Factors Predictive of Everolimus Efficacy in Tuberous Sclerosis Complex

Adjunctive everolimus treatment has been found to significantly reduce frequency of treatment-resistant seizures in TSC.

HOUSTON – Patients with lower baseline seizure frequency and greater drug exposure are more likely to benefit from treatment with everolimus, according to analysis of EXIST-3 data. Results of the study were presented at the 2016 American Epilepsy Society Annual Meeting.

Results previously reported indicate that treatment with adjunctive everolimus was associated with significant reductions in frequency of treatment-resistant seizures in patients with tuberous sclerosis complex (TSC).

In this study, Jacqueline French, MD, of NYU Langone Medical Center in New York, and colleagues sought to better understand the relationship between everolimus efficacy and drug exposure, baseline seizure frequency, age, and seizure type.

Patients included in EXIST-3 (N=366; aged 2 to 56 years) were randomly assigned to receive everolimus low exposure (LE; 3 to 7 ng/mL; n=117), everolimus high exposure (HE; 9 to 15 ng/mL; n=130), or placebo (n=119). Median baseline seizure frequency was 37.5 per 28 days (LE: 34.5; HE: 37.8; placebo: 42).

Overall, treatment with everolimus (LE and HE) was associated with improved response rate (RR) and percent reduction in seizure frequency (PRSF); however, this effect was greater in patients with fewer seizures at baseline. Additionally, an increased response rate was seen in patients younger than 6 years compared with other age groups. Notably, pediatric patients in the HE arm as a whole had greater blood plasma concentrations (Cmin) than adults, with the median dose intensity highest for patients younger than 6 years.

Logistic and linear regression models confirmed that higher Cmin concentrations and baseline seizure frequency predicted RR and seizure frequency during the maintenance period (SFM); however, age was no longer significant. A 2-fold increase in time-normalized Cmin and a 0.5-fold reduced baseline seizure frequency was found to be associated with significant 28% and 49% reductions in SFM, respectively.

Overall, greater drug exposure and lower baseline seizure frequency were significant predictors of everolimus efficacy.

Disclosures: This study was supported by Novartis Pharmaceuticals, manufacturer of Afinitor® (everolimus).

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French J, Wiemer-Kruel A, Fan P, et al. Predictors of efficacy in patients with adjunctive everolimus therapy for treatment-resistant seizures associated with tuberous sclerosis complex. Presented at: 2016 American Epilepsy Society Annual Meeting; December 2-6, 2016; Houston, TX. Abstract 2.099.