XYRA Doses First European Patient in Phase 2/3 HARBOR-AF Study of Budiodarone for Atrial Fibrillation
核心洞察
XYRA LLC (搜索) announced that the first patient in Poland has been dosed with budiodarone in the Phase 2/3 HARBOR-AF study of paroxysmal and persistent atrial fibrillation (搜索).
The open-label, dose-escalation trial is the first to titrate an antiarrhythmic drug against continuously monitored AF burden and long episodes of AF reported in real time.
HARBOR-AF begins as a 100-subject Phase 2 feasibility study in the EU and will extend to US sites in 2027 as one of three FDA-required Phase 3 pivotal registration studies.
XYRA LLC (搜索), a private biopharmaceutical company developing therapies for cardiac rhythm disorders, announced that the first patient in Poland has been dosed with budiodarone in HARBOR-AF (CLN-209), its Phase 2/3 open-label, dose-escalation study in subjects with paroxysmal and persistent atrial fibrillation (搜索) (AF). The milestone marks the first European patient dosed in a program that the company describes as the first to titrate an antiarrhythmic drug against continuously monitored AF burden (AFB) and long episodes of AF (LEAF) reported in real time from a range of wearable and implanted devices.
Study Design and Dosing Strategy
HARBOR-AF is a global, multicenter, open-label, dose-escalation Phase 2/3 study of budiodarone in approximately 600 subjects with highly symptomatic paroxysmal and persistent AF who have failed rhythm control with antiarrhythmic drugs or AF catheter ablation, or who have failed rate control. The study's objective is to determine, in a real-world setting, the effectiveness of dose-adjusted budiodarone therapy — guided by currently available AF monitoring tools — in eliminating harmful LEAF greater than 5 hours over 6 months and in reducing AF burden and symptoms. The trial is also intended to help define the doses to be used in a future potential randomized, placebo-controlled registration study.
Following a 28-day run-in period to confirm eligibility based on AF burden, multiple LEAF, and AF symptoms, subjects enter a 6-month treatment period starting with budiodarone 200 mg twice daily. Treating physicians may escalate the dose monthly in 200 mg twice-daily increments, up to 800 mg twice daily, according to predefined responder criteria. Responder status is defined by the absence of LEAF greater than 5 hours and by maintaining cumulative AF burden below 5 hours or 21% in any rolling 24-hour period. The study is designed to identify, for each subject, the lowest effective dose of budiodarone that controls AF symptoms and suppresses prolonged AF episodes associated with increased risk of stroke (搜索), heart failure (搜索), and progression to permanent AF.
HARBOR-AF is starting as a 100-subject Phase 2 feasibility study in the European Union and is planned to extend to the United States in 2027 as one of three Phase 3 pivotal registration studies the FDA requires for approval. Further details of the study design, eligibility criteria, and monitoring methods are available in the HARBOR-AF listing on clinicaltrials.gov (NCT07792239).
Monitoring-Guided Titration
The study uniquely integrates AF monitoring into both subject eligibility assessment and treatment response, using the resulting rhythm data to guide budiodarone dose titration. XYRA is using a range of implantable and wearable AF monitoring technologies available to cardiologists. Where present, AF data are collected from pre-implanted cardiac implantable electronic devices (CIEDs), including pacemakers and implantable loop recorders; when CIED data are not available, subjects are monitored using wearable devices. Rhythm data from either source are relayed to the treating physician and used to quantify AF burden and the number and duration of LEAF episodes monthly or quarterly. At each monthly visit, physicians review AF burden, LEAF, and Responder Status data to make individualized dose-titration decisions.
"Evidence from large epidemiological studies indicates that stroke (搜索) risk is influenced not only by the overall burden of atrial fibrillation (搜索) but also by its pattern, particularly, prolonged episodes or clusters of episodes which we refer to as long episodes of AF, or LEAF," said Peter Milner, M.D., FACC, founder and managing member of XYRA. "These are either discrete episodes of at least five hours or periods of daily AF burden exceeding five hours both readily identified in an individual with AF using modern digital technologies and AI tools, and probably long enough time in AF to form a clot in the left atrium."
Milner added that the study plans to identify patients who experience frequent LEAF using reliable, FDA-approved AF-monitoring technologies, including existing pacemakers and low-cost, convenient wearable devices such as patches and wristbands. "Once each patient's AF burden, risk profile, and symptoms have been established at baseline, we plan to administer budiodarone using a dose-escalation strategy to identify the appropriate dose for that individual over six months," he said. "Treatment will be guided by the AF-monitoring systems, with the aim of eliminating LEAF, thereby establishing a safe harbor, while reducing monthly AF burden and associated symptoms. We believe this study could establish a precedent of the first use of cardiac rhythm data collected from smart watches, beyond simply using them for irregular rhythm notifications."
Investigator Perspective
Professor Andrzej Przybylski, M.D., Head of Cardiology at the University of Rzeszów, Poland, and principal investigator at the first activated site, said the trial represents the first antiarrhythmic drug to be individually dose adjusted to maximize efficacy and safety using the wide range of AF monitoring tools currently available in practice. "We believe that the combination of an investigational antiarrhythmic drug and AF monitoring tools may be a relatively low-cost solution to improve AF rhythm control and improve patient outcomes," he said.
Professor A. John Camm, M.D., Emeritus Professor of Clinical Cardiology at City St George's, University of London, and a long-standing advisor to the budiodarone program, described the approach as innovative. "The use of sophisticated continuous or near-continuous heart rhythm monitoring to assess AF-related stroke (搜索) risk and guide individualized dose adjustment represents an exciting and innovative approach to evaluating the efficacy of budiodarone, a drug already well known to shorten or suppress episodes of atrial fibrillation (搜索)," Camm said.
Regulatory Pathway and Next Steps
Budiodarone is being developed under a regulatory pathway agreed with the FDA that incorporates wearable AF monitoring into the clinical development program and proposed labeling strategy. Charlie Rampersaud, XYRA's Chief Operating Officer, said his immediate focus is on building the operational framework required to support next year's randomized, placebo-controlled CLN-210 study.
Drug Profile and Disease Burden
Budiodarone is currently in Phase 2/3 clinical development and is described as a potentially first-in-class mixed ion channel blocker with esterase metabolism, with a significantly shorter half-life than amiodarone and no evidence of tissue accumulation in human or animal studies. In clinical studies to date, budiodarone has demonstrated reductions in AF burden and prolonged AF episodes, improvements in AF symptoms, and maintenance of sinus rhythm.
Atrial fibrillation (搜索) is the most common sustained arrhythmia in adults, affecting more than 50 million people worldwide. It is associated with an increased risk of thromboembolism, impaired cardiac function, and other morbidities. While many patients experience symptomatic AF, the condition may also first be identified following a stroke (搜索), the development of left ventricular dysfunction, or incidentally. As evidence supporting improved outcomes with rhythm-control strategies has accumulated, management has evolved so that, in appropriately selected patients, treatment increasingly aims to restore and maintain sinus rhythm rather than relying solely on ventricular rate control. Rhythm-control options include antiarrhythmic drugs, catheter ablation, or a combination of the two.
XYRA's stated mission is to make AF management comparable to that of other common cardiac conditions such as hypertension and hypercholesterolemia, in which upward dose titration of effective drugs, guided by simple, widely available monitoring tools to confirm compliance and response to therapy, has consistently improved outcomes.