Adjunctive everolimus therapy for treatment-resistant focal-onset seizures associated with tuberous sclerosis (EXIST-3): a phase 3, randomised, double-blind, placebo-controlled study

RCT (n=366) found that low-exposure everolimus (le-EV) and high exposure EV (he-EV) had superior response rates (defined as the proportion of patients achieving a ≥50% reduction in seizure frequency) vs placebo (28.2% and 40% vs 15.1%, p=0.0077 and p<0.0001 respectively).

The response rate (primary endpoint), was defined as the proportion of patients achieving a ≥50% reduction in seizure frequency.

 

A commentary on this study highlights some concerns that may temper enthusiasm with regards to the results.  First, about 12% of patients in the high exposure group had at least a 25% increase in seizure frequency, and only 4% became seizure free. Second, everolimus therapy is very expensive, meaning the cost was about $1000 per seizure eliminated.  Third, the optimum everolimus dose or trough concentration is uncertain.  It highlights that the precise mechanism of benefit at the anatomic or neurochemical level is unknown in patients with tuberous sclerosis complex and refractory epilepsy.  Better understanding of this mechanism could pave the way toward further improvements in treatment of epilepsy in tuberous sclerosis complex.