Among adults with focal onset seizures in Xenon’s ongoing X-TOLE open-label extension, monthly median percent reduction in seizure frequency deepened from 69.8% in the first OLE month to 90.9% at month 48 (n=131). At month 48, participants who entered the double-blind period on 1–2 concomitant anti-seizure medicines showed a 100% median monthly reduction versus 81.8% for those on three ASMs. Sustained seizure freedom was common over long horizons: 38.2% achieved at least 12 consecutive months without seizures, 25.2% achieved 24 months, 19.8% achieved 36 months, and 10.7% achieved 48 months. Safety and tolerability appeared consistent with the double-blind phase. In a separate OLE analysis, most patients who experienced a breakthrough event after at least six months of seizure freedom subsequently regained extended seizure-free intervals with continued treatment; 69.7% regained at least six months and 57.6% regained at least 12 months, with a mean regained duration of 18.9 months (n=33).
The core news is a multi-pronged data package at AES 2025: long-term azetukalner outcomes from X-TOLE’s OLE, real-world analyses quantifying depression burden and the operational drag of ASM titration in epilepsy, and preclinical data for a NaV1.1 potentiator in Dravet models showing seizure suppression and prevention of SUDEP in mice alongside motor and synaptic readouts. With Phase 3 X-TOLE2 in focal onset seizures approaching a readout in early 2026, Xenon is setting clinical and operational context around durability, patient-reported burden, and care complexity.
Strategically, the durability and “regained seizure freedom” framing aim to extend the conversation beyond single-epoch endpoints toward longitudinal control that resonates with clinicians and payers. The subgroup signal by ASM background suggests the company will lean into broad add-on positioning while exploring where concomitant complexity blunts effect size. The real-world depression and titration studies are market conditioning: they underline unmet needs that a well-tolerated, operationally simple therapy could address, and they pre-stage arguments around quality of life, healthcare utilization, and clinic workload. The tension is that the most impressive figures come from an open-label population subject to survivor and adherence bias; translation into a randomized Phase 3 with contemporary background therapy remains the decisive hurdle.
For sites, the data reinforce two practical shifts. First, routine depression screening and management need to be embedded in workflows to reduce discontinuations and improve outcomes, which has implications for staffing, PRO capture, and referral pathways. Second, the spotlight on titration complexity validates site complaints about visit cadence, phone follow-up, and dose-management burden; any therapy with fewer adjustments could lower operational load and dropout risk. For sponsors and CROs, the seizure-free epoch analysis invites alternative endpoint architectures that track repeated intervals of control rather than a single binary milestone, along with longer retention windows. Regulators are increasingly receptive to durability narratives and patient-centered endpoints, but will require robust randomized evidence. Payers will scrutinize whether sustained control correlates with reduced ER visits, hospitalizations, and psychiatric comorbidity costs.
Next, attention shifts to X-TOLE2: effect size versus placebo, consistency across concomitant ASM strata, cognitive and mood safety, and discontinuation rates will determine the credibility of the OLE durability story. If signals hold, expect discussions on label scope, initiation and titration requirements, and potential for streamlined monitoring that could materially affect site burden. Outside focal epilepsy, the NaV1.1 program points to a Dravet path that will demand pediatric center networks, genetic confirmation, and careful endpoint selection; preclinical SUDEP findings are hypothesis-generating, not registrational. Risks that remain unresolved include drug–drug interaction profile, long-term tolerability under polytherapy, and the ability to sustain adherence in real-world settings. Watch for Phase 3 protocol specifics, depression-related PRO integration, and whether Xenon backs its durability thesis with health economics data to support access arguments.
Jon Napitupulu is Director of Media Relations at The Clinical Trial Vanguard. Jon, a computer data scientist, focuses on the latest clinical trial industry news and trends.
