美国加州大学戴维斯医学中心George R Thompson III团队比较了rezafungin与卡泊芬净治疗念珠菌血症和侵袭性念珠菌病的疗效。2022年11月25日出版的《柳叶刀》杂志发表了这项成果。

Rezafungin是一种每周一次的新一代棘白菌素类药物，用于治疗念珠菌血症和侵袭性念珠菌病，以及预防血液和骨髓移植后由念珠菌、曲霉和肺孢子虫引起的侵袭性真菌病。该研究旨在比较静脉注射rezafungin和静脉注射卡泊芬净对念珠菌血症和侵袭性念珠菌病患者的疗效和安全性。

研究组在15个国家的66个三级护理中心进行了一项多中心、双盲、双模拟、随机3期临床试验。招募有全身症状和真菌学证实为念珠菌血症或侵袭性念珠菌病的成年患者（≥18岁），并随机分配（1:1）每周静脉注射rezafungin一次（第1周400 mg，随后每周200 mg，共2至4次）或静脉注射卡泊芬净（第1天70 mg负荷剂量，随后每天50 mg）均不超过4周。

主要终点是欧洲医疗机构（EMA）第14天的全球治愈率（包括临床治愈、放射治疗和真菌根除）和美国食品和药物管理局（FDA）的30天全因死亡率，两者的目标非劣效性边缘均为20%，在改良意向治疗人群中进行评估（所有接受一剂或多剂研究药物且根据随机分组前96小时内获得的血液培养物或其他正常无菌部位记录念珠菌感染的患者）。通过安全人群中不良事件和死亡的发生率和类型来评估安全性，安全人群定义为接受任何数量研究药物的所有患者。

2018年10月12日至2021年8月29日，共222名患者接受了纳入筛查，199名患者（男性118人，占59%；女性81人，占41%；平均年龄61岁）被随机分配，其中rezafungin组100人，卡泊芬净组99人。Rezafungin组93名患者中有55名（59%）在第14天完全治愈，卡泊芬净组94名患者中有57名（61%）（EMA主要终点）。

Rezafungin组93名患者中有22名（24%）在第30天死亡或生存状态未知，卡泊芬净组94名患者中有20名（21%）（治疗差异为2.4%；FDA主要终点）。在安全性分析中，rezafungin组98名患者中有89名（91%）发生了至少一次治疗紧急不良事件，卡泊芬净组98例患者中有83名（85%）。两组中至少5%患者发生的最常见治疗紧急不良事件是发热、低钾血症、肺炎、感染性休克和贫血。Rezafungin组中有55名（56%）患者出现严重不良事件，卡泊芬净组有52名（53%）患者。

研究数据表明，在14天全球治愈率（EMA）和30天全因死亡率（FDA）的主要终点方面，rezafungin不逊于卡泊芬净。治疗初期的疗效值得评估。治疗紧急或严重不良事件没有相关趋势。这些临床3期结果显示了rezafungin的有效性和安全性，并支持其持续研发。

附：英文原文

Title: Rezafungin versus caspofungin for treatment of candidaemia and invasive candidiasis (ReSTORE): a multicentre, double-blind, double-dummy, randomised phase 3 trial

Author: George R Thompson, Alex Soriano, Oliver A Cornely, Bart Jan Kullberg, Marin Kollef, Jose Vazquez, Patrick M Honore, Matteo Bassetti, John Pullman, Methee Chayakulkeeree, Ivan Poromanski, Cecilia Dignani, Anita F Das, Taylor Sandison, Peter G Pappas, Murat Akova, Rawan AlAgha, George Alangaden, Svenja J Albrecht, Barbara Alexander, Mohanad Al-Obaidi, German Ambasch, Fernando Armestar Rodriguez, Alpay Azap, Anthony Baffoe-Bonnie, Leila Belkhir, Ronen Ben-Ami, David Boutoille, Antonio Cascio, Louis YA Chai, Romanee Chaiwarith, Methee Chayakulkeeree, Sharon Chen, Yee-Chun Chen, Yen-Hsu Chen, Jun Yong Choi, Young Hwa Choi, Darunee Chotiprasitsakul, Jin Won Chung, Franois Danion, Blandine Denis, Emilio Diaz Santos, Miguel O Dictar, Marc Diltoer, Herve Dupont, Sizhou Feng, Maria Angeles Ferre Colomer, Ricard Ferrer, Jean-Marie Fernand Roger Forel, Jesús Fortún-Abete, Julia Garcia-Diaz, Massimo Girardis, Fang He, Maya Hites, Mao-Wang Ho, Patrick Honore, Juan Pablo Horcajada Gallego, Haihui Huang, Po-Yen Huang, Yong Huang, Osamah Hussein, Poj Intalapaporn, Sutep Jaruratanasirikul, Luis Jauregui-Peredo, Misty Johnson, Dong Sik Jung, Kamonwan Jutivorakool, Winfried V Kern, Daniel H Kett, Thana Khawcharoenporn, Young Keun Kim, Philipp Koehler, Anastasia Kotanidou, Anne Lachiewicz, Qinhan Lin, Luis Eduardo Lopez Cortes, Hong Luo, Roberto Luzzati, Yasmin Maor, Todd McCarty, Maria Merelli, Paloma Merino Amador, John Midturi, Guglielmo Marco Migliorino, Jean-Paul Mira, Piroon Mootsikapun, Orla Morrissey, Patricia Munoz Garcia de Paredes, Cristina Mussini, Eleftherios Mylonakis, Saadalla Nseir, William Nseir, Zekaver Odabasi, Vasileios Papastamopoulos, David Paterson, Thomas F Patterson, Kyong Ran Peck, Zhiyong Peng, Nitipong Permpalung, Gaetan J Plantefeve, Ivan G Poromanski, Debra Powell, Mina Psichogiou, Ser Hon Puah, John Pullman, Galia Rahav, Antonio Ramos Martinez, Juan Carlos Ramos Ramos, Ayelet Raz-Pasteur, Carlos A Restrepo Castro, Fernando Riera, France Roblot, Regino Jose Rodriguez Alvarez, Benjamin Rogers, Emmanuel Roilides, Gregorio Sanchez Vallejo, Gabriele Sganga, Nikolaos Sipsas, Monica Slavin, Alex Soriano, Andrej Spec, Jacob Strahilevitz, Dora M Tancheva, Zhen Tao, Daniel Teschner, George R Thompson, Eric Van Wijngaerden, Jose Vazquez, Paschalis Vergidis, Pierluigi Viale, Fu-Der Wang, Shifu Wang

Issue&Volume: 2022-11-25

Abstract:

Background

Rezafungin is a next-generation, once-a-week echinocandin in development for the treatment of candidaemia and invasive candidiasis and for the prevention of invasive fungal disease caused by Candida, Aspergillus, and Pneumocystis spp after blood and marrow transplantation. We aimed to compare the efficacy and safety of intravenous rezafungin versus intravenous caspofungin in patients with candidaemia and invasive candidiasis.

Methods

ReSTORE was a multicentre, double-blind, double-dummy, randomised phase 3 trial done at 66 tertiary care centres in 15 countries. Adults (≥18 years) with systemic signs and mycological confirmation of candidaemia or invasive candidiasis were eligible for inclusion and randomly assigned (1:1) to receive intravenous rezafungin once a week (400 mg in week 1, followed by 200 mg weekly, for a total of two to four doses) or intravenous caspofungin (70 mg loading dose on day 1, followed by 50 mg daily) for no more than 4 weeks. The primary endpoints were global cure (consisting of clinical cure, radiological cure, and mycological eradication) at day 14 for the European Medical Agency (EMA) and 30-day all-cause mortality for the US Food and Drug Administration (FDA), both with a target non-inferiority margin of 20%, assessed in the modified intention-to-treat population (all patients who received one or more doses of study drug and had documented Candida infection based on a culture from blood or another normally sterile site obtained within 96 h before randomisation). Safety was evaluated by the incidence and type of adverse events and deaths in the safety population, defined as all patients who received any amount of study drug. The trial is registered with ClinicalTrials.gov, NCT03667690, and is complete.

Findings

Between Oct 12, 2018, and Aug 29, 2021, 222 patients were screened for inclusion, and 199 patients (118 [59%] men; 81 [41%] women; mean age 61 years [SD 15·2]) were randomly assigned (100 [50%] patients to the rezafungin group and 99 [50%] patients to the caspofungin group). 55 (59%) of 93 patients in the rezafungin group and 57 (61%) of 94 patients in the caspofungin group had a global cure at day 14 (weighted treatment difference 1·1% [95% CI 14·9 to 12·7]; EMA primary endpoint). 22 (24%) of 93 patients in the rezafungin group and 20 (21%) of 94 patients in the caspofungin group died or had an unknown survival status at day 30 (treatment difference 2·4% [95% CI 9·7 to 14·4]; FDA primary endpoint). In the safety analysis, 89 (91%) of 98 patients in the rezafungin group and 83 (85%) of 98 patients in the caspofungin group had at least one treatment-emergent adverse event. The most common treatment-emergent adverse events that occurred in at least 5% of patients in either group were pyrexia, hypokalaemia, pneumonia, septic shock, and anaemia. 55 (56%) patients in the rezafungin group and 52 (53%) patients in the caspofungin group had serious adverse events.

Interpretation

Our data show that rezafungin was non-inferior to caspofungin for the primary endpoints of day-14 global cure (EMA) and 30-day all-cause mortality (FDA). Efficacy in the initial days of treatment warrants evaluation. There were no concerning trends in treatment-emergent or serious adverse events. These phase 3 results show the efficacy and safety of rezafungin and support its ongoing development.

DOI: 10.1016/S0140-6736(22)02324-8

Source: https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(22)02324-8/fulltext