Authors :
Presenting Author: Arnold Gammaitoni, PharmD – Rapport Therapeutics, Inc.
Martha Morrell, MD – NeuroPace
Jacqueline French, MD – New York University Comprehensive Epilepsy Center
Daniel Friedman, MD – New York University Grossman School of Medicine, NYU Langone Health
Kathryn Davis, MD – University of Pennsylvania
Thomas Tcheng, PhD – NeuroPace
Cairn Seale, MS – NeuroPace
Bradley Galer, MD – Rapport Therapeutics, Inc.
William Motley, MD – Rapport Therapeutics, Inc.
Rationale:
Novel proof-of-concept (POC) designs utilizing biomarkers with positive predictive ability of antiseizure medication (ASM) treatment effects are needed, as they could require smaller patient numbers to detect a signal than traditional trials. Long episode (LE) frequency (abnormal electrographic activity that does not return to baseline within a set period [~30-60s]) on a responsive neurostimulator (RNS® System, NeuroPace) in patients with drug-resistant focal epilepsy following a new ASM start has been shown to correlate with change in clinical seizure (CS) frequency (Quigg et al., 2020; Quraishi et al., 2020).
We examined the optimal cut point for LE frequency reduction to predict clinically meaningful
(≥ 50%) CS frequency reduction using responder rate and receiver operator characteristic (ROC) analyses in patients with an RNS® System.Methods:
Retrospective data from a long-term treatment study of the RNS® System was obtained from the 8 weeks prior to (“baseline”) and 8 weeks following ASM start. Inclusion criteria: no setting changes to the RNS® System during baseline or 8 weeks following ASM start, ≥8 LEs per 28 days during baseline, and data available for LE and CS frequency. Outcomes assessed in patients following ASM start vs baseline: median percentage change in CS and LE frequency per 28 days, LE responder rate, and LE reduction cut point for accurately predicting a clinically meaningful improvement (≥ 50% reduction) in CS.Results:
Patients (n=45; mean age=36.5y; female: 34.8%) who initiated clobazam (CLB; n=15, 33.3%), levetiracetam (LEV; n=4, 8.9%), or lacosamide (LCM; n=26, 57.8%) were included.
Overall, the patients experienced median 30% and 50% reductions in LE and CS, respectively, following initiation of ASM vs baseline. Patients starting new treatment with CLB, LEV, and LCM experienced median 50%, 73.4%, and 8.8% reductions in LEs and 29.4%, 78.6%, and 51% reductions in CSs, respectively.
Responder rates for ≥ 30% LE reduction following CLB, LEV, and LCM starts were 60%, 100%, and 39%, respectively. Overall, the ≥ 30% LE responder group experienced a median 60% reduction in CS. Of patients in the ≥ 30% responder group, 70% (16/23) also experienced an ≥ 50% CS reduction regardless of ASM. The cut points identified for predicting clinically meaningful (≥ 50%) and profound (≥75%) reductions in CS were ≥ 30% (AUC=0.765) and ≥ 50% (AUC=0.735) reductions in LEs, respectively (Table 1).Conclusions:
The likelihood of meaningful response in CS frequency following ASM initiation is better predicted by responder analyses than median change in LE frequency. These results suggest that a patient who achieves an ≥ 30% reduction in LE frequency following ASM initiation will also experience a clinically meaningful (≥ 50%) reduction in CS 70% of the time. Higher LE response thresholds were associated with a profound (≥ 75%) reduction in CS. LEs may serve as a biomarker for use in POC studies with positive predictive ability of clinical meaningful efficacy in CSs in later stages of ASM development.Funding:
Funded by Rapport Therapeutics, Inc.