William W. Motley, MD, RAP-219 Program Leader at Rapport Therapeutics, discusses follow-up data of RAP-219 for the treatment of focal onset seizures.
Focal onset seizures refer to abnormal neural activity in one brain area within one brain hemisphere with a fixed focal or localized onset. These seizures can manifest in various ways, with symptoms ranging from subtle sensory disturbances to more pronounced motor movements and altered consciousness. Focal onset seizures are divided into 2 subtypes: motor onset and nonmotor onset. The motor manifestations of focal motor onset seizures can be characterized as automatism, atonic, clonic, epileptic spasms, hyperkinetic, myoclonic, or tonic movements. The behavioral manifestations of focal nonmotor onset seizures can be described by autonomic, behavioral arrest, cognitive, emotional, or sensory symptoms.
At the 2026 American Academy of Neurology (AAN) Annual Meeting, results from the phase 2a trial of RAP-219 in patients with drug-resistant focal onset seizures (FOS) and an implanted responsive neurostimulator (RNS) system were presented. This included data from an 8 week follow-up period.
RAP-219 is a potential first-in-class, TARPγ8-specific AMPA receptor negative allosteric modulator. It is designed to target the TARPγ8 protein that is expressed in brain regions where focal seizures often originate. Because of this protein’s minimal expression in the hindbrain, it is hypothesized that the drug will avoid causing intolerable adverse events often associated with traditional neuroscience medications.
Patients with drug-resistant focal onset seizures, an RNS system, 16 or more long episodes, and 1 or more clinical seizure 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. Patients had a median 8.5 CSs/28d at baseline. Patients had the RNS implanted a median 4.6 years before first RAP-219 dose and had a baseline median 48 LEs/28d with median 92% concordance between LEs and electrographic seizures.
As previously reported, primary endpoints were achieved with statistical significance. This included a 71% median reduction in long episodes with 85.2% of patients achieving at least a 30% reduction over the 8 week treatment period. Clinical seizures also showed a median 77.8% reduction with 72% of patients achieving a reduction of at least 50% over the treatment period. Additionally, 24% of patients achieved seizure freedom for the entire 8 week treatment period. The most common treatment-emergent adverse events in the safety population included dizziness, headache, fatigue, and falls.
Based on recent data and population PK modeling from the 8 week follow-up period, RAP-219 has demonstrated an approximately 22 day half life. An 80% reduction in median long episodes relative to baseline during the first four weeks of follow-up was observed, compared to 75% for the first four weeks of the initial treatment period. Follow-up also illustrated a 90% reduction in median clinical seizures relative to baseline during the first four weeks of follow-up, compared to 85% for the first four weeks of the treatment period. Continued significant reductions from baseline in both median long episodes and median clinical seizures in the last four-weeks of follow-up were also observed.
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Reference:
Kumar, A., & Sharma, S. (2019, April 2). Simple Partial Seizure. Nih.gov; StatPearls Publishing. https://www.ncbi.nlm.nih.gov/books/NBK500005/