Efficacy and Tolerability of RAP-219, a Potential First-in-class Negative Allosteric Modulator of γ8 Transmembrane AMPA Receptor Regulatory Protein: Impact on RNS Long Episodes and Clinical Seizures
William Motley1, Imran Quraishi2, Neal Nolan1, Daniel Friedman3, Patrick Landazuri4, Vikram Rao5, Kathryn Davis6, Bradley Galer1, Nancy Wyant1, Martha Morrell7, Arnold Gammaitoni1, Jacqueline French8
1Rapport Therapeutics, Inc., 2Department of Neurology, Yale University School of Medicine, 3Department of Neurology, New York University Grossman School of Medicine, NYU Langone Health, 4Department of Neurology, University of Kansas Medical Center, 5Department of Neurology and Weill Institute for Neurosciences, University of California, San Francisco, 6Center for Neuroengineering and Therapeutics and Penn Epilepsy Center, Department of Neurology, University of Pennsylvania, 7NeuroPace, Inc., 8Department of Neurology and Comprehensive Epilepsy Center, New York University Grossman School of Medicine
Objective:
Assess the effect of RAP-219, a selective and potent transmembrane AMPA receptor regulatory protein (TARP)-γ8 negative allosteric modulator, using a novel biomarker (long episodes [LEs]) in patients with an implanted responsive neurostimulator (RNS® System, NeuroPace) for drug-resistant focal seizures (FOS).
Background:
Due to high expression of TARPγ8 in the neocortex and mesial temporal lobe (MTL), RAP-219 may provide efficacy and tolerability for patients with drug-resistant FOS. To date, there has been no proof-of-concept design specific to FOS. LEs were measured as a novel and objective biomarker in patients with drug-resistant FOS and an implanted RNS System to evaluate RAP-219. Recent analyses suggest that a ≥30% LE reduction is associated with a ≥50% clinical seizure (CS) reduction.
Design/Methods:
Adults (18-65y) with drug-resistant FOS, an RNS System (≥1 MTL electrode), ≥16 LEs, and >1 CS during an 8-week retrospective period were entered into a prospective baseline followed by an 8-week treatment period. Enrolled patients received RAP-219 0.75 mg/d (5d), then RAP-219 1.25 mg/d for the remainder of the treatment period, followed by an 8-week washout period. Key outcomes were change from baseline in LEs (primary), change from baseline in CSs, and incidence of adverse events (AEs).
Results:
Patients (modified intent-to-treat: N=27; 55.6% male; mean age 40.2y; median 3 concomitant antiseizure medications) had a median 8.5 CSs/28d at baseline. Patients had the RNS implanted a median 4.6y before first RAP-219 dose and had a baseline median 48 LEs/28d with median 92% concordance between LEs and electrographic seizures. Patients achieved median 71.0% and 77.8% reductions in LEs and CSs, respectively. The most common treatment-emergent AEs (10%) in the safety population included dizziness, headache, fatigue, and falls.
Conclusions:
In this proof-of-concept open-label study of RAP-219 using a novel objective biomarker, patients achieved statistically and clinically meaningful reductions in both LEs and CSs. RAP-219 was generally well tolerated.
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