RAP-219: A Clinical and Pharmacological Monograph on a Novel TARPγ8-Specific AMPA Receptor Modulator

Executive Summary

RAP-219 is a clinical-stage, investigational small molecule being developed by Rapport Therapeutics as a potential first-in-class precision medicine for neurological and psychiatric disorders. Its primary mechanism of action is as a highly selective negative allosteric modulator (NAM) of α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors that are specifically associated with the Transmembrane AMPA Receptor Regulatory Protein γ8 (TARPγ8). This mechanism confers neuroanatomical specificity, as TARPγ8 is enriched in brain regions critical to seizure generation, such as the hippocampus and cortex, while being largely absent from areas like the cerebellum and brainstem, where off-target drug activity often leads to dose-limiting side effects.

The clinical development program for RAP-219 has yielded compelling results, particularly in its lead indication of drug-resistant focal onset seizures. A Phase 2a proof-of-concept trial (RAP-219-FOS-201) in a heavily treatment-experienced patient population demonstrated exceptional efficacy. The study met its primary and key secondary endpoints with high statistical significance, showing a 77.8% median reduction in clinical seizure frequency and achieving complete seizure freedom in 24% of patients over an 8-week treatment period. This level of efficacy positions RAP-219 among the most promising new antiseizure medications (ASMs) in development.