Hi, I'm Hannah Goldstein, and I'm currently the Pediatric Neurosurgery Fellow at Seattle Children's Hospital. Today I will be talking about our initial results from a Phase I study of ABI 009, or NAB serolimus, for surgically refractory epilepsy, also known as RESHER. This clinical trial is funded in part by Audi Biosciences. Epilepsy affects approximately five out of every 10,000 children per year, with up to one-third of these children having medically refractory epilepsy, with limited to no options for improved seizure control. mTOR, a kinase in the PI3K-related kinases family, is dysregulated in a number of human diseases, including TSC and epilepsy. In cell and animal models of epilepsy and TSC, rabamycin, an mTOR inhibitor, has been shown to decrease seizure frequency and duration and prolong animal survival. Clinical studies have mainly focused on patients with TSC. Everolimus, a chemically modified rabamycin derivative, has been shown to reduce seizure frequency with reasonable safety and tolerability. RESHER is a hypothesis-driven Phase I study that aims to evaluate the use of an mTOR inhibitor, ABI 009, in patients with medically and surgically refractory epilepsy. The underlying hypotheses being tested are 1. ABI 009 is safe and well tolerated in this patient population, and 2. The addition of ABI 009 therapy results in improved seizure control. This is unique among trials of antiepileptic medications in that it studies mTOR inhibition in a non-TSC population. The primary objectives of this study are to determine dose-limiting toxicities and maximum tolerated dose, and record the adverse events and their severity. Secondary objectives are to evaluate drug efficacy, measuring rabamycin levels in order to assess a relationship to response. This is a prospective single-center Phase I safety study with a standard 3 plus 3 dose-finding design. Patients are monitored before, during, and after treatment. To date, eight patients have been successfully enrolled and treated at all dosing cohorts. All patients have been compliant and none have withdrawn during or after treatment. Common AEs include asymptomatic mild thrombocytopenia, mild epistaxis, and skin rash, all easily managed without dosing modification. There has been no increased risk of suicidality during or after treatment. Preliminary data suggests variability in efficacy, with three subjects demonstrating dramatic reductions in seizures while on study drug. Anecdotal reports from family have noted improvements in behavior, such as increased verbalization, better sleep, and calmer demeanor. Despite a very short treatment period of only three weeks, there appears to be significant efficacy in some patients. These three responders have shown a reduction in their average weekly seizure frequency and an increase in the percentage of seizure-free days during the treatment period. Furthermore, the treatment effect appeared to persist past the treatment duration, followed by a gradual deterioration back towards baseline. Preliminary results from this Phase I study of ABI-009 in patients with medically and surgically refractory epilepsy suggest that ABI-009 is safe and well-tolerated in this patient population. Additionally, several patients have had dramatic reductions in seizure frequency and increases in seizure-free days. This data has led to justification for open-label extension with three patients currently enrolled. Further work is necessary to understand optimal dosing for a Phase II multi-institutional study to determine efficacy and to better understand which patients benefit most. Thank you.

ABI 009

surgically refractory epilepsy

mTOR inhibitor

seizure reduction

patient selection