Abstracts

Rationale: EXIST-3 evaluated the efficacy and safety of everolimus 3-7 ng/mL (low exposure, LE) and 9-15 ng/mL (high exposure, HE) target trough concentration (Cmin) ranges vs placebo as adjunctive therapy in patients with treatment-resistant seizures associated with tuberous sclerosis complex (TSC). The study demonstrated a statistically significant and clinically meaningful reduction in seizure frequency and tolerable safety profile among patients treated with everolimus vs placebo. Analyses were conducted to determine the relationship of exposure, baseline seizure frequency, age and seizure type with everolimus efficacy. Methods: EXIST-3 (clinicaltrials.gov NCT01713946) included multiple age strata (4 strata: < 6, 6- < 12, 12- < 18 and ?-18 years) and multiple epilepsy syndromes (focal, epileptic spasms, Lennox?"Gastaut). Along with focal aware (SPS, 1A), and focal with altered awareness (CPS, IB), seizures typically categorized as "generalized" (tonic, atonic, myoclonic, GTCC) were classified as IC for the purpose of the study. Efficacy parameters included response rate (RR; ?-50% reduction) and median percentage reduction in seizure frequency (PRSF) from baseline during maintenance period. The relationship between efficacy parameters and potential predictors (exposure to study drug, age, baseline seizure frequency) was assessed using regression models (with logit function for RR and linear function for seizure frequency observed in the maintenance period [SFM]). Results: A total of 366 patients were randomized to everolimus LE (n=117), HE (n=130), or placebo (n=119). The overall median baseline seizure frequency was 37.5 per 28 days (placebo, 42; LE, 34.5; HE, 37.8). Everolimus LE and HE were both associated with improved RR and PRSF relative to placebo irrespective of the baseline seizure frequency, although the everolimus effect was more pronounced for patients with fewer seizures at baseline (Table 1). The youngest patients ( < 6 years) achieved the highest response rate among all age groups (Table 1). At the same time, compared to adults, pediatric patients achieved higher Cmin concentrations in the HE arm with a median dose intensity highest for patients < 6 years old (Table 2). Logistic and linear regression models confirmed exposure (expressed as time-normalized [TN] Cmin which denotes an estimated average of Cmin over the maintenance period) and baseline seizure frequency as predictors of RR and SFM. The significance was absent for age. A 2-fold increase in TN Cmin and a 0.5-fold lower baseline seizure frequency were associated with a significant 28% reduction (95% CI; 12%, 42%) and 49% reduction (95% CI; 44%, 53%) in SFM, respectively. The RR and PRSF were higher in everolimus LE and HE arms vs placebo irrespective of the seizure type (Table 1). Conclusions: Higher everolimus exposure and lower baseline seizure frequency, rather than age, were strong predictors of efficacy. A treatment effect was observed across the different subtypes of seizures, but an effect on generalized seizures was less pronounced. Funding: This study was sponsored by Novartis Pharmaceuticals Corporation.