XYRA doses first European patient in budiodarone AF trial
XYRA LLC has dosed the first European patient in HARBOR-AF (CLN-209), its Phase 2/3 open-label dose-escalation study of budiodarone in paroxysmal and persistent atrial fibrillation. The milestone was reached at the University of Rzeszów in Poland, where cardiologist Andrzej Przybylski is serving as principal investigator at the first activated site.
The study is enrolling approximately 600 patients with highly symptomatic AF who have already failed rhythm or rate control, either through antiarrhythmic drug therapy, catheter ablation, or both. Following a 28-day run-in period to establish baseline AF burden, participants enter a six-month treatment phase starting at budiodarone 200 mg twice daily. Treating physicians can escalate the dose in monthly increments of 200 mg twice daily up to 800 mg twice daily, guided by real-time rhythm data from implantable cardiac devices or wearable monitors such as patches and smartwatches.
The monitoring-guided titration approach
What makes HARBOR-AF methodologically distinctive is its formal integration of continuous AF monitoring into both eligibility assessment and dose adjustment. Responder status is defined by the absence of long episodes of AF (LEAF) exceeding five hours, and by keeping cumulative AF burden below five hours or 21% in any rolling 24-hour period. XYRA says the study will be the first to titrate an antiarrhythmic drug prospectively against these continuously measured endpoints.
Peter Milner, founder and managing member of XYRA, said that LEAF, whether discrete episodes of at least five hours or sustained daily AF burden at that level, is "probably long enough time in AF to form a clot in the left atrium," making its elimination a meaningful surrogate for stroke risk reduction. The company is positioning this as potentially the first clinical validation of smartwatch-derived cardiac data beyond simple irregular-rhythm notifications.
The EU phase is structured as a 100-subject Phase 2 feasibility study. XYRA plans to extend enrolment to US sites in 2027, at which point HARBOR-AF will serve as one of three Phase 3 pivotal registration studies the FDA requires as part of a regulatory pathway the agency has agreed with the company. A separate randomised, placebo-controlled study, CLN-210, is also being prepared for next year.
Market context and competitive landscape
Atrial fibrillation is the most common sustained arrhythmia in adults, with an estimated 50 million people affected globally. Rhythm-control pharmacotherapy is dominated by established agents including flecainide, propafenone, sotalol, and amiodarone, the last of which carries significant toxicity concerns owing to tissue accumulation. Budiodarone is described by XYRA as a mixed ion channel blocker with esterase metabolism and a substantially shorter half-life than amiodarone, with no evidence of tissue accumulation observed in human or animal studies to date. The company is positioning it as potentially first-in-class on this pharmacokinetic profile, though that claim awaits Phase 3 confirmation.
The monitoring-integrated dose-titration model XYRA is pursuing also places it at the intersection of digital health and pharmacotherapy, a space that regulators on both sides of the Atlantic have been actively engaging. The FDA's Digital Health Centre of Excellence has progressively broadened its guidance on software-as-a-medical-device in clinical trial design, which could smooth the regulatory path for a development programme that formally embeds wearable data into labelling strategy.
Charlie Rampersaud, who joined XYRA as chief operating officer ahead of the trial start, said his immediate focus is on building the operational infrastructure needed to support the CLN-210 randomised study in 2027. Investors and cardiologists will be watching the EU feasibility readout for dose-response signals and safety data before the programme scales to the larger US pivotal cohorts.