Onfi (clobazam), as an adjunct seizure treatment for Lennox-Gastaut syndrome (LGS), significantly reduced the number of weekly drop seizures and its effects were maintained in some patients for up to five years, a study summarizing clinical evidence reports.
The study, “An evaluation of clobazam tablets and film (AQST-120) for the treatment of Lennox-Gastaut syndrome,” was published in the journal Expert Opinion on Pharmacotherapy.
Lennox-Gastaut syndrome (LGS) is a form of epilepsy primarily affecting young children, and characterized by different types of seizures such as atonic or drop seizures (loss of muscle tone), tonic (stiffening of the body), and atypical absence seizures (loss of awareness).
No single therapy has been effective in treating seizures in all LGS patients, and the condition is particularly resistant to many types of anti-seizure drugs (ASD). As a consequence, add-on therapies (adjunct therapies) are prescribed for most patients.
It is generally recommended that sodium valproate (VPA) — marketed under the brand name Depakote (by AbbVie), among others — be prescribed as first-line treatment for seizures in LGS. When this single therapy fails to prevent seizures, adjunct therapies such as clobazam are recommended.
Clobazam is a medicine used for decades to treat epilepsy. In tablet or oral suspension form, it was approved in the US in 2011 as an adjunct therapy for LGS seizures in patients age 2 or older under the brand name Onfi (by Lundbeck). A clobazam oral soluble film (COSF) — a dissolving film applied on top of the tongue — was approved in 2018 for use under the brand name Sympazan.
Researchers based in the U.K. summarized the findings of clinical trials that support the use of Onfi (and Sympazan) as an anti-seizure adjunct medicine in treating LGS patients.
A Phase 2 clinical trial (NCT00162981) — a double-blind study involving 68 LSG patients between 2 and 30 years of age — compared the effectiveness of Onfi at a low dose (0.25 mg/kg/day) and a high dose (1.0 mg/kg/day).
This study showed a dose-dependent reduction in the number of weekly seizures, in particular atonic and tonic seizures — also known as “drop” seizures that cause a patient to fall. In the low-dose group, drop seizure frequency lowered by 12%, and by 85% in the high-dose group. In 83% of the high-dose group patients, weekly drop seizures were reduced by more than 50%.
A Phase 3 clinical trial (NCT00518713), named CONTAIN (ClObazam in PatieNTs with Lennox-GAstaut SyNdrome), investigated the effectiveness of Onfi in 238 LGS patients between the ages of 2 and 60 at three doses.
These results showed that the average weekly rate of drop seizures was reduced by 41.2% in the low-dose group (0.25 mg/kg/day), by 49.4% in the medium-dose group (0.5 mg/kg/day), and by 68.3% in the high-dose group (1.0 mg/kg/day) compared to 12% among those taking placebo.
Complete elimination of drop seizures was seen in 7.5% in the low-dose group, 12.1% in the medium-dose group, and 24.5% in the high-dose group compared to two patients (3.5%) in the placebo group.
Following the clinical trials, a long-term, open-label extension study (NCT01160770) was completed, with 267 LGS patients given the treatment and followed for up to six years. During the first five years of follow-up, the average number of weekly drop seizures and the total number of seizures were reduced and remained stable. Complete elimination of drop seizures at any point during the study was found in more than 32% of patients.
Sympazan — the film-based formulation of clobazam — was developed to improve ease of administration and reliability of its use in LSG patients who may be uncooperative due to cognitive or behavioral impairments or are at risk of inhaling the tablets or suspension.
Although clinical trials to show the effectiveness of Sympazan were not required for its approved use, a small study in 51 healthy adult volunteers comparing Sympazan to Onfi showed that both medications were absorbed into the blood in the same fashion (bioequivalence).
An analysis of reported adverse events linked to Onfi treatment showed they were generally mild to moderate in severity, with sedative-like effects being the most common. These side effects were dose-dependent, with more patients discontinuing the treatment at the higher doses.
“In summary, although [clobazam] has been shown to be of benefit in the treatment of seizures, especially drop seizures, related to LGS, it is particularly important for the clinician to balance any beneficial effect against the risk of unacceptable AEs [adverse events], particularly if higher doses are being considered,” the researchers concluded.
They also highlighted “tolerance” to the medication, in which effectiveness drops as a person’s body becomes accustomed to it, as an issue of concern because it might encourage use of higher doses. “Intermittent therapy may … help to mitigate the risk of tolerance developing,” the team noted.
“Because the seizures in LGS can impair quality of life to a major degree and are often highly resistant to treatment, [clobazam] is likely to continue to have a role in the treatment of this syndrome until more effective and better-tolerated compounds become available.”