ARTICLE IN BRIEF
Clobazam received FDA approval for an orphan drug, clobazam, on the basis of two phase 3 clinical trials.
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On Oct. 24, the US FDA approved the use of clobazam as an adjunct treatment to reduce seizures in adults and children over the age of two years with Lennox-Gastaut syndrome, a rare and severe form of epilepsy.
Lennox-Gastaut syndrome (LGS) typically appears between the ages of two and eight years and can result in brain malformation, psychomotor difficulties, CNS infection and degeneration, and/or metabolic abnormalities. Most children with LGS also have some degree of impaired intellectual functioning or information processing ability, as well as developmental delays and behavioral problems.
Because fewer than 200,000 individuals in the US suffer from LGS, it was cleared under the FDA orphan drug approval program. The manufacturer, Lundbeck Inc., of Deerfield, IL, will market the drug under the trade name Onfi. Clobazam is already approved in many countries and is marketed by other pharmaceutical companies around the world under the trade names Frisium and Urbanyl.
In its announcement, the FDA said that it approved the drug based on data from two randomized multicenter studies involving patients with drop seizures, including a phase 3 trial. In both studies treatment resulted in a significant decrease in seizures.
The phase 3 trial, which involved 238 patients, found treatment resulted in an almost 70 percent decrease in seizures when compared to patients given a placebo instead.
Drop seizures cause patients to suddenly fall or lose their posture, and they can be both physically and socially disabling. The cause of LGS is unknown in 30 to 35 percent of patients, but individuals typically have a wide variety of seizures, including tonic, atonic, myoclonic, or atypical absence seizures.
In an FDA announcement, Russell Katz, MD, director of the Division of Neurology Products at the FDA's Center for Drug Evaluation and Research, said approval of clobazam should help many LGS patients reduce their seizures. “This is a difficult condition to treat, and it will be helpful to have an additional treatment option,” he said.
Clobazam is a benzodiazepine, and like many other antiepileptic medications, it can impair thinking and motor skills. Patients need to avoid driving or operating dangerous machinery until they see how they will be affected by treatment, the FDA cautioned. There is also the risk of suicidal ideation or behavior in a small number of patients taking clobazam, so all patients should be carefully monitored and closely questioned about any unusual changes in mood or behavior, especially depression. It can also result in abuse and dependence, and should never be abruptly discontinued. Instead, patients should gradually be tapered off the drug.
CLINICAL TRIAL DATA
The phase 3 trial that led to the approval was conducted by Yu-tze Ng, MD, associate professor of neurology at University of Oklahoma in Oklahoma City, and Joan A. Conry, MD, a research neurologist at the Children's National Medical Center in Washington, DC. The results were published in the Oct. 11 issue of Neurology.
Patients ranged in ages from 2 to 60 years, and were randomized to receive clobazam at 0.25, 0.5, or 1.0 mg/kg/day, or placebo, over a four-week baseline period, a three-week titration period, and 12-week maintenance phase, followed by a two- or three-week tapering off the drug or the option to continue in an open-label extension of the study. In all, 305 patients were screened, 238 were randomized, and 217 were treated with the drug.
Average weekly drop seizure rates decreased 12.1 percent for patients who were given placebo versus 41.2 percent (p = 0.0120), 49.4 percent (p=0.0015), and 68.3 percent (p< 0.0001) for those receiving clobazam 0.25-, 0.5-, and 1.0-mg/kg/day groups. Response rates (≥50 percent) were 31.6 percent for the placebo group versus 43.4 percent (p = 0.3383), 58.6 percent (p= 0.0159), and 77.6 percent (p< 0.0001) for the clobazam patients taking 0.25-, 0.5-, or 1.0-mg/kg/day, respectively.
According to the report, physicians and patient caregivers also reported that clobazam significantly improved symptoms.
Data drawn from the same pool of subjects were presented in December 2010 at the annual American Epilepsy Society meeting in San Antonio, TX. The researchers reported that among 177 patients who completed the study, those treated with the two highest doses of clobazam (1.0 mg/kg/day and 0.5mg/kg/day) also experienced significantly fewer drop seizures over a 12-week period when compared with patients given a placebo.
In all, 77.6 percent of those given the higher doses achieved 50 percent or greater reduction in their average weekly of drop seizures. The patient's ages ranged from 2 to 54 years, with a median of 12.5 years.
Participants who received the highest dose had 68.3 fewer drop seizures, while those taking the median dosage had a 49.4 reduction.
Among the most common adverse events associated with clobazam were fatigue and sedation, fever, aggression, and upper respiratory tract infections. Because it can also result in slow thinking and impaired motor skills, it is important that patients not drive or operate heavy machinery until they know how they are affected by clobazam, the agency said.
It also warned that in a small number of patients, clobazam might increase suicidal thoughts and behaviors. Therefore all patients should be closely monitored for depression, suicidal thoughts, and unusual behavioral of mood changes.
A LONG WAIT
Edwin Trevathan, MD, professor of epidemiology, pediatrics, and neurology, and dean of the School of Public Health, Saint Louis University in Missouri, said the approval of clobazam is to be welcomed, even though the US has lagged behind many other countries in approving the drug.
“Patients in the United States finally have access to a medication that has been helpful for those with Lennox-Gastaut syndrome in over 100 countries for many years,” he said in an e-mail to Neurology Today. “A reasonable question for US physicians and patients to ask is ‘Why did US patients have to wait so long for access to such a beneficial treatment found to be safe and effective throughout the world?’” he wrote in an e0mail to Neurology Today.
“The clobazam story suggests that we need to re-evaluate our FDA approval process so that US patients can benefit from anti-seizure drugs sooner.”
Clobazam should be available in drug store in January 2012, according the manufacturer.