Authors :
Presenting Author: William Motley, MD – Rapport Therapeutics, Inc.
Imran Quraishi, MD, PhD – Yale School of Medicine
Neal Nolan, MD – Rapport Therapeutics, Inc.
Daniel Friedman, MD – Department of Neurology, New York University Grossman School of Medicine, NYU Langone Health
Patrick Landazuri, MD – Department of Neurology, University of Kansas Medical Center
Vikram Rao, MD – Department of Neurology and Weill Institute for Neurosciences, University of California, San Francisco
Kathryn Davis, MD – Center for Neuroengineering and Therapeutics and Penn Epilepsy Center, Department of Neurology, University of Pennsylvania
Bradley Galer, MD – Rapport Therapeutics, Inc. at time of study
Nancy Wyant, BA – Rapport Therapeutics, Inc.
Martha Morrell, MD – NeuroPace
Arnold Gammaitoni, PharmD – Rapport Therapeutics, Inc.
Jacqueline French, MD – Department of Neurology and Comprehensive Epilepsy Center, New York University Grossman School of Medicine, NYU Langone Health
Rationale:
New antiseizure medications (ASMs) with novel mechanisms of action and improved tolerability for drug-resistant focal epilepsy are needed. RAP-219 is a selective and potent negative allosteric modulator of transmembrane AMPA receptor regulatory protein γ8 (TARPγ8). TARPγ8 is highly expressed in the neocortex and mesial temporal lobes, the regions of the brain where nearly all focal seizures (FOS) originate.
Recent analyses suggest a ≥30% reduction in long episodes (LEs) as measured by the responsive neurostimulator (RNS® System, NeuroPace) is associated with a ≥50% reduction in clinical seizures (CSs) as recorded in patient seizure diaries.
In this Phase 2 proof-of-concept (POC) study, the effect of RAP-219 in patients with drug-resistant FOS and an implanted RNS System was assessed. The key outcomes were change in LEs and CSs along with safety, tolerability, and PK.
Methods:
Adults (18-65 years) with drug-resistant FOS who had an RNS System device with at least one electrode implanted within the mesial temporal lobe ≥15 months before screening and had ≥16 LEs and >1 CS during an 8-week retrospective analysis period were eligible to enter the prospective baseline. Patients who had ≥8 LEs and ≤2 doses of rescue benzodiazepines during the prospective baseline were eligible to enroll in the treatment period. Patients were also required to be on stable doses of ≤4 ASMs and have stable RNS device settings for at least 8 weeks prior to screening. Use of perampanel was exclusionary. Changes in concomitant ASMs or RNS settings were not permitted 8 weeks prior to screening or during the study.
Following a 4-week prospective baseline period, patients entered an 8-week, open-label treatment period receiving RAP-219 0.75 mg/day for 5 days followed by RAP-219 1.25 mg/day. Patients subsequently entered an 8-week washout period. The primary outcome was change from baseline in LEs, and key secondary outcomes included change from baseline in CSs and incidence of adverse events.
Results: Thirty patients were enrolled. Of these, 60% were male with a mean age of 39 years (range, 20-61). The median age at first seizure was 19.5 years (range, 0.5-32), the median CS frequency per 28 days was 8.5 (range, 0-314.59), and the median number of concomitant ASMs was 3 (range, 1-4). The most common ASMs were lamotrigine, cenobamate, levetiracetam, zonisamide, and clobazam. RNS baseline characteristics included: median of 4.5 years (range, 1.4-10.9) since RNS implantation, median LE frequency per 28 days of 46.33 (range, 8.0-751.7), and median concordance between LE and electrographic seizures of 90% (range, 30-100%). Overall, 26 (86.7%) patients completed the 8-week treatment period.
Conclusions: The baseline characteristics of the patients enrolled in this innovative POC study testing the electrographic and clinical effect of RAP-219 in RNS patients with FOS are similar to those reported in contemporary Phase 2 and 3 studies. Efficacy, safety, and tolerability of RAP-219 (to be reported) as evaluated during the 8-week, open-label treatment trial are expected to be highly relevant to patients with drug-resistant FOS.
Funding: Supported by Rapport Therapeutics, Inc.