LOS ALTOS, Calif., Feb. 26, 2024 /PRNewswire/ -- XYRA LLC, a private biopharmaceutical company committed to developing innovative therapies for cardiac rhythm disorders with high unmet need, is pleased to announce today it has reached agreement with the FDA ('Agency') at a series of End of Phase 2 (EoP2) meetings, on the key studies that will form the basis of approval and labeling of orally administered budiodarone for the long-term management of symptomatic non-permanent atrial fibrillation (AF).  The evidence from outcomes studies suggests patients with symptomatic non-permanent AF, whether paroxysmal (PAF) or persistent, characterized by long episodes of atrial fibrillation (LEAF) lasting longer than 5.5 hours are at highest risk for stroke, heart failure and progression to permanent AF.

加利福尼亚州洛斯阿尔托斯，2024年2月26日/PRNewswire/--XYRA LLC是一家致力于开发针对未满足需求的心律失常的创新疗法的私营生物制药公司，今天很高兴地宣布，它已在一系列第二阶段结束（EoP2）会议上与FDA（“机构”）达成协议，这些关键研究将成为口服布地达隆长期治疗症状性非永久性心房颤动（AF）的批准和标记的基础。结果研究的证据表明，有症状的非永久性房颤患者，无论是阵发性房颤（PAF）还是持续性房颤，其特征是持续时间超过5.5小时的长时间房颤（LEAF）发作，中风，心力衰竭和进展为永久性房颤的风险最高。

The Agency agrees that reducing LEAF could reduce progression to permanent AF and reduce the risk of stroke.  To help identify and manage at risk individuals, the Agency has recently approved multiple wearable AF monitoring devices (e.g. patches and watches) that allow for continuous or semi-continuous monitoring of AF Burden and characterization of harmful LEAF typically over a two-week period..

该机构同意减少LEAF可以减少永久性房颤的进展并降低中风的风险。为了帮助识别和管理处于危险中的个体，该机构最近批准了多种可穿戴AF监测设备（例如贴片和手表），这些设备可以在两周内连续或半连续监测AF负担和有害叶片的特征。。

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Of the 7 million diagnosed patients with AF in the US approximately 50% suffer from paroxysmal or persistent AF (non-permanent AF), the most severe cases are characterized by worsening symptomatic LEAF prior to progressing to untreatable permanent AF.  The FDA and XYRA agree that the 2 key studies are required for approval.  The first is an open label, long term dose titration study of the 4 doses of budiodarone that were effective in Phase 2.

在美国700万确诊的房颤患者中，约有50%患有阵发性或持续性房颤（非永久性房颤），最严重的病例是在进展为无法治疗的永久性房颤之前症状恶化。FDA和XYRA同意这两项关键研究需要批准。第一个是对第二阶段有效的4剂布地达隆进行的开放标签长期剂量滴定研究。

Dosing will be guided and titrated upwards by concomitant use of an FDA approved wearable AF monitoring device to ascertain the safety and effectiveness of the therapy at each dose level in a Phase 3 trial.  In addition, this study will establish the lowest most effective dose for an individual that controls AF symptoms and eliminates LEAF of any length, and then to discontinue any subjects who are non-responders at the highest dose.  The second key study is a 6 month double blind randomized controlled trial of the 4 fixed active doses of budiodarone versus placebo in 500 subjects with symptomatic non-permanent AF and LEAF lasting longer than 5.5 hours.  The agreed endpoints for success are the control of symptoms and the proportion of subjects achieving a safe harbor for AF stroke risk reduction by elimination of LEAF >5 hours in the final 4 weeks as reported from validated wearable devices.  Both endpoints were achieved with statistical significance in Phase 2 studies.

通过同时使用FDA批准的可穿戴式AF监测设备来指导剂量并向上滴定，以确定在3期试验中每个剂量水平下治疗的安全性和有效性。此外，这项研究将为控制房颤症状并消除任何长度叶片的个体确定最低最有效剂量，然后停止任何最高剂量无反应的受试者。第二项关键研究是一项为期6个月的双盲随机对照试验，对500名症状性非永久性房颤和叶片持续时间超过5.5小时的受试者进行了4种固定活性剂量的布地达隆与安慰剂的比较。商定的成功终点是控制症状和受试者的比例，通过在最后4周内消除叶子>5小时来实现AF卒中风险降低的安全港，如验证的可穿戴设备所报告的。在第二阶段研究中，两个终点均具有统计学意义。

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The Agency agrees that there is no need to perform a large long term cardiovascular (CV) outcomes study, either before or after approval. This is a testament to the improved design features introduced into a widely used and well characterized class of drugs, absence of EKG changes at therapeutics doses heretofore used and the need for monitoring with a wearable device to establish a subject on the lowest most effective dose and to discontinue if ineffective.

该机构同意，无论是在批准之前还是之后，都不需要进行大规模的长期心血管（CV）结果研究。这证明了广泛使用且特征明确的一类药物引入了改进的设计特征，迄今为止使用的治疗剂量没有EKG变化，并且需要使用可穿戴设备进行监测，以确定最低最有效剂量的受试者，如果无效则停药。

In addition, if the drug continues to be safe and effective in the agreed AF pivotal studies above and a short-term study of ventricular tachycardia (VT) subjects with an implantable cardiac defibrillator (ICD), then approval may be possible within International Conference on Harmonization (ICH) guidance.

此外，如果该药物在上述商定的房颤关键研究和使用植入式心脏除颤器（ICD）对室性心动过速（VT）受试者进行的短期研究中仍然安全有效，那么在国际协调会议（ICH）指南中可能会获得批准。

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'Budiodarone is a potentially best-in-class mixed ion channel blocker with features that are designed to enhance safety and efficacy in the treatment of symptomatic non-permanent AF.  We wish to thank the Agency for a timely and successful series of EoP2 meetings at which we obtained clear, specific, and useful guidance on the pathway to approval.  Integrating FDA approved and validated wearable AF monitoring devices into the development will allow us to identify eligible subjects and ensure they are then established on the lowest effective approved dose.' said Peter Milner M.D., FACC, managing member XYRA.

“布地达隆是一种潜在的同类最佳混合离子通道阻滞剂，其功能旨在提高治疗症状性非永久性房颤的安全性和有效性。我们希望感谢该机构及时成功地召开了一系列EoP2会议，我们在会上获得了关于批准途径的明确，具体和有用的指导。将FDA批准和验证的可穿戴AF监测设备整合到开发中，将使我们能够识别符合条件的受试者，并确保他们以最低有效批准剂量建立。”管理成员XYRA的FACC医学博士彼得·米尔纳说。

'We look forward to collaborating with the Agency to demonstrate budiodarone is both safe and effective for the management of symptomatic non-permanent AF.  This is a sizable and growing population with an unmet need and includes subjects with persistent AF that can be cardioverted, and those with PAF at high risk because of LEAF that is refractory to other therapies'.About Budiodarone:  Budiodarone is a Phase 3 enabled potentially best-in-class mixed ion channel blocker with esterase metabolism and thus a significantly shorter half-life than amiodarone with no evidence of accumulation to date in human or animal studies, whilst having superior efficacy due to its enhanced late sodium channel blocking properties.  It has been shown to treat AF by controlling symptoms, eliminating LEAF, reducing AF burden, and maintaining normal sinus rhythm.About Atrial Fibrillation:Atrial Fibrillation (AF) is the most common sustained arrhythmia in adults, with approximately 44 million individuals estimated to have AF worldwide.

“我们期待着与该机构合作，证明布地达隆对症状性非永久性房颤的治疗既安全又有效。这是一个规模庞大且不断增长的需求未得到满足的人群，其中包括持续性房颤患者，可以进行心脏复律，以及那些PAF风险高的患者，因为LEAF对其他疗法无效”。关于布地达隆：布地达隆是一种具有酯酶代谢的3期潜在最佳混合离子通道阻滞剂，因此半衰期比胺碘酮短得多，迄今为止在人类或动物研究中没有积累的证据，同时由于其增强的晚期钠通道阻断特性而具有优异的功效。它已被证明可以通过控制症状，消除叶片，减轻房颤负担和维持正常窦性心律来治疗房颤。关于心房颤动：心房颤动（AF）是成人中最常见的持续性心律失常，据估计全世界约有4400万人患有房颤。

It is associated with thromboembolic risk, impairment in cardiac performance, and other morbidities. In addition to the patients with symptomatic AF, the dia.

它与血栓栓塞风险，心脏功能受损和其他疾病有关。除了有症状的房颤患者外，dia。