Montefiore Medical Center, Bronx, New York.
David Geffen School of Medicine at UCLA, Los Angeles, California.
Clin Ther. 2024 Nov;46(11):891-899. doi: 10.1016/j.clinthera.2024.08.019. Epub 2024 Sep 30.
Early in the course of the SARS-CoV-2 pandemic it was hypothesised that host genetics played a role in the pathophysiology of COVID-19 including a suggestion that the CCR5-Δ32 mutation may be protective in SARS-CoV-2 infection. Leronlimab is an investigational CCR5-specific humanized IgG4 monoclonal antibody currently in development for HIV-1 infection. We aimed to explore the impact of leronlimab on the severity of disease symptoms among participants with mild-to-moderate COVID-19.
The TEMPEST trial was a randomized, double-blind, placebo-controlled study in participants with mild-to-moderate COVID-19. Participants were randomly assigned in a 2:1 ratio to receive subcutaneous leronlimab (700 mg) or placebo on days 0 and 7. The primary efficacy endpoint was assessed by change in total symptom score based on fever, myalgia, dyspnea, and cough, at end of treatment (day 14).
Overall, 84 participants were randomized and treated with leronlimab (n = 56) or placebo (n = 28). No difference was observed in change in total symptom score (P = 0.8184) or other pre-specified secondary endpoints between treatments. However, in a post hoc analysis, 50.0% of participants treated with leronlimab demonstrated improvements from baseline in National Early Warning Score 2 (NEWS2) at day 14, compared with 20·8% of participants in the placebo group (post hoc; p = 0.0223). Among participants in this trial with mild-to-moderate COVID-19 adverse events rates were numerically but not statistically significantly lower in leronlimab participants (33.9%) compared with placebo participants (50.0%).
At the time the TEMPEST trial was designed although CCR5 was known to be implicated in COVID-19 disease severity the exact pathophysiology of SARS-CoV-2 infection was poorly understood. Today it is well accepted that SARS-CoV-2 infection in asymptomatic-to-mild cases is primarily characterized by viral replication, with a heightened immune response, accompanied by diminished viral replication in moderate-to-severe disease and a peak in inflammatory responses with excessive production of pro-inflammatory cytokines in critical disease. It is therefore perhaps not surprising that no differences between treatments were observed in the primary endpoint or in pre-specified secondary endpoints among participants with mild-to-moderate COVID-19. However, the results of the exploratory post hoc analysis showing that participants in the leronlimab group had greater improvement in NEWS2 assessment compared to placebo provided a suggestion that leronlimab may be associated with a lower likelihood of people with mild-to-moderate COVID-19 progressing to more severe disease and needs to be confirmed in other appropriately designed clinical trials.
gov number, NCT04343651 https://classic.
gov/ct2/show/NCT04343651.
在 SARS-CoV-2 大流行早期，人们假设宿主遗传学在 COVID-19 的病理生理学中起作用，包括提示 CCR5-Δ32 突变可能对 SARS-CoV-2 感染具有保护作用。Leronlimab 是一种正在研究中的 CCR5 特异性人源化 IgG4 单克隆抗体，目前正在开发用于治疗 HIV-1 感染。我们旨在探讨 lerolimab 对 COVID-19 轻症至中度患者疾病症状严重程度的影响。
TEMPEST 试验是一项在 COVID-19 轻症至中度患者中进行的随机、双盲、安慰剂对照研究。参与者按 2:1 的比例随机分配，在第 0 天和第 7 天接受皮下注射 lerolimab（700mg）或安慰剂。主要疗效终点是根据治疗结束时（第 14 天）发热、肌痛、呼吸困难和咳嗽的总症状评分变化来评估。
总体而言，84 名参与者被随机分配接受 lerolimab（n=56）或安慰剂（n=28）治疗。治疗组之间总症状评分的变化（P=0.8184）或其他预先指定的次要终点无差异。然而，在事后分析中，与安慰剂组（20.8%）相比，接受 lerolimab 治疗的 50.0%的患者在第 14 天的国家早期预警评分 2（NEWS2）从基线水平有所改善（事后分析；p=0.0223）。在这项试验中，与安慰剂组相比，接受 lerolimab 治疗的 COVID-19 轻症至中度患者的不良事件发生率虽略有降低，但无统计学意义（33.9%比 50.0%）。
在 TEMPEST 试验设计时，尽管 CCR5 被认为与 COVID-19 疾病严重程度有关，但 SARS-CoV-2 感染的确切病理生理学仍知之甚少。今天，人们普遍认为，无症状至轻度的 SARS-CoV-2 感染主要以病毒复制为特征，伴有强烈的免疫反应，中度至重度疾病中病毒复制减少，炎症反应高峰伴有过度产生促炎细胞因子，在危急疾病中出现细胞因子风暴。因此，在轻症至中度 COVID-19 患者中，主要终点或预先指定的次要终点之间未观察到治疗组之间的差异，这也许并不奇怪。然而，事后分析的结果显示，与安慰剂相比，接受 lerolimab 治疗的患者在 NEWS2 评估方面有更大的改善，这表明 lerolimab 可能与降低轻症至中度 COVID-19 患者发展为更严重疾病的可能性有关，需要在其他适当设计的临床试验中得到证实。
gov 注册号，NCT04343651，https://classic.
gov/ct2/show/NCT04343651。
