Abstract Details

Title Optimal Cut Point for Reduction in Long Episode Frequency to Predict Meaningful Change in Clinical Seizure Frequency

Topic Epilepsy/Clinical Neurophysiology (EEG)

Presentation(s) P5 - Poster Session 5 (8:00 AM-9:00 AM)

Poster/Presentation
Number 9-002

Objective To examine the optimal cut point for long episode (LE; prolonged abnormal electrographic activity) frequency reduction that predicts clinically meaningful clinical seizure (CS) frequency reduction in patients with a responsive neurostimulator (RNS^® System, NeuroPace).

Background Novel proof-of-concept designs utilizing biomarkers with positive predictive ability of antiseizure medication (ASM) efficacy may require lower patient numbers for signal detection than traditional clinical trials. In drug-resistant focal epilepsy patients with an RNS® System, LE and CS frequency changes were correlated following a new ASM start.

Design/Methods

Retrospective data from a long-term RNS® System study were analyzed. Analysis period: 8 weeks prior to (“baseline”) and 8 weeks following ASM start. Key inclusion criteria: no RNS® System setting changes during the analysis period; ≥8 LEs per 28d (baseline); LE and CS data available.

Outcomes, following ASM start vs baseline: median percentage change in CS and LE frequency per 28d, LE responder rate, and receiver operating characteristics (LE reduction required to predict clinically meaningful [≥50%] or profound [≥75%] CS reduction).

Results Overall, patients (n=45) experienced median 30% (LE) and 50% (CS) reductions following ASM initiation vs baseline. LE median reductions: clobazam (n=15), 50%; levetiracetam (n=4), 73.4%; lacosamide (n=26), 8.8%. CS median reductions: clobazam, 29.4%; levetiracetam, 78.6%; lacosamide, 51%. Responder rates (≥30% LE reduction): clobazam, 60%; levetiracetam, 100%; lacosamide, 39%. Overall, LE responders experienced a median 60% reduction in CS; ≥50% CS reduction was seen in 16/23 (70%) LE responders. LE reduction thresholds for predicting clinically meaningful and profound CS reductions were ≥30% (AUC=0.765) and ≥50% (AUC=0.735), respectively.

Conclusions Results suggest that a patient achieving ≥30% LE reduction following ASM initiation will experience clinically meaningful CS reduction 70% of the time. Higher LE response thresholds were associated with profound reductions in CS. LE responder analysis may serve as a biomarker in proof-of-concept studies with positive predictive ability of clinically meaningful efficacy.

Authors/Disclosures
Neal Nolan, MD PRESENTER	Dr. Nolan has received personal compensation for serving as an employee of Vertex Pharmaceuticals and Rapport Therapeutics. Dr. Nolan has stock in Rapport Therapeutics.
Arnold Gammaitoni, PharmD (Zogenix)	Dr. Gammaitoni has received personal compensation for serving as an employee of Zogenix Inc.. Dr. Gammaitoni has received stock or an ownership interest from Zogenix Inc..
Martha Morrell, MD, FAAN (NeuroPace/Stanford University)	Dr. Morrell has received personal compensation for serving as an employee of NeuroPace. Dr. Morrell has stock in NeuroPace. The institution of Dr. Morrell has received research support from National Institutes of Health.
Jacqueline French, MD, FAAN (NYU Comprehensive Epilepsy Ctr)	Dr. French has received personal compensation in the range of $50,000-$99,999 for serving as an officer or member of the Board of Directors for Epilepsy Foundation. The institution of Dr. French has received research support from Epilepsy Study Consortium/ Epilepsy Foundation (Funded by UCB). The institution of Dr. French has received research support from GW/One8 Foundation/FACES. The institution of Dr. French has received research support from NINDS. The institution of Dr. French has received research support from Xenon. The institution of Dr. French has received research support from Cerevel. The institution of Dr. French has received research support from FACES. The institution of Dr. French has received research support from UCB. The institution of Dr. French has received research support from Epilepsy Study Consortium. The institution of Dr. French has received research support from UCB. The institution of Dr. French has received research support from Praxis. Dr. French has received personal compensation in the range of $50,000-$99,999 for serving as a Chief Medical/Innovation Officer with Epilepsy Foundation. Dr. French has a non-compensated relationship as a Consultant with Acadia Pharmaceuticals Inc that is relevant to AAN interests or activities. Dr. French has a non-compensated relationship as a consultant with Access Industries that is relevant to AAN interests or activities. Dr. French has a non-compensated relationship as a consultant with Acuta Capital Partners LLC that is relevant to AAN interests or activities. Dr. French has a non-compensated relationship as a Consultant with AFASCI Inc that is relevant to AAN interests or activities. Dr. French has a non-compensated relationship as a Consultant, Advisory Board with Agrithera, Inc. that is relevant to AAN interests or activities. Dr. French has a non-compensated relationship as a Consultant with Alkermes that is relevant to AAN interests or activities. Dr. French has a non-compensated relationship as a consultant with Alterity Therapeutics Limited that is relevant to AAN interests or activities. Dr. French has a non-compensated relationship as a Consultant, Advisory Board with Angelini Pharma S.p.A. that is relevant to AAN interests or activities. Dr. French has a non-compensated relationship as a Consultant with Autifony Therapeutics Limited that is relevant to AAN interests or activities. Dr. French has a non-compensated relationship as a Consultant with Axonis Therapeutics that is relevant to AAN interests or activities. Dr. French has a non-compensated relationship as a Consultant with Bain Capital that is relevant to AAN interests or activities. Dr. French has a non-compensated relationship as a Consultant, Advisory Board with Beacon Biosciences that is relevant to AAN interests or activities. Dr. French has a non-compensated relationship as a Consultant, Advisory Board with Biogen that is relevant to AAN interests or activities. Dr. French has a non-compensated relationship as a Consultant, Advisory Board with Biohaven Pharma that is relevant to AAN interests or activities. Dr. French has a non-compensated relationship as a Consultant, Advisory Board with Bloom Science, Inc that is relevant to AAN interests or activities. Dr. French has a non-compensated relationship as a Consultant with Bright Minds Biosciences, Inc. that is relevant to AAN interests or activities. Dr. French has a non-compensated relationship as a Consultant with Capsidia Biotherapeutics that is relevant to AAN interests or activities. Dr. French has a non-compensated relationship as a Consultant, Advisory Board with Cerebral Therapeutics that is relevant to AAN interests or activities. Dr. French has a non-compensated relationship as a Consultant with Cerecin, Inc that is relevant to AAN interests or activities. Dr. French has a non-compensated relationship as a Consultant, SAB with Cerevel that is relevant to AAN interests or activities. Dr. French has a non-compensated relationship as a Consulting, SAB with Cognizance Biomarkers that is relevant to AAN interests or activities. Dr. French has a non-compensated relationship as a Consulting with Ceribell that is relevant to AAN interests or activities. Dr. French has a non-compensated relationship as a Consultant with Cowen that is relevant to AAN interests or activities. Dr. French has a non-compensated relationship as a Consultant with Crossject that is relevant to AAN interests or activities. Dr. French has a non-compensated relationship as a Advisory Board with EcoR1 Capital that is relevant to AAN interests or activities. Dr. French has a non-compensated relationship as a Consultant with EG 427 that is relevant to AAN interests or activities. Dr. French has a non-compensated relationship as a consultant, Advisory Board with Eisai that is relevant to AAN interests or activities. Dr. French has a non-compensated relationship as a Consultant with Encoded Therapeutics that is relevant to AAN interests or activities. Dr. French has a non-compensated relationship as a Consultant/Advisory Board with Engrail that is relevant to AAN interests or activities. Dr. French has a non-compensated relationship as a Consultant with Epitel, Inc that is relevant to AAN interests or activities. Dr. French has a non-compensated relationship as a Consultant with EpiMinder that is relevant to AAN interests or activities. Dr. French has a non-compensated relationship as a Consultant with Grin Therapeutics that is relevant to AAN interests or activities. Dr. French has a non-compensated relationship as a Consultant with Harmony that is relevant to AAN interests or activities. Dr. French has a non-compensated relationship as a Advisory Board with Ionis Pharmaceutical that is relevant to AAN interests or activities. Dr. French has a non-compensated relationship as a Consultant with iQure Pharma, Inc that is relevant to AAN interests or activities. Dr. French has a non-compensated relationship as a Consultant with IQVIA that is relevant to AAN interests or activities. Dr. French has a non-compensated relationship as a Consultant, Advisory Board with Janssen Pharma that is relevant to AAN interests or activities. Dr. French has a non-compensated relationship as a Consultant with Jazz Pharmaceutical that is relevant to AAN interests or activities. Dr. French has a non-compensated relationship as a Consultant with Leal Therapeutics that is relevant to AAN interests or activities. Dr. French has a non-compensated relationship as a Consultant, with Livanova that is relevant to AAN interests or activities. Dr. French has a non-compensated relationship as a Consultant, SAB with London Research & Pharmaceuticals that is relevant to AAN interests or activities. Dr. French has a non-compensated relationship as a Consultant, Advisory Board with Longboard Pharmaceutical that is relevant to AAN interests or activities. Dr. French has a non-compensated relationship as a Consultant with Maplight Therapeutics that is relevant to AAN interests or activities. Dr. French has a non-compensated relationship as a Consultant, Advisory Board with Marinus that is relevant to AAN interests or activities. Dr. French has a non-compensated relationship as a Consultant with Medscape/Web MD that is relevant to AAN interests or activities. Dr. French has a non-compensated relationship as a consultant with Modulight Bio that is relevant to AAN interests or activities. Dr. French has a non-compensated relationship as a Consultant with Montara Therapeutics that is relevant to AAN interests or activities. Dr. French has a non-compensated relationship as a Consultant with Mosaica Therapeutics that is relevant to AAN interests or activities. Dr. French has a non-compensated relationship as a consultant with Neumarker that is relevant to AAN interests or activities. Dr. French has a non-compensated relationship as a Consultant, Advisory Board with Neumirna Therapeutics that is relevant to AAN interests or activities. Dr. French has a non-compensated relationship as a Consultant with Neurelis that is relevant to AAN interests or activities. Dr. French has a non-compensated relationship as a consulting, Advisory Board with Neurocrine that is relevant to AAN interests or activities. Dr. French has a non-compensated relationship as a consultant with Neuropace that is relevant to AAN interests or activities. Dr. French has a non-compensated relationship as a Consultant with NeuroPro Therapeutics that is relevant to AAN interests or activities. Dr. French has a non-compensated relationship as a Consulting with Neuroventis that is relevant to AAN interests or activities. Dr. French has a non-compensated relationship as a Consulting with Neurona Therapeutics that is relevant to AAN interests or activities. Dr. French has a non-compensated relationship as a Consulting, Advisory Board with Neuvarti that is relevant to AAN interests or activities. Dr. French has a non-compensated relationship as a Consultant, Advisory Board with Noema that is relevant to AAN interests or activities. Dr. French has a non-compensated relationship as a Consulting with Ono Pharmaceutical that is relevant to AAN interests or activities. Dr. French has a non-compensated relationship as a Consulting, Advisory Board with Otsuka that is relevant to AAN interests or activities. Dr. French has a non-compensated relationship as a consulting, Advisory Board with Ovid Therapeutics that is relevant to AAN interests or activities. Dr. French has a non-compensated relationship as a Consulting with Praxis that is relevant to AAN interests or activities. Dr. French has a non-compensated relationship as a Consultant with PureTech LYT Inc that is relevant to AAN interests or activities. Dr. French has a non-compensated relationship as a Consultant with QurAlis Corp that is relevant to AAN interests or activities. Dr. French has a non-compensated relationship as a Consultant, Advisory Board with Rapport Therapeutics that is relevant to AAN interests or activities. Dr. French has a non-compensated relationship as a Consultant with Receptor Holdings, Inc that is relevant to AAN interests or activities. Dr. French has a non-compensated relationship as a Consultant with Rivervest Venture Partners that is relevant to AAN interests or activities. Dr. French has a non-compensated relationship as a Consultant, Advisory Board with Sage Therapeutics, Inc that is relevant to AAN interests or activities. Dr. French has a non-compensated relationship as a Consultant with SK Life Science that is relevant to AAN interests or activities. Dr. French has a non-compensated relationship as a Consultant, Advisory Board with Stoke that is relevant to AAN interests or activities. Dr. French has a non-compensated relationship as a Consultant, Advisory Board with Stream Neuroscience that is relevant to AAN interests or activities. Dr. French has a non-compensated relationship as a Consultant with Supernus that is relevant to AAN interests or activities. Dr. French has a non-compensated relationship as a Consultant with Takeda that is relevant to AAN interests or activities. Dr. French has a non-compensated relationship as a Consultant with Taysha Gene Therapies that is relevant to AAN interests or activities. Dr. French has a non-compensated relationship as a Consultant, Advisory Board with UCB, Inc that is relevant to AAN interests or activities. Dr. French has a non-compensated relationship as a Consultant with uniQure that is relevant to AAN interests or activities. Dr. French has a non-compensated relationship as a Consultant, Advisory Board with Ventus Therapeutics that is relevant to AAN interests or activities. Dr. French has a non-compensated relationship as a Consultant with Vida Ventures Management that is relevant to AAN interests or activities. Dr. French has a non-compensated relationship as a Consultant, Advisory Board with Xenon Pharmaceuticals that is relevant to AAN interests or activities.
Daniel Friedman, MD, FAAN (NYU Langone Medical Center)	The institution of Dr. Friedman has received personal compensation in the range of $50,000-$99,999 for serving as a Consultant for Epilepsy Study Consortium (non-profit). Dr. Friedman has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Meili Technology. Dr. Friedman has received personal compensation in the range of $5,000-$9,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Neurelis. Dr. Friedman has stock in Neuroview Technology. The institution of Dr. Friedman has received research support from NIH. The institution of Dr. Friedman has received research support from CDC. The institution of Dr. Friedman has received research support from Epitel. The institution of Dr. Friedman has received research support from Neuropace. The institution of Dr. Friedman has received research support from Rapport Therapeutics. Dr. Friedman has received intellectual property interests from a discovery or technology relating to health care. Dr. Friedman has received intellectual property interests from a discovery or technology relating to health care. Dr. Friedman has received publishing royalties from a publication relating to health care. Dr. Friedman has received personal compensation in the range of $500-$4,999 for serving as a Speaker Honorarium with SK Life Sciences. Dr. Friedman has received personal compensation in the range of $500-$4,999 for serving as a Speaker Honorarium with AAN. Dr. Friedman has received personal compensation in the range of $500-$4,999 for serving as a Travel Reimbursement with Epilepsy Foundation of America.
Kathryn A. Davis, MD (University of Pennsylvania)	Dr. Davis has received personal compensation in the range of $500-$4,999 for serving as a Consultant for GW Pharmaceuticals/Jazz Pharmaceuticals. Dr. Davis has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Spark Therapeutics. Dr. Davis has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for UCB. Dr. Davis has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for UNEEG. Dr. Davis has received personal compensation in the range of $500-$4,999 for serving as an Editor, Associate Editor, or Editorial Advisory Board Member for Epilepsia Open. Dr. Davis has received personal compensation in the range of $10,000-$49,999 for serving as an Expert Witness for Pfizer. The institution of Dr. Davis has received research support from Eisai. The institution of Dr. Davis has received research support from Liminal. Dr. Davis has received publishing royalties from a publication relating to health care.
Thomas K. Tcheng, PhD	No disclosure on file
Cairn Seale (NeuroPace)	No disclosure on file
Bradley Galer, MD	No disclosure on file
William Motley, MD	Dr. Motley has received personal compensation for serving as an employee of Rapport Therapeutics. An immediate family member of Dr. Motley has received personal compensation for serving as an employee of Eli Lilly & Co.

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