DORAs Carry Lower Real-World Abuse, New Phase 3 Argus Data, RAP-219 Meets Primary End Point

Welcome to this special edition of Neurology News Network. I'm Marco Meglio.

A real-world study using data from the FDA Adverse Event Reporting System (FAERS) database revealed that among several different classes of medications for insomnia, dual orexin receptor agonists (DORA) had the lowest reported cases of abuse, misuse, overdose, and other safety risks. Overall, the case reports for abuse related features were far less than approved benzodiazepine (BZ) and z-drugs as well as the non-approved and unscheduled drug, tradozone. Presented at the World Sleep Congress (WSC), the rates of abuse, dependence, and withdrawal were highest for BZs approved for any indication (27.7%), followed by BZs approved for insomnia (23.0%), trazodone (22.7%), doxepin (22.3%), z-drugs (15.3%), ramelteon (8.0%), and DORAs (2.6%). The analysis included the 3 approved DORAs–suvorexant, Lemborexant, and daridorexant–which came into the market in 2014, 2019, and 2022, respectively.

Interim safety and tolerability results from the phase 3 Argus clinical trial (NCT04462770) showed that investigational EPX-100 (Harmony Biosciences) was safe and generally tolerated in patients with Dravet syndrome (DS), further supporting the agent’s development in this patient population. Presented at the 36th International Epilepsy Congress, held August 30-September 3, in Lisbon, Portugal, 100% of the 24-patient cohort who completed the 16-week double-blind, placebo-controlled phase entered the open-label extension (OLE). In total, 139 treatment-emergent adverse events (TEAEs) were recorded in 21 patients (87.5%), of which 28 (33.3%) were deemed related to EPX-100. Upper respiratory tract infection, found in 13.7% of treated patients, was the most common TEAE, followed by generalized tonic-clonic seizure (7.9%), pyrexia (7.2%), and change in seizure presentation (6.5%).

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).

For more direct access to expert insight, head to NeurologyLive.com. This has been Neurology News Network. Thanks for watching.