Treatment of status epilepticus and refractory status epilepticus with intravenous topiramate.

Abstract Status epilepticus (SE) is a common neurologic emergency that fails to respond to first- and second-line anti-seizure medications (ASMs) in about one third of instances, thus progressing to refractory SE (RSE). Patients with RSE are at grave risk for neurological morbidity and mortality. The recently completed NIH-funded Established SE Treatment Trial (ESETT) highlights the need for improved SE therapies. In that study, >50% of people who failed to respond to the first line agent (i.e. a benzodiazepine; BDZ also failed to respond to the commonly used intravenous (i.v.) second-line agents (e.g. fosphenytoin, valproate, or levetiracetam (LEV)). An improved second-line injectable ASM, with higher likelihood to terminate SE than presently-available injectable ASMs, is thus an important unmet medical need. Of the currently available ASMs, topiramate (TPM) is an attractive medication to evaluate for seizure suppression in treatment-resistant SE given (1) its multimodal mechanism of action, (2) favorable data from parenteral administration in cases of highly resistant SE, and (3) its potential for neuroprotection. Oral and nasogastric tube TPM can ameliorate RSE and super-refractory SE (SRSE, a condition where seizures persist for more than 24 hours) where numerous other ASMs have failed. Yet, TPM is not clinically available for i.v. administration, which is the route of choice in SE treatment. We (PrevEp, Inc.) developed a novel, intellectual property-protected i.v. TPM formulation (PrevEp004) using the FDA-approved excipient meglumine, which provides excellent i.v. tolerability and enables rapid TPM administration across ages for treatment of SE/RSE. We now propose to test the PrevEp004 capacity to terminate SE/RSE. We will (1) measure the tolerability and efficacy of i.v. TPM (PrevEp004) in comparison to i.v. LEV in the rat lithium-pilocarpine model of established SE, following treatment with a BDZ to mimic a realistic clinical situation, using a randomized, blinded design with continuous video EEG monitoring of treatment outcome; (2) measure plasma and brain pharmacokinetics (PK) of the most effective dose of i.v. TPM in rats in order to determine effective drug plasma and brain concentrations to target in clinical trials; (3) further optimize the novel i.v. formulation of PrevEp004 (i.v. TPM), and establish a GMP manufacturing process for the i.v. formulation to enable clinical trial supply; (4) Evaluate the toxicity of the i.v. TPM formulation in rats by conducting a GLP compliant multiple dose toxicity study with i.v. administration of PrevEp004; and (5) prepare a pre-IND meeting with the FDA to enable clinical trials using data obtained from aims 1-4. The pilocarpine experiments and PK studies will be done by Dr. Goodkin at UVA. The pharmaceutical development will be done with Dr. Rogawski at UCD. Expected outcome: Within two years of funding we will (a) test PrevEp004 tolerability and efficacy in an etiologically realistic rat SE model; (b) develop a suitable PrevEp004 formulation and characterize its safety; and (c) conduct a pre-IND meeting to enable the future conduct of a phase I and Ila program in volunteers and SE/RSE patients as a step toward the first-in-human proof of concept (PoC) study, which will be the basis of a subsequent SBIR phase II application. Beyond the scope of this proposal, PrevEp004 may also serve as an i.v. TPM replacement that can be used in instances where patients (>2 million in US) who apply TPM for seizure or migraine management cannot tolerate enteric medication (e.g. after gastrointestinal surgery).