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

Advertisement Commentary|Videos|September 13, 2025 DORAs Carry Lower Real-World Abuse, New Phase 3 Argus Data, RAP-219 Meets Primary End Point Author(s)NeurologyLive® Staff Neurology News Network. for the week ending September 13, 2025. [WATCH TIME: 4 minutes] Advertisement WATCH TIME: 4 minutesWelcome 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. NewsletterKeep your finger on the pulse of neurology—subscribe to NeurologyLive for expert interviews, new data, and breakthrough treatment updates.Subscribe Now! 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[WATCH TIME: 4 minutes] Advertisement WATCH TIME: 4 minutesWelcome 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. NewsletterKeep your finger on the pulse of neurology—subscribe to NeurologyLive for expert interviews, new data, and breakthrough treatment updates.Subscribe Now! 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Hersh, DO, MSc, FAAN; Anna Shah, MDView moreMultimediaBurst CME™: Optimizing Migraine Management – Addressing Unmet Needs, Individualizing Care for Diverse Populations, and Utilizing CGRP Targeted AgentsJessica Ailani, MD, FAHS, FAAN; Paul G. Mathew, MD, DNBPAS, FAAN, FAHSView moreMultimediaBurst CME™: Setting the Stage – Individualizing Migraine Care for Diverse Populations Across Care SettingsJessica Ailani, MD, FAHS, FAAN; Paul G. Mathew, MD, DNBPAS, FAAN, FAHSView moreMultimediaCommunity Practice Connections™: Optimizing the Management of Tardive Dyskinesia—Addressing the Complexity of Care With Targeted TreatmentIlan Melnick, MD; Alejandro Alva, MD; Linda Trinh, DNP, PMHNP, FNP, MPHView moreMultimediaBurst CME™: Optimizing the Use of CGRP Targeted Agents for the Treatment of MigraineJessica Ailani, MD, FAHS, FAAN; Paul G. 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Schwaede, MD; Emmanuelle (Noelle) Tiongson, MDView moreVideoA New Era in NMOSD Treatment: Optimizing Therapeutic Transitions and Reducing Patient BurdenShamik Bhattacharyya, MD, MS, FAAN; Mirla Avila, MD; Dean Wingerchuk, MDView moreAudioPER Podcast™: Maximizing the Multidisciplinary Care Outcomes of Patients with Amyotrophic Lateral Sclerosis (ALS)Richard Bedlack, MD, PhDView moreAudioPER Podcast™: Best Strategies for Approaching the Diagnosis of Amyotrophic Lateral Sclerosis (ALS)Terry Heiman-Patterson, MDView moreVideoPER Postgame™: Updates from ANNA in the Management of IgA NephropathyGerald Bernard Appel, MD; Ellie Kelepouris, MD, FACP, FAHAView moreVideoPatient, Provider, and Caregiver Connection: Turning a New Leaf in Acute Pain Management – How Recent Advancements Impact the Treatment ParadigmJeffrey Gudin, MD; Jeffrey Bettinger, PharmDView morePrevious slideNext slide Advertisement Advertisement Trending on NeurologyLive1Expanding the Alzheimer Drug Development Pipeline 2FDA Hands Complete Response Letter to SL1009 for Pyruvate Dehydrogenase Complex Deficiency3Patient-Reported Study Identifies Common Symptoms and Timing During Migraine Prodrome 4DORAs Carry Lower Real-World Abuse, New Phase 3 Argus Data, RAP-219 Meets Primary End Point5NeurologyLive® Friday 5 — September 12, 2025