EXPECTED THERAPEUTIC MECHANISM

Focal cortical dysplasia (FCD) is a disease entity that presents with specific pathological features, often encountered in cases of refractory epilepsy indicated for resective surgery. FCD’s pathology is characterized by the appearance of abnormal cells and layer structure (lamination) in cerebral cortex and is classified into three types. Type I primarily exhibits abnormal lamination and is difficult to detect on MRI, while type II presents with abnormal cells (i.e., dysmorphic neurons/balloon cells) in addition to abnormal laminar structure. Type III presents with features such as hippocampal sclerosis, brain tumors, and destructive lesions in addition to cortical malformation. Gain-of-function mutations in MTOR—the gene encoding mammalian target of rapamycin (mTOR)—or mTOR pathway genes are commonly observed in FCD type II. Significant mTOR activation has been noted in cellular experiments and human pathology specimens of FCD type II. Sirolimus has been found to normalize abnormal cells and effectively suppress epileptic seizures in animal models.

SIROLIMUS’ EFFECTS IN FCD TYPE II

FCD type II causes epileptic seizures in early childhood. Seizures are often tonic or tonic-clonic, but subtypes vary with age in cases of early age of onset to include partial (focal) seizures. These epileptic seizures are intractable: as the disease progresses, children develop focal neurologic signs as hemiplegia and cognitive impairment. Since drugs are effective in only 17% of cases, and even then, their effects are only temporary, surgical intervention is overwhelmingly preferred as a treatment approach today; however, even its efficacy peaks at a mere 50–65%. Epileptic seizures in FCD are believed to originate in the dysplastic cortical areas that define the disease. No information on the effectiveness of mTOR inhibitors against epileptic seizures in FCD has been reported to date. However, mTOR inhibitors have been shown to prevent seizures effectively in tuberous sclerosis, the pathology of which exhibits mTOR over-activation as in FCD.

ROADMAP TO COMMERCIALIZATION

We performed a pilot clinical study to demonstrate proof of concept (POC) in 2017, observing reductions in seizure incidence and no major adverse events. From 2018 to 2020, we conducted an uncontrolled open-label study to assess the efficacy and safety of sirolimus for epileptic seizures associated with focal cortical dysplasia type-II (FCDS-01). Since 2019, we have been conducting a continuation trial to assess the safety of sirolimus for epileptic seizures associated with focal cortical dysplasia type II (FCDS-02).

STATUS OF CLINICAL TRIALS

RELATED LINKS/TRIAL INFORMATION

■Focal Cortical Dysplasia (FCD) Consortium - Homepage
http://plaza.umin.ac.jp/~fcd_com/sp/guide.html