Neuropediatrics 2017; 48(S 01): S1-S45
DOI: 10.1055/s-0037-1602925
PP – Poster Presentations
Georg Thieme Verlag KG Stuttgart · New York

Predictors of Efficacy in Patients with Adjunctive Everolimus Therapy for Treatment-Resistant Seizures Associated with Tuberous Sclerosis Complex

G. Wiegand
1   Asklepios Klinik Nord, Heidelberg, Germany
,
T. Polster
2   Epilepsiezentrum Bethel, Bethel, Germany
,
C. Hertzberg
3   Vivantes-Klinikum Neukölln, Berlin, Germany
,
A. Wiemer-Kruel
4   Epilepsiezentrum Kork, Kehl, Germany
,
J. French
5   NYU Comprehensive Epilepsy Center, New York, New York, United States
,
P. Fan
6   National Taiwan University, Taipei, Taiwan
,
P. de Vries
7   Division of Child and Adolescent Psychiatry, University of Cape Town, Cape Town, South Africa
,
N. Berkowitz
8   Novartis Pharmaceuticals Corporation, United States
,
A. Vaury
9   Novartis Pharmaceuticals S. A. S., France
,
S. Peyrard
9   Novartis Pharmaceuticals S. A. S., France
,
P. Curatolo
10   Tor Vergata University Hospital, Roma, Italy
› Author Affiliations
Further Information

Publication History

Publication Date:
26 April 2017 (online)

 

Background/Purpose: The EXIST-3 study on efficacy and safety of everolimus in patients with treatment-resistant seizures associated with tuberous sclerosis complex demonstrated a significantly reduced seizure frequency and a tolerable safety profile (target trough concentration [Cmin]: 3–7 ng/mL [low exposure, LE]; 9–15 ng/mL [high exposure, HE]). Here, we assessed potential predictors of efficacy (baseline seizure frequency, age, seizure type, exposure).

Methods: EXIST-3 (NCT01713946) included four age strata (<6, 6–<12, 12–<18, >18 years), multiple epilepsy syndromes, and seizure types (simple, complex partial and generalized). The relationship between efficacy parameters (response rate [RR]: ≥50% reduction; median percentage reduction in seizure frequency from baseline [PRSF]) and potential predictors of efficacy was assessed in regression models (logistic: RR; linear: seizure frequency during maintenance [SFM]).

Results: Overall median baseline seizure frequency for 366 patients was 37.5 per 28 days (placebo: 42 [n = 119], LE: 34.5 [n = 117], HE: 37.8 [n = 130]). Everolimus (LE, HE) improved RR and PRSF (vs. placebo) irrespective of seizure type and baseline seizure frequency (more pronounced with fewer seizures). Patients <6 years had higher RRs than other ages, and children (HE arm) achieved higher Cmin concentrations than adults (highest median dose intensity: <6 years). Regression models confirmed exposure (time normalized [TN] Cmin = estimated average during maintenance) and baseline seizure frequency as RR and SFM predictors (not significant: age). A twofold increase in TN Cmin and a 0.5-fold lower baseline seizure frequency were associated with a SFM reduction of 28% (95% CI: 12–42%) and 49% (95% CI: 44–53%), respectively.

Conclusion: Higher everolimus exposure and lower baseline seizure frequency, rather than age, were strong predictors of efficacy. A treatment effect was observed in all seizure types (less pronounced: generalized seizures).