Department of Medicine, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, CA, USA.
Department of Medicine, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, CA, USA; Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, TX, USA.
EBioMedicine. 2024 Apr;102:105042. doi: 10.1016/j.ebiom.2024.105042. Epub 2024 Mar 11.
An ongoing important need exists to rapidly develop novel therapeutics for COVID-19 that will retain antiviral efficacy in the setting of rapidly evolving SARS-CoV-2 variants and potential future development of resistance of SARS-COV-2 to remdesivir and protease inhibitors. To date, there is no FDA-approved treatment for post-exposure prophylaxis against SAR-CoV-2. We have shown that the mitochondrial antioxidant mitoquinone/mitoquinol mesylate (Mito-MES), a dietary supplement, has antiviral activity against SARS-CoV-2 in vitro and in SARS-CoV-2 infected K18-hACE2 mice.
In this exploratory, pragmatic open label clinical trial (ClinicalTrials.gov identifier NCT05381454), we studied whether Mito-MES is an effective post-exposure prophylaxis treatment in people who had high-grade unmasked exposures to SARS-CoV-2 within 5 days prior to study entry. Participants were enrolled in real-world setting in Los Angeles, United States between May 1 and December 1, 2022 and were assigned to either mito-MES 20 mg daily for 14 days (n = 40) or no mito-MES (controls) (n = 40). The primary endpoint was development of SARS-CoV-2 infection based on 4 COVID-19 diagnostic tests [rapid antigen tests (RATs) or PCR] performed during the study period (14 days post exposure).
Out of 40 (23 females; 57.5%) study participants who took Mito-MES, 12 (30%) developed SARS-CoV-2 infection compared to 30 of the 40 controls (75%) (difference -45.0%, 95% confidence intervals (CI): -64.5%, -25.5%). Out of 40 (19 females; 47.5%) study participants in the control group, 30 (75.0%) had at least one positive COVID-19 diagnostic test and 23 (57.5%) were symptomatic. With regards to key secondary outcomes, among symptomatic SARS-CoV-2 infections, the median duration of viral symptoms was lower in the Mito-MES group (median 3.0, 95% CI 2.75, 3.25) compared to the control group (median 5.0, 95% CI 4.0, 7.0). None of the study participants was hospitalized or required oxygen therapy. Mito-MES was well tolerated and no serious side effect was reported in any study participant.
This work describes antiviral activity of mito-MES in humans. Mito-MES was well tolerated in our study population and attenuated transmission of SARS-CoV-2 infection. Given established safety of Mito-MES in humans, our results suggest that randomized control clinical trials of Mito-MES as post-exposure prophylaxis against SARS-CoV-2 infection are warranted.
This work was supported in part by National Institutes of Health grant R01AG059501 (TK), National Institutes of Health grant R01AG059502 04S1 (TK), NIH/National Center for Advancing Translational Sciences (NCATS) UCLA CTSI Grant Number UL1TR001881 and California HIV/AIDS Research Program grant OS17-LA-002 (TK).
目前，迫切需要快速开发针对 COVID-19 的新型疗法，这些疗法在 SARS-CoV-2 变体迅速进化和 SARS-COV-2 对瑞德西韦和蛋白酶抑制剂耐药性潜在发展的情况下，仍能保持抗病毒疗效。迄今为止，还没有 FDA 批准的用于预防 SARS-CoV-2 暴露后感染的治疗方法。我们已经证明，线粒体抗氧化剂米托醌/米托醌甲磺酸盐（Mito-MES），一种膳食补充剂，对 SARS-CoV-2 具有体外抗病毒活性，对 SARS-CoV-2 感染的 K18-hACE2 小鼠也具有抗病毒活性。
在这项探索性、实用的开放性标签临床试验（ClinicalTrials.gov 标识符 NCT05381454）中，我们研究了 Mito-MES 是否是在研究入组前 5 天内对 SARS-CoV-2 有高度无掩蔽暴露的人有效的暴露后预防治疗方法。参与者在美国洛杉矶的真实环境中招募，招募时间为 2022 年 5 月 1 日至 12 月 1 日，并被分配到 Mito-MES 每天 20mg，连续 14 天（n=40）或不使用 Mito-MES（对照组）（n=40）。主要终点是根据研究期间（暴露后 14 天）进行的 4 次 COVID-19 诊断测试[快速抗原测试（RATs）或 PCR]确定的 SARS-CoV-2 感染。
在服用 Mito-MES 的 40 名（23 名女性；57.5%）研究参与者中，有 12 名（30%）感染了 SARS-CoV-2，而对照组的 40 名参与者中有 30 名（75%）（差异-45.0%，95%置信区间（CI）：-64.5%，-25.5%）。在对照组的 40 名（19 名女性；47.5%）研究参与者中，有 30 名（75.0%）至少有一次 COVID-19 诊断检测呈阳性，23 名（57.5%）出现症状。关于关键次要结局，在有症状的 SARS-CoV-2 感染中，Mito-MES 组的病毒症状持续时间中位数较低（中位数 3.0，95%CI 2.75，3.25），而对照组的中位数为 5.0（95%CI 4.0，7.0）。研究参与者均未住院或需要吸氧治疗。Mito-MES 耐受性良好，任何研究参与者均未报告严重副作用。
这项工作描述了 Mito-MES 在人类中的抗病毒活性。Mito-MES 在我们的研究人群中耐受性良好，并减轻了 SARS-CoV-2 感染的传播。鉴于 Mito-MES 在人类中的安全性已得到确立，我们的结果表明，Mito-MES 作为 SARS-CoV-2 感染暴露后预防的随机对照临床试验是合理的。
这项工作部分得到了美国国立卫生研究院 R01AG059501 资助（TK）、美国国立卫生研究院 R01AG059502 04S1 资助（TK）、美国国立卫生研究院/国家转化科学推进中心（NCATS）UCLA CTSI 资助号 UL1TR001881 和加利福尼亚艾滋病研究项目资助号 OS17-LA-002（TK）。
