H. Lundbeck A/S (Lundbeck) today presented positive data from its pivotal phase III study to determine the efficacy and safety profiles of the investigational compound clobazam as adjunctive therapy in treating seizures associated with Lennox-Gastaut syndrome (LGS).
In the study, clobazam met its primary efficacy endpoint and was further supported by several key secondary efficacy endpoints.
LGS is a rare and severe form of epilepsy that is typically diagnosed in childhood and persists into adulthood.
Results from this largest clinical trial to date in LGS patients were presented at the 64th annual meeting of the American Epilepsy Society in San Antonio, Texas (Poster No. 1.283).
This prospective, double-blind, placebo controlled study randomized 238 patients diagnosed with LGS to one of three different dosages of clobazam or placebo. Efficacy analyses were done for the modified intent to treat population (mITT), which included all randomized patients who had baseline data, at least one dose of study drug and at least one daily seizure measurement during the maintenance period (N=217).
Data from the study’s primary endpoint showed that the high (1.0 mg/kg/day; N=49) and medium (0.5 mg/kg/day; N=58) dosages of clobazam, evaluated versus placebo (N=57), met a robust statistically significant (p≤0.01) reduction in the average weekly rate of drop seizures from the four-week baseline period compared to the 12-week maintenance period.
Patients in the high-dosage clobazam group achieved a mean decrease in average weekly rate of drop seizures of 68.3% (p<0.0001 vs. placebo) while those in the medium-dosage arm had an average decrease of 49.4% (p=0.0015 vs. placebo).
A secondary endpoint of the study was responder rates. For each group treated with one of the three different dosages of clobazam, the percentage of patients with a decrease in average weekly rate of drop seizures of ≥25%, ≥50%, ≥75% or 100% from baseline to the maintenance period was compared to placebo.
Among patients in the high-dosage arm, 77.6% had a 50% or greater reduction (p<0.01); 63.3% had a 75% or greater reduction (p<0.01); and 24.5% achieved 100% reduction.
Among patients in the medium-dosage arm, 58.6% had a 50% or greater reduction (p<0.05); 37.9% had a 75% or greater reduction (p<0.01); and 12.1% achieved 100% reduction.
The logistic regression model used in this study was unable to provide valid p-value estimates for the 100% response thresholds due to the small number of patients enrolled in this group.
“LGS is a devastating form of epilepsy associated with multiple types of seizures, including dangerous drop seizures which may cause falls that often result in injury. This can take a tremendous toll on even the strongest families,” said Joan A. Conry, MD, professor of neurology at Children’s National Medical Center in Washington, D.C., and a principal investigator in the study.
“While several medications are approved in the U.S. for treatment of LGS, many patients continue to have seizures due to the intractable nature of the disease. The focus on this small patient population and the results of this study provide hope for LGS patients, their families and the medical community.”
The study also evaluated the effect of clobazam in decreasing total seizures (drop and non-drop) as another key secondary endpoint.
Robust statistical significance was observed in patients who received the high- and medium-dosage clobazam (p<0.01 in each arm versus placebo).
In the study, the most common treatment emergent adverse events (AEs) included somnolence, lethargy, drooling, fever, and constipation.
Serious AEs occurring in ≥2 patients were lobar pneumonia and pneumonia, which occurred in both clobazam and placebo treatment arms.
“Lundbeck makes several treatment options available in the U.S. for people affected by epilepsy, and the development of clobazam for those with LGS represents our ongoing commitment to making a difference in the lives of those affected by rare and challenging seizure disorders,” said Timothy M. Cunniff, PharmD, vice president of global regulatory affairs at Lundbeck.
“We are encouraged by these phase III results and look forward to submitting an NDA very soon for clobazam.”