FDA rejects Aquestive's oral diazepam-based seizure drug Libervant
Aquestive Therapeutics announced that the FDA has issued a complete response letter (CRL) regarding its filing for Libervant, a buccal film formulation of diazepam for the management of seizure clusters in refractory patients with epilepsy who are on stable regimens of anti-epileptic drugs. Aquestive is developing Libervant as an alternative to Diastat (diazepam), a rectal gel that is the current standard rescue therapy for patients with refractory epilepsy, and it has said that approval of Libervant would make it the first oral diazepam-based treatment for this patient population.
According to the company, the FDA noted that in a study submitted by Aquestive to back its filing, "certain weight groups showed a lower drug exposure level than desired." The application was supported by data from a single-dose crossover study that was presented last year at the American Epilepsy Society (AES) conference. Aquestive said findings demonstrated that Libervant provided similar systemic diazepam exposures to Diastat and exhibited significantly less variability, backing its use as "an easily-administered treatment for patients with epilepsy experiencing seizure emergencies."
Aquestive said it now intends to provide the FDA with "additional information on PK [pharmacokinetic] modeling to demonstrate that dose adjustments will obtain the desired exposure levels." It added that the FDA also highlighted a "small number" of protocol deviations in blood draws in one of the studies in the filing. However, no other safety, clinical pharmacology/biopharmaceutics or chemistry, manufacturing, and controls issues were identified, and based on discussions with the FDA, the company said it will not need to conduct any further clinical studies.
Not a barrier to approval
"As the CRL was limited to providing additional information on PK modeling for an adjusted dosing regimen for a limited subset of patient weight categories," Aquestive said it believes that "this CRL will not be a barrier to ultimate approval." The company plans to resubmit a filing for Libervant before the end of the year, which it expects would result in an FDA action date in the first half of 2021. It noted that "the agency did not include any indication regarding approval of US market access for Libervant at this time."
Aquestive says that as treatment with Diastat "is invasive, inconvenient, and difficult to administer…a large portion of the patient population does not receive adequate treatment or foregoes treatment altogether." CEO Keith Kendall remarked that "epilepsy patients have been underserved for some time with little choice beyond device-based products such as rectally administered gels and nasal sprays," while Libervant offers "a meaningful and improved therapy for patients who can't or won't use the alternatives."