Authors :
Presenting Author: Branden Stansley, PhD – Cassava Sciences
Dean J. Aguiar, PhD – Tuberous Sclerosis Complex Alliance
Zoe Fuchs, BS – Tuberous Sclerosis Complex Alliance
Mackenzie Catron, PhD – PsychoGenics, Inc.
Stephen Morairty, PhD – PsychoGenics, Inc.
Ying Yuan, PhD – The University of Texas MD Anderson Cancer Center
George Ben Thornton, PhD – Cassava Sciences, Inc.
James Kupiec, MD – Cassava Sciences, Inc.
Angelique Bordey, PhD – Cassava Sciences & Yale
Rationale:
Epilepsy treatments for patients with mechanistic target of rapamycin (mTOR) disorders, such as tuberous sclerosis complex (TSC) or focal cortical dysplasia type II (FCDII), are urgently needed. In these patients, the presence of focal cortical malformations often causes intractable epilepsy accompanied by other neuropsychiatric sequelae. Recent evidence suggests that expression of the actin cross-linking protein filamin A (FLNA) is increased in resected cortical tissue from patients with TSC and in mice modeling TSC and FCDII. Restoring proper FLNA expression in a mouse model of FCDII that recapitulated the human pathology reduced neuronal cytomegaly and seizure activity. Experiments further demonstrated that treating these mice with simufilam, a small molecule thought to modulate FLNA function, either before or after seizure onset, alleviated neuronal abnormalities and reduced seizure activity compared to vehicle-treated mice. Here, we further tested the efficacy of simufilam in treating seizure activity in a TSC mouse model. We also report data related to its brain permeability and toxicity in rodents, and its safety profile in humans.
Methods:
Experiments were performed using EEG recordings in conditional Tsc1 knockout (cKO) mice. Simufilam was administrated BID at three doses. Simufilam plasma concentration was measured 1 hour following the last dose using LC-MS/MS.
Results:
Simufilam treatment in juvenile conditional Tsc1 cKO mice prevented the progression of seizure activity. In addition, there was a significant correlation between simufilam dose as well as plasma concentrations and the mean number of daily seizures. Importantly, simufilam exhibited a brain-to-plasma ratio greater than 0.4 in both mice and rats and was detectable in the cerebrospinal fluid (CSF) of human volunteers. Furthermore, chronic oral toxicology studies revealed no adverse effects at doses exceeding those reported to be efficacious in mice. In two recently completed double-blind phase 3 clinical studies involving 1,929 patients with mild-to-moderate Alzheimer’s disease, simufilam demonstrated a favorable safety profile. Non-serious adverse events were typically mild and not considered study drug related, and no specific adverse event was clearly associated with simufilam administration. None of the reported serious adverse events in these phase 3 studies or any other clinical study with simufilam were assessed as study drug related.
Conclusions:
Based on these findings, Cassava Sciences is preparing to submit an IND application to the FDA and enroll patients in a proof-of-concept trial of simufilam for the treatment of epilepsy in TSC.
Funding: Cassava Sciences, Inc.