Sirolimus TSC Epilepsy Prevention Study (STEPS) IND#145820 11/8/2019

SUMMARY/ABSTRACT Epilepsy is very prevalent and highly refractory to currently available medical treatments in Tuberous Sclerosis Complex (TSC), a genetic disorder affecting 1:6000 live births. Medically-refractory epilepsy in TSC is associated with lifelong intellectual disability and neurodevelopmental deficits. Everolimus and sirolimus, pharmacological inhibitors of the mechanistic target of rapamycin complex 1 (mTORC1), have been successfully repurposed to treat may clinical manifestations of TSC, including focal-onset epilepsy. However, few patients become seizure- free following treatment with mTORC1 inhibitors and 60% of patients with TSC are still in need of effective treatment. Mouse models of TSC and human clinical trials indicate early treatment with mTORC1 inhibitors, before the onset of seizures, may be a more effective treatment strategy against epilepsy and epilepsy- associated deficits in neurodevelopment in patients diagnosed with TSC. The current study proposes a Phase IIb multicenter, randomized, double-blind, placebo-controlled clinical trial with sirolimus to test this hypothesis. The primary aims of the clinical trial are (1) to demonstrate that sirolimus prevents or delays seizures in infants with TSC that are 0-12 months of age; and (2) to demonstrate that sirolimus is safe and well-tolerated in infants with TSC that are 0-12 months of age. Additional (secondary) aims of the trial are: (1) to demonstrate that early sirolimus treatment improves developmental delay, language impairment, adaptive skills, and autism risk; (2) to assess the utility of EEG and MRI biomarkers for measuring mTORC1 inhibition in the brain; and (3) to validate precision dosing of sirolimus in infants with TSC.