New Drug Application in the Works for Clobazam in Lennox Syndrome

Allison Gandey

December 07, 2010

December 7, 2010 — The largest clinical trial to date in Lennox syndrome has shown a statistically significant reduction in drop seizures with clobazam add-on therapy. The drug manufacturer Lundbeck reports it plans to submit an application to the US Food and Drug Administration in early 2011.

"Clobazam could be on the market as early as later next year," lead investigator Joan Conry, MD, from the Children's National Medical Center in Washington, DC, said during an interview.

"These results have been a long time in coming," Jacqueline French, MD, from New York University's Comprehensive Epilepsy Center in New York City, said in an interview. Asked by Medscape Medical News to comment, Dr. French said, "This compound is and will continue to be useful."

Clobazam is already available outside of the United States in more than 100 countries and is marketed under various brand names, such as Frisium and Urbanyl. It is a 1,5-benzodiazepine that reportedly increases the inhibitory action of gamma-aminobutyric acid to receptors. The specific mechanism of action by which clobazam exerts its antiepileptic effects is unknown.

"These are the most positive trial results I've ever seen," said Dr. Conry, who has worked on 35 clinical trials. Her team conducted this prospective, double-blind, placebo-controlled trial comparing 3 oral doses of adjunctive clobazam with placebo. She presented the findings at the American Epilepsy Society 64th Annual Meeting in San Antonio, Texas.

Percentage decrease in average weekly rate of drop seizures from baseline to maintenance period.

This was not a head-to-head comparison with other already-available drugs, and the trial focused on a single seizure type.

The new trial studied 177 patients with Lennox syndrome at 66 centers. Following a 4-week baseline phase, patients with drop seizures were randomized to placebo or to clobazam. Treatment included a 3-week titration phase followed by a 12-week maintenance phase.

The primary endpoint was the percentage decrease in mean weekly frequency of drop seizures during the maintenance vs baseline phases for the modified intention-to-treat population.

The researchers found the high and medium doses of clobazam had a statistically significant reduction in the average weekly rate of drop seizures (P < .01). Patients in the high-dose clobazam group achieved a mean decrease in average weekly rate of drop seizures of 69.5%. Those in the medium-dose group had an average decrease of 47.8%.

A secondary endpoint of the study was responder rates. Investigators found that patients in the high-dose group experienced a reduction in drop seizures (P < .01). Patients in the medium-dose group also experienced reductions, but at lower rates (P < .05).

Table. Responder Rates

Clobazam ≥50% Reduction, % ≥75% Reduction, % ≥100% Reduction, %
High dose 77.6 63.3 24.5
Medium dose 58.6 37.9 12.1

 

The logistic regression model used in this study was unable to provide valid P value estimates for the 100% response thresholds because of the small number of patients enrolled in this group.

"All 3 doses led to improvements in global assessments by physicians and caregivers versus placebo," report the investigators. Somnolence, lethargy, drooling, upper respiratory tract infections, and behavioral abnormalities were the most frequent treatment-emergent adverse events reported for clobazam in this trial.

Lennox syndrome is responsible for an estimated 1% to 4% of all childhood epilepsies. It typically occurs between 2 and 8 years of age. This difficult-to-treat form of epilepsy often results in delayed psychomotor development and behavior disorders.

Currently, 5 antiepileptic drugs, clonazepam, felbamate, lamotrigine, topiramate, and rufinamide, have been approved in the United States for treatment of Lennox syndrome. However, continued seizures — including dangerous drop attacks that often result in injury — remain common. The majority of patients will have seizures throughout childhood and into their adult years.

"This can take a tremendous toll on even the strongest families," Dr. Conry said. "In my own office, when we see these drop seizures, they can be very startling."

This study was funded by Lundbeck. The investigators received compensation for their work on the trial.

American Epilepsy Society 64th Annual Meeting: Poster 1.283. Presented December 4, 2010.

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