Rapport Therapeutics has announced findings on the correlation between a seizure biomarker and clinical seizure frequency, which is being used in the company's proof-of-concept trial for RAP-219. The data, presented at the American Epilepsy Society (AES) Annual Meeting, reveal a linear relationship between changes in long episode (LE) frequency and clinical seizure frequency, identifying a benchmark for predicting clinically meaningful seizure reduction.
Biomarker Validation
In a post-hoc analysis of data from NeuroPace's long-term study database, patients with refractory focal epilepsy who met the enrollment criteria for the ongoing RAP-219 proof-of-concept trial were selected. Long episodes (LEs), recorded via intracranial electroencephalography (iEEG) data captured by the RNS® System, serve as subclinical seizures and are considered an objective biomarker for assessing seizure efficacy. The biomarker analysis aimed to define the percent reduction in LE frequency that correlated with a clinically meaningful change in clinical seizure frequency (≥50% reduction).
Clinical Correlation
The data confirmed that a 30% reduction in LE frequency was the optimal cut point associated with a clinically meaningful (≥50%) reduction in clinical seizures, irrespective of the antiseizure medication initiated. These findings establish a new benchmark for evaluating the potential efficacy of RAP-219 and other anti-seizure medications, providing a consistent metric to help inform the development of future treatments.
RAP-219: A Novel Approach
RAP-219 is a clinical-stage AMPAR (α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor) negative allosteric modulator (NAM) designed to achieve neuroanatomical specificity through its selective targeting of a RAP known as TARPγ8, which is associated with the neuronal AMPAR. TARPγ8 is expressed only in discrete regions, including the hippocampus and cortex. Rapport believes RAP-219 has the potential to provide a differentiated clinical profile, including improved activity and tolerability along with a higher therapeutic index, potentially providing more patients with sustained therapeutic benefit without intolerable side effects, as compared to traditional neuroscience medications.
Additional Data
Additional data presented at the AES Annual Meeting included:
- Safety, Tolerability, and Pharmacokinetics of RAP-219 in Healthy Volunteers (Poster #372): RAP-219 was generally well tolerated at target therapeutic exposures, and the projected target receptor occupancy (RO) was achieved following multiple dosing.
- Impact of Food on the PK and Tolerability of RAP-219 in Healthy Volunteers (Poster #409): Food is not expected to have a clinically meaningful impact on RAP-219, allowing for dosing regardless of mealtime in Phase 2 trials.
- Antiseizure Effects with Selective TARPγ8 Negative Allosteric Modulators in Preclinical Seizure Models (Poster #390): RAP-219 provided potent, dose-dependent antiseizure effects in both preclinical seizure models tested, pentylenetretrazol (PTZ) and corneal kindling, with maximal protection observed with 70% RO and RAP-219 mean plasma concentration of 7 ng/mL.
Future Directions
"The long episode seizure biomarker provides a potentially transformative approach to evaluating the efficacy of anti-seizure medications," said Dr. Brad Galer, chief medical officer of Rapport Therapeutics. "These new data reveal a clear, linear relationship between long episode and clinical seizure frequencies. We look forward to advancing our research of RAP-219 using this novel biomarker in our proof-of-concept trial, enabling a more precise and expedited development path to hopefully deliver a new potential antiseizure medication for refractory focal epilepsy patients."
The topline data from Rapport’s ongoing Phase 2a proof-of-concept trial in focal epilepsy is expected in mid-2025.
