Program for Advanced Coronary Disease, Duke University Medical Center and Duke Clinical Research Institute, Durham, NC (T.J.P., E.M.O.).
The Carl and Edyth Lindner Center for Research and Education at The Christ Hospital, Cincinnati, OH (T.D.H.).
Circ Cardiovasc Interv. 2023 Aug;16(8):e012997. doi: 10.1161/CIRCINTERVENTIONS.123.012997. Epub 2023 Jul 28.
New therapies are needed for patients with refractory angina. Encoberminogene rezmadenovec (XC001), a novel adenoviral-5 vector coding for all 3 major isoforms of VEGF (vascular endothelial growth factor), demonstrated enhanced local angiogenesis in preclinical models; however, the maximal tolerated dose and safety of direct epicardial administration remain unknown.
In the phase 1 portion of this multicenter, open-label, single-arm, dose-escalation study, patients with refractory angina received increasing doses of encoberminogene rezmadenovec (1×10, 1×10, 4×10, and 1×10 viral particles) to evaluate its safety, tolerability, and preliminary efficacy. Patients had class II to IV angina on maximally tolerated medical therapy, demonstrable ischemia on stress testing, and were angina-limited on exercise treadmill testing. Patients underwent minithoracotomy with epicardial delivery of 15 0.1-mL injections of encoberminogene rezmadenovec. The primary outcome was safety via adverse event monitoring over 6 months. Efficacy assessments included difference from baseline to months 3, 6 (primary), and 12 in total exercise duration, myocardial perfusion deficit using positron emission tomography, angina class, angina frequency, and quality of life.
From June 2, 2020 to June 25, 2021, 12 patients were enrolled into 4 dosing cohorts with 1×10 viral particle as the highest planned dose. Seventeen serious adverse events were reported in 7 patients; none were related to study drug. Six serious adverse events in 4 patients were related to the thoracotomy, 3 non-serious adverse events were possibly related to study drug. The 2 lowest doses did not demonstrate improvements in total exercise duration, myocardial perfusion deficit, or angina frequency; however, there appeared to be improvements in all parameters with the 2 higher doses.
Epicardial delivery of encoberminogene rezmadenovec via minithoracotomy is feasible, and up to 1×10 viral particle appears well tolerated. A dose response was observed across 4 dosing cohorts in total exercise duration, myocardial perfusion deficit, and angina class. The highest dose (1×10 viral particle) was carried forward into phase 2.
URL: https://www.
gov; Unique identifier: NCT04125732.
需要新的疗法来治疗难治性心绞痛患者。新型腺病毒 5 载体编码的内皮生长因子（血管内皮生长因子）所有 3 种主要同工型的 Encoberminogene rezmadenovec（XC001）在临床前模型中显示出增强的局部血管生成；然而，直接心外膜给药的最大耐受剂量和安全性仍不清楚。
在这项多中心、开放性、单臂、剂量递增的 1 期研究的 1 期部分，难治性心绞痛患者接受递增剂量的 Encoberminogene rezmadenovec（1×10、1×10、4×10 和 1×10 病毒颗粒），以评估其安全性、耐受性和初步疗效。患者在最大耐受药物治疗下患有 II 至 IV 级心绞痛，在应激试验中显示有缺血迹象，在运动跑步机试验中因心绞痛而受限。患者接受微创开胸术，在心外膜部位给予 15 个 0.1 毫升 Encoberminogene rezmadenovec 注射。主要结局是通过 6 个月的不良事件监测来评估安全性。疗效评估包括与基线相比 3 个月、6 个月（主要）和 12 个月的总运动时间、正电子发射断层扫描心肌灌注缺陷、心绞痛分级、心绞痛发作频率和生活质量的差异。
从 2020 年 6 月 2 日至 2021 年 6 月 25 日，12 名患者被纳入 4 个剂量组，其中 1×10 病毒颗粒为最高计划剂量。7 名患者报告了 17 例严重不良事件；没有一个与研究药物有关。4 名患者的 6 例严重不良事件与开胸术有关，3 例非严重不良事件可能与研究药物有关。2 个最低剂量组的总运动时间、心肌灌注缺陷或心绞痛发作频率均未显示改善；然而，2 个较高剂量组的所有参数似乎都有改善。
微创开胸术经心外膜给予 Encoberminogene rezmadenovec 是可行的，高达 1×10 病毒颗粒的剂量似乎可以耐受。在 4 个剂量组中，总运动时间、心肌灌注缺陷和心绞痛分级均观察到剂量反应。最高剂量（1×10 病毒颗粒）被推进到 2 期。
网址：https://www.
gov；独特标识符：NCT04125732。
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