乌鸦传媒

HOUSTON -- Full data from two cannabidiol (Epidiolex) randomized controlled trials that reported top-line findings earlier this year showed that the drug has efficacy in treating Dravet syndrome and Lennox-Gastaut syndrome (LGS) over placebo, researchers reported here.

Children with Dravet syndrome given cannabidiol had significantly greater reductions in convulsive seizures over 14 weeks than those on placebo (41% versus 16%, P=0.005), according to , of University College London, and colleagues.

Pediatric and adult patients with LGS treated with the cannabis derivative showed significantly greater reductions in drop seizures over 14 weeks compared with a placebo group (49% versus 20%, P=0.0096), according to , of Massachusetts General Hospital, and colleagues.

Both were reported during poster sessions at the .

"The bottom line is that cannabidiol works," , of NYU Langone Medical Center, who is a co-author on the Dravet study, told 乌鸦传媒. "There are side effects, but the overall safety and tolerability is good -- especially compared to other anti-epileptic drugs."

Drugmaker GW Pharmaceuticals released top-line results from the Dravet study in March, followed by top-line results from one LGS study in June, and a second LGS study in September. The latter LGS study was not presented here at the AES meeting.

The company is running additional studies of cannabidiol in tuberous sclerosis and infantile spasms, but these trials have not yet reported data. Devinsky said the tuberous sclerosis study is currently enrolling, and the infantile spasms study is in "early stages."

Lennox-Gastaut Results

For the Lennox-Gastaut trial, Thiele and colleagues enrolled 171 patients ages 2 to 55 in the trial, which included a 4-week baseline observation period during which those who had at least two drop seizures a week were selected. A drop seizure was defined as an atonic, tonic, or tonic-clonic seizure involving the entire body, trunk, or head that led or could have led to a fall, injury, slumping in a chair, or sustaining a blow to the head.

Patients were then randomized to cannabidiol or placebo, and had a 2-week titration period where the oral drug was started at 2.5 mg/kg a day given in two doses and titrated up to 20 mg/kg a day. They then proceeded to the 12-week maintenance period.

Thiele and colleagues saw a significant reduction in drop seizures in both the dose-escalation period (44% versus 22%, P=0.01), and in the maintenance period (49% versus 20%, P=0.0096).

Also, more patients on cannabidiol had at least a 50% reduction in drop seizures (44% versus 23.5%, P=0.0043), they reported.

The researchers also saw a reduction in total seizures during dose escalation (41% versus 14%, P=0.0005) and during maintenance (45% versus 15%, P=0.0004) that favored cannabidiol.

No patients were completely free of drop seizures during the dose escalation period, but during the maintenance phase, five cannabidiol patients had no drop seizures whereas all the placebo patients had at least one, Thiele reported.

Patients and caregivers were more likely to report an overall improvement on the Subject/Caregiver Global Impression of Change (S/CGIC) scale with cannabidiol than with placebo (OR 2.54, P=0.0008).

There were more all-cause treatment-emergent adverse effects with cannabidiol (86% versus 69%), and the most common side effects were diarrhea, somnolence, pyrexia, decreased appetite, and vomiting, they reported.

There were also more serious adverse events with the drug (23% versus 5%), although a smaller proportion were deemed to be related to treatment (11% versus 1%).

Increases in liver enzymes ALT or AST more than 3 times the upper limit of normal occurred in 20 cannabidiol patients compared with 1 placebo patient; 16 of these patients were on concomitant valproic acid.

The researchers noted that 94% of patients were on multiple concomitant anti-epileptic drugs, and that those relationships will be explored in a future pooled analysis. The drug has a known interaction with clobazam, and another study presented here also showed a relationship between the combination of cannabidiol and valproic acid and an increase in liver enzymes.

Dravet Results

The Dravet study design was similar, except only pediatric patients (age 2-18) were enrolled (n=120).

Cross and colleagues found significantly greater reductions in convulsive seizures with cannabidiol during both the primary treatment period (39% versus 13%, P=0.0123), and the maintenance period (41% versus 16%, P=0.005).

More patients on cannabidiol also had at least a 50% reduction in convulsive seizures compared with those on placebo (43% versus 27%), they reported.

There was also a greater reduction in total seizures for during both the dose escalation (29% versus 9%, P=0.0335) and maintenance phases (37% versus 10%, P=0.0234).

However, a reduction in non-convulsive seizures wasn't significantly different between drug and placebo groups among a subgroup of patients with non-convulsive seizures (40% versus 35%), they added.

Cross noted that three patients on cannabidiol became free from convulsive and total seizures, while none of the placebo patients achieved this endpoint.

Caregivers were also more likely to report an overall improvement on the CGIC scale (OR 2.29, P=0.0155).

As with the LGS study, there were more treatment-emergent adverse events in the cannabidiol group (93% versus 75%), and these most commonly were somnolence, diarrhea, decreased appetite, fatigue, pyrexia, vomiting, and lethargy.

Cannabidiol brought more serious adverse events as well (16% versus 5%), and an increases in ALT or AST that was more than 3 times the normal limit occurred in 12 drug patients and one placebo patient -- all of whom were on concomitant valproic acid.

Again, the majority (93%) of patients were taking multiple concomitant anti-epileptic drugs, and Cross said further analyses are needed, adding that in this study investigators were unable to change the doses of anti-epileptic drugs that patients were already taking.

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