RAP-219 Meets Primary End Point in Phase 2a Trial for Focal-Onset Seizures

Jacqueline French, MD

(Credit: NYU Langone Health)

New data from Rapport Therapeutics’ ongoing phase 2a RAP-219-FOS-201 trial (NCT06377930) revealed that RAP-219, an investigational TARPγ8-specific AMPAR negative allosteric modulator, met its primary end point in reducing long episodes (LE) among patients with drug-resistant focal onset seizures over an 8-week period.¹ The company plans to have an end-of-phase 2 meeting with the FDA in the fourth quarter of 2025 and expects to initiate 2 phase 3 pivotal trials of RAP-219 in the third quarter of 2026.

Among 30 patients with focal onset seizures in the phase 2a trial, the data showed that the agent achieved statistically significant results for primary LE end points and key secondary end points of clinical seizures compared with baseline. During the 8-week treatment period, the company reported that 85.2% of patients achieved at least a 30% reduction in LEs from baseline (P <.0001), 72.0% achieved at least a 50% reduction in clinical seizures from baseline (P <.0001), and 24% of patients achieved seizure freedom (P <.0001).

“Despite the available therapies, up to 40% of patients with focal epilepsy continue to experience seizures. There is still tremendous need for additional effective anti-seizure medications with novel mechanisms of action. Physicians and patients need new options that deliver meaningful benefits and the potential to offer the promise of seizure freedom,” principal investigator Jacqueline French, MD, professor in the Department of Neurology at NYU Langone Health's Comprehensive Epilepsy Center, said in a statetment.¹ “This trial represents the first time a novel antiseizure medication was evaluated in focal seizure patients using the RNS system with an objective biomarker of seizure activity. The magnitude of the reduction in clinical seizure frequency seen in this trial, and the corroboration of the clinical activity from the objective biomarker, give me confidence that a medication like RAP-219 has the potential to be a highly effective ASM for drug-resistant focal seizure patients."

The phase 2a trial is a proof-of-concept, multicenter, open-label study aimed to assess the efficacy, safety, and tolerability of RAP-219 in adults with focal onset seizures who had an implanted responsive neurostimulation system. Participants received 0.75-mg RAP-219 oral tablet daily for 5 days, followed by 1.25-mg RAP-219 oral tablet daily for the remainder of the treatment period. The trial’s primary efficacy end point was the change in frequency of RNS-recorded LEs in patients with focal onset seizures explored both as the proportion of responders achieving at least a 30% reduction in LEs from baseline and median percent change from baseline in LE frequency. The secondary end points of the study included clinical seizure frequency reductions, safety, and tolerability.

In terms of demographics and baseline characteristics, participants enrolled in the phase 2a trial were consistent with that of patients expected in future clinical trials. The study enrolled 12 women and 18 men, with a mean age of 40.1 years and time of their first seizure being 16.6 years. Enrolled patients had a median of 3 concomitant antiseizure medications, with the highest proportion of them on lamotrigine (50%), levetiracetam (40%), and cenobamate (37%).

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“The efficacy data and tolerability profile seen in the Phase 2a trial demonstrate RAP-219’s potential to be an important treatment for patients with drug-resistant focal onset seizures. What’s particularly encouraging is the consistency of the significant improvements seen in the long episode biomarker responses and the clinical seizure reductions,” Abe Ceesay, chief executive officer at Rapport, said in a statement.¹ “With these data and RAP-219’s emerging best-in-class profile, if approved, we believe RAP-219 could address a significant unmet need among patients, with the potential to support broad adoption among epileptologists and neurologists treating patients living with drug-resistant focal seizures.”

The company noted that RAP-219 was generally well-tolerated in the study, with the majority of treatment-emergent adverse events (TEAEs) reported as being mild and a low discontinuation rate. During the treatment period, researchers observed no serious AEs and all treatment-emergent AEs reported were mild (78.5%) or moderate (21.5%) in severity. Notably, 3 patients (10%) discontinued treatment because of TEAEs. The most common treatment-emergent AEs reported by participants included dizziness (26.7%), headache (16.7%), fatigue (13.3%), fall (10.0%), nausea (10.0%), and somnolence (10.0%).

“We are excited by the strength of these data in both the electrographic biomarker and clinical seizure reductions. These results give us the confidence to progress RAP-219 into its next stage of clinical development,” Jeffrey Sevigny, MD, chief medical officer at Rapport, said in a statetment.¹ “Importantly, the baseline characteristics of patients enrolled, together with the broad cortical expression of TARPγ8 and the robust results in the trial, give us confidence in the translatability of the data into the Phase 3 drug-resistant focal onset seizure patient population. Given the persistent unmet need in focal epilepsy, we plan to move into two Phase 3 trials using traditional clinical seizure endpoints, with initiation expected in the third quarter of 2026.”

Rapport plans to also initiate an open-label long term safety trial to allow patients enrolled into the phase 2a trial of RAP-219 to continue treatment with the agent by the end of 2025, with preliminary results anticipated in the second half of 2026. Furthermore, the company noted that a long-acting injectable (LAI) formulation of RAP-219 is in continued development to potentially improve patient adherence and expand the clinical utility of the therapy.

Data reported in January 2025 from the phase 1 PET and MAD-2 trials of RAP-219 showed that treatment with RAP-219 for focal epilepsy was generally well tolerated, with target exposures and receptor occupancy (RO) achieved in 5 days of dosing. The PET trial (RAP-219-103) and MAD-2 trial (RAP-219-104) were complementary studies in healthy volunteers investigating RAP-219.²

REFERENCES
1. Rapport Announces Positive Topline Results from Phase 2a Clinical Trial of RAP-219 in Patients with Focal Onset Seizures. News Release. Rapport Therapeutics. September 8, 2025. Accessed September 8, 2025. https://investors.rapportrx.com/news-releases/news-release-details/rapport-announces-positive-topline-results-phase-2a-clinical
2. Rapport Therapeutics Announces New Phase 1 Data, Further Supporting RAP-219's Transformative Potential for CNS Disorders. News Release. Rapport Therapeutics. Published January 9, 2025. Accessed September 8 2025. https://investors.rapportrx.com/news-releases/news-release-details/rapport-therapeutics-announces-new-phase-1-data-further