Development of a novel, preferring potentiator of GABAA receptor for treatment of epilepsy

PROJECT SUMMARY
Epilepsy is one of the most common brain conditions affecting 70 million people globally, contributing to 5% of
total disability-adjusted life-years (DALY) due to neurological disorders, and to 1.3% of all deaths, reflecting the
heavy burden of the disease. Additionally, the US annual epilepsy-specific cost estimate ranges from $1,022 to
$19,749 per patient, and costs are considerably higher ($138,600 per patient) for uncontrolled/treatment -
resistant epilepsy. Although some approved anticonvulsant drugs are able to decrease the frequency of seizures,
they do not become fully controlled and patients are generally maintained on daily multiple antiepileptic drugs to
increase the efficacy of seizure control. Despite this polypharmacy approach, as many as 60% to 70% of patients
continue to have seizures. Repeated uncontrolled seizures and the side effects arising from seizure medications
have a negative impact on the developing and adult brain and can lead to severe impairment of neurocognitive
function. KRM-II-81 is a novel γ-aminobutyric acid receptor potentiator developed by RespireRx that will improve
on the anti-seizure control of standard of care (SOC) drugs by reducing side-effect burden (sedation,
somnolence, cognition), enabling greater neural inhibition for seizure dampening, and reduce tolerance
development and abuse liability. The efficacy and primary safety profile of KRM-II-81 has been demonstrated
using pre-clinical models. In this SBIR Direct-to-Phase II project, RespireRx will develop the chemistry,
manufacture and control (CMC) product synthesis method for KRM-II-81 in lab scale and scale up manufacture
(Aim 1) that can be used for pre-clinical GMP toxicity evaluation. Further, the in vitro absorption, distribution,
metabolism, and excretion (ADME) properties and in vivo pharmacokinetics properties of KRM-II-81 will be
evaluated using cell cultures, and rat and dog models (Aim 2). In addition, pivotal IND-enabling toxicology studies
will be performed in rats and dogs (Aim 3) to produce translatable data for conducting human clinical trials. These
pre-clinical results along with clinical development plans will further be packaged into an IND-dossier for pre-IND
meeting with the FDA (Aim 4). The successful completion of this SBIR Direct-to-Phase II project will uniquely
position RespireRx to initiate Phase I clinical trials after obtaining regulatory clearance. If the broad anti-epileptic
properties is confirmed in patients, without developing tolerance, KRM-II-81 would be a true breakthrough drug
for the treatment of epilepsy and seizures that have become pharmacoresistant to treatment. With the unique
ability to increase the quality of life by effectively treating pharmaco-resistance epilepsy, and with minimal side
effects unlike other drugs currently on the market, KRM-II-81 is in line to become the gold standard in epilepsy
treatment.

Grant Number: 1R44NS143576-01
NIH Institute/Center: NIH
Principal Investigator: ROK CERNE