Authors :
Presenting Author: Jordi Serrats, PhD – Mosaica Medicines
Hannah Mae Bohn, BSc – Mosaica Medicines
Deven Sanon, BSc – Mosaica Medicines
Sattar Khoshkhoo, MD – Mass General Brigham and Harvard Medical School
Brad Galer, MD – Mosaica Medicines
Rationale:
Mesial temporal lobe epilepsy (MTLE), which is the most frequent focal epilepsy in adults, is a common, chronic neurological disease with significant morbidity. While previously genetic factors were thought to play a minor role in MTLE, recent advances in deep sequencing of surgically resected brain tissue has revealed somatic variants, which are developmentally acquired, as a novel and likely major contributor to disease pathogenesis. Somatic variants in Ras-MAPK pathway genes have been identified in patients with drug-resistant MTLE. These variants are all predicted to activate the Ras/Raf/mitogen activated protein kinase (MAPK) pathway and cause cell autonomous neuronal hyperexcitability. Beyond the direct contribution of somatic Ras-MAPK variants, it is well-established that the MAPK pathway is activated in epilepsy broadly and plays a central role in mediating network hyperexcitability. MEK is a kinase downstream of Ras and Raf whose primary function is to phosphorylate ERK, the final common effector of this pathway, leading to increased MAPK signaling. MEK and ERK are also directly activated with neuronal hyperexcitability suggesting that MSCA-7136, a brain-penetrant MEK inhibitor, can provide a novel and differentiated therapy to treat focal epilepsy.
Methods:
Spontaneous, recurrent seizures were induced in mice by stereotaxic injection of kainic acid (KA) into the right dorsal hippocampus, which serves as a model of unilateral MTLE. Subsequently bipolar electrodes were implanted for EEG recording and measurement of hippocampal paroxysmal discharges (HPDs) in freely behaving mice to monitor seizure activity. One month after KA injection, mice with sufficient seizure count based on an initial screen period were randomized to receive vehicle, 0.1, 1, or 10mg/kg MSCA-7136, twice daily (PO) or 800mg/kg levetiracetam, once daily (IP). To assess the acute response to treatment, EEG was recorded for 2 hours prior to dosing and continued for 8 hours following each dose. HPDs were marked using an automated, and previously validated algorithm, and then manually inspected. HPD number and duration were evaluated in specific time bins for each sampling period. Results:
MSCA-7136, a brain-penetrant MEK inhibitor, administered either as a single dose, or dosed twice a day for 7 dayssignificantly reduced the number, average duration, and cumulative duration of HPDs in a mouse model of MTLE. The observed effect demonstrated clear dose-dependence with robust and sustained response for 7 days of treatment, while levetiracetam, the positive control, was efficacious only after a single dose and lost efficacy by the 7th day due to significant tachyphylaxis. No abnormal behavior was observed in the animals treated with MSCA-7136.
Conclusions:
MSCA-7136, a novel brain penetrant MEK inhibitor, demonstrated dose-dependent, significant efficacy in this MTLE model without any CNS adverse events or tachyphylaxis observed after 7 days of dosing. MSCA-7136 may provide therapeutic benefit in patients with refractory focal onset seizures via a novel MOA and with the potential of good tolerability due to its superior brain penetration, resulting in low systemic exposure.
Funding: Mosaica Medicines