Rationale:
Status epilepticus (SE) is a severe neurologic emergency marked by prolonged convulsive and nonconvulsive seizures [1]. A significant portion of SE patients fail to respond to standard therapies and are diagnosed with refractory SE and placed into a medically-induced coma as third line treatment [2]. JBPOS0101 is a modulator of metabotropic glutamate receptors discovered by Bio-Pharm Solutions Co., Ltd. and developed in conjunction with the NINDS Epilepsy Therapy Screening Program. JBPOS0101 shows superior efficacy compared to other antiepileptic drugs (AED) in benzodiazepine-resistant SE animal models and the nonclinical data correlates well with outcomes observed in clinical SE settings. It is currently being developed for the treatment of SE and is intended to be used as a third line treatment prior to attempting general anesthesia.
Methods: In nonclinical studies, SE was induced in rats using lithium and pilocarpine and EEG signals were monitored for ten hours. The raw EEG signal was bandpass filtered (20~70 Hz, gamma band), normalized to the power of the test compound administration time and expressed as percent change [3].
An open-label phase IIa clinical study was conducted using doses of 1,800, 2,200, and 2,600 mg in three cohorts (A, B and C, respectively). SE patients who failed first line lorazepam were administered JBPOS0101 together with second line levetiracetam. In cohort C, only patients who failed both lorazepam and levetiracetam were administered JBPOS0101.
Results: In nonclinical studies, the effect of JBPOS0101 was compared with nine other AEDs in the benzodiazepine-resistant electrographic SE (ESE) rat model. JBPOS0101 attenuated electrographic SE while the other AEDs showed no effect. In a separate ESE study, JBPOS0101 showed a synergistic effect with lorazepam (first line SE treatment); the effective dose of JBPOS0101 alone is 75~100 mg/kg, however, when administered with lorazepam, the effective dose of JBPOS0101 is 50~68 mg/kg.
In phase IIa studies, eight patients resolved treatment-resistant SE after being administered JBPOS0101 (one from cohort A [1,800mg], three from cohort B [2,200mg], and five from cohort C [2,600mg]). In these patients, convulsive and/or nonconvulsive seizures were resolved after JBPOS0101 administration and the response rate was 100%.
Conclusions: This data suggests that the efficacy of JBPOS0101 observed in nonclinical models appears to translate well to clinical settings, making JBPOS0101 a strong potential candidate for the treatment of refractory SE patients.
Funding: This research was funded by Bio-Pharm Solutions Co. Ltd.