A new drug candidate has shown impressive results in a mid-stage clinical trial for drug-resistant epilepsy, raising hopes for patients who continue to suffer seizures despite being on multiple medications.
Rapport Therapeutics has announced that its experimental compound RAP-219 reduced seizures by an average of 77.8% in a Phase 2a study, with almost a quarter of participants remaining seizure-free over the two-month treatment period.
The trial enrolled 30 adults with focal onset seizures, also known as partial seizures – a common form of epilepsy marked by how electrical activity begins in one part of the brain. All participants were fitted with an implanted responsive neurostimulation (RNS) device, which continuously monitored brain activity and allowed researchers to measure clinical seizures and an objective electrographic marker called “long episodes.”
Patients began treatment on a low dose of RAP-219, increasing to a daily oral tablet of 1.25 mg for the rest of the eight-week study. By the trial's conclusion, 85% of patients had at least a 30% drop in long episodes, and 72% had their clinical seizures cut in half or more. Most strikingly, 24% of patients were free of seizures – something rarely seen in a treatment-resistant population.
“We are excited by the strength of these data in both the electrographic biomarker and clinical seizure reductions," said Jeffrey Sevigny, M.D., Chief Medical Officer at Rapport Therapeutics. "These results give us the confidence to progress RAP-219 into its next stage of clinical development."
What makes RAP-219 different is its precision mechanism. It targets TARPγ8, a protein that helps regulate AMPA receptors – key players in excitatory brain signaling. While AMPA receptors can be found throughout the brain, TARPγ8 is concentrated in the cortex and hippocampus – the regions focal seizures often stem from. By dampening activity only in these areas, RAP-219 is designed to dial down seizures without triggering any sedating/motor function side effects often associated with broader-acting drugs.
Reported side effects were mild to moderate, including dizziness, headache and fatigue. No serious safety issues emerged during the trial period, though three patients discontinued due to adverse events.
“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," Sevigny added. "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 now plans to meet with the US Food and Drug Administration (FDA) and then launch two crucial Phase 3 trials next year. The company will also continue developing a long-acting injectable version in order to address medication adherence, a frequent challenge in epilepsy.
“Despite the available therapies, up to 40% of patients with focal epilepsy continue to experience seizures," said the study's principal investigator Jacqueline French, M.D., a professor in the Department of Neurology at NYU Langone Health's Comprehensive Epilepsy Center. "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.
“This trial represents the first time a novel anti-seizure medication was evaluated in focal seizure patients using the RNS system with an objective biomarker of seizure activity," she added. "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."
Around a third of the 50 million people worldwide living with epilepsy do not have their condition under control using existing medication. Depending on the Phase 3 trials, more broadly assessing RAP-219’s efficacy and safety, this drug has the potential to be a much-needed advance in seizure management.
The latest data comes from the ongoing phase 2a RAP-219-FOS-201 trial (NCT06377930).
Source: Rapport Therapeutics
