RAP-219 cut median clinical seizure frequency by 77.8% over eight weeks in a 30-patient Phase 2a study of drug‑resistant focal onset seizures, with a 71.0% median reduction in RNS-recorded long episodes and 24% achieving seizure freedom during the treatment window. The trial met its primary endpoint versus baseline, was generally well tolerated, and had a 10% discontinuation rate. Post‑hoc analyses showed early onset of effect (week 1–4 median reductions matched or exceeded weeks 5–8) and similar response rates across baseline disease severities.
The new data, presented at the American Epilepsy Society meeting, add patient‑reported outcomes and target‑engagement evidence to the previously reported topline. Improvements on the Seizure Severity Response Questionnaire were observed at week 8 among patients with moderate or greater baseline impairment, reaching statistical significance for ability to think or concentrate, interference with daily activity, and overall intensity; the time‑to‑recovery signal was directionally favorable but underpowered. A PET receptor‑occupancy study confirmed TARPγ8 expression in cortical and mesial temporal regions and indicated therapeutic concentrations after two weeks of daily dosing. Rapport plans an end‑of‑Phase 2 FDA meeting this quarter and is targeting initiation of two pivotal Phase 3 trials using traditional clinical seizure endpoints in Q3 2026.
Strategically, the program blends a precision pharmacology story with pragmatic regulatory positioning. By anchoring Phase 2a in an RNS‑implanted cohort, Rapport leveraged objective long‑episode measures and dense neurophysiologic data to de‑risk signal detection in a small, open‑label study. The pivot to conventional seizure endpoints for Phase 3 aligns with FDA’s preference for diary‑based primary measures and should avoid overreliance on device‑specific biomarkers that could complicate generalizability. The TARPγ8‑selective AMPAR NAM mechanism is designed to concentrate activity in seizure‑relevant forebrain regions and spare hindbrain circuitry, a differentiation angle in a market where efficacy gains often come with neuropsychiatric tolerability trade‑offs.
For sites and CROs, the methodology shift matters. A Phase 3 program untethered from RNS expands the recruiting footprint beyond epilepsy surgery centers and reduces dependency on device data pipelines, but it increases operational risk around diary fidelity, baseline establishment, and background polytherapy management. The refractory population enrolled here was on a median of three concomitant ASMs, implying Phase 3 designs will need robust run‑in periods, centralized ePRO oversight, and careful control of permitted medication changes. Patient‑reported measures that reflect functional burden may gain weight as secondary endpoints if regulators continue to encourage incorporation of meaningful health aspects, but the small-n, post‑hoc nature of the current PRO signals will require replication. The PET occupancy results can inform dose selection and titration speed, potentially supporting an early‑effect narrative that could be relevant to adherence and payer value assessments.
The next inflection is FDA’s feedback on pivotal design: add‑on therapy in drug‑resistant FOS is the likely path, but comparator choice, responder definition hierarchy, and seizure‑freedom and durability analyses will determine sample size and cycle time. Placebo response remains a nontrivial risk in epilepsy, particularly with short treatment windows; sustained separation beyond 12–24 weeks and a clean neuropsychiatric profile versus established AMPAR antagonists will be scrutinized. Readouts from the open‑label extension in 2H 2026 will help on durability and safety. Parallel development of a long‑acting injectable formulation introduces CMC and bridging-study complexity but could become a commercial lever if adherence benefits are demonstrated. In a crowded adjunctive ASM market with powerful generic options, differentiation will have to rest on consistent efficacy across severities, tolerability, and tangible improvements in daily functioning.
Jon Napitupulu is Director of Media Relations at The Clinical Trial Vanguard. Jon, a computer data scientist, focuses on the latest clinical trial industry news and trends.
