The FDA told Xeris that it could advance diazepam directly into a phase 3 registration study for both pediatric and adult patients with epilepsy after reviewing phase 1b results.
Xeris Pharmaceuticals announced that its investigational treatment, diazepam non-aqueous injection, also known as XP-0863, was granted fast track designation by the FDA for the treatment of acute repetitive seizures.1
The complete results of the company’s phase 1b study were shared with the FDA as well, to which the agency responded by informing Xeris it may directly advance diazepam into a phase 3 registration study in both pediatric and adult patients with epilepsy.
“The FDA’s fast track designation highlights the clear unmet need in treating acute repetitive seizures with the preparations of diazepam available today and highlights our opportunity to dramatically improve care through the introduction of a ready-to-use injection formulation,” Paul R. Edick, chairman and chief executive officer, Xeris, said in a statement.
The phase 1b open-label, weight-based dose, 3-treatment, 3-way crossover study aimed to investigate the pharmacokinetics, safety, and tolerability of the agent in healthy subjects randomized to diazepam 0.25 mg/kg, diazepam 0.125 mg/kg, or diazepam rectal gel 0.2 mg/kg (Diastat; Bausch Health).2
Investigators monitored blood levels for over 21 days after drug dosing and found that the injection formulation was comparable in terms of pharmacokinetics to the rectal gel, with similar partial area under the curves (AUCs) of the 0.25 mg/kg dose group to diazepam rectal gel early after dosing and with increased overall exposure (18800 h/mL versus 10900 h/mL, respectively).
Diazepam injection 0.25 mg/kg also had comparable maximum concentration (Cmax)to the rectal gel (355 ng/mL versus 384 ng/mL, respectively). Both doses of the investigational diazepam were found to be safe and well tolerated, with minimal sedation and injection site reactions, and no serious adverse events (AEs) occurred.
"We are working to identify the right development and commercialization partner who can accelerate our efforts to evaluate and deliver this simple format that could make all the difference in urgent seizure setting,” Edick added.
Benzodiazepines such as diazepam work by calming abnormal over-reactivity in the brain and are often are used in emergency situations to stop cluster seizures, or episodes of increased seizure activity, in people who are already taking medications to control their seizures.
This Xeris formulation of diazepam is yet another variation of the agent making its way through the clinical and regulatory process. In January 2020, the FDA approved an intranasal diazepam formulation (Valtoco; Neurelis) for the treatment of acute intermittent, stereotypic episodes of frequent seizure activity, becoming the first nasal spray approved as rescue medication in patients 6 years and older with epilepsy.3 That variation was also granted 7 years of Orphan Drug Exclusivity and later become commercially available for prescription in March.
Another formulation, diazepam buccal film (Libervant; Aquestive Therapeutics) had its new drug application (NDA) accepted by the FDA in February for the treatment of seizure clusters.4 In September, when the agency was set to make a decision, the FDA sent a complete response letter (CRL) to Aquestive Therapeutics for its NDA for diazepam buccal film, indicating that certain weight groups in a study that was part of the NDA showed a lower drug exposure level than what was desired. Aquestive added that it planned to request a Type A meeting with the FDA in the coming weeks with plans to resubmit the NDA before the end of 2020, which would result in a new Prescription Drug User Fee Act (PDUFA) action date sometime in the first half of 2021.5