifth consecutive positive phase III pivotal trial for Epidiolex, GW Pharma said. To date, Epidiolex is the only CBD product approved by the FDA.

This study was funded by GW Research Ltd.

Researchers disclosed relevant relationships with GW Pharmaceuticals companies.

2019-12-07T18:45:00-0500


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