Regeneron Pharmaceuticals, Tarrytown, NY, USA.
Regeneron Pharmaceuticals, Tarrytown, NY, USA.
Lancet Infect Dis. 2022 Oct;22(10):1444-1454. doi: 10.1016/S1473-3099(22)00416-9. Epub 2022 Jul 5.
There is an unmet need for COVID-19 prevention in patient populations who have not mounted or are not expected to mount an adequate immune response to complete COVID-19 vaccination. We previously reported that a single subcutaneous 1200 mg dose of the monoclonal antibody combination casirivimab and imdevimab (CAS + IMD) prevented symptomatic SARS-CoV-2 infections by 81·4% in generally healthy household contacts of SARS-CoV-2-infected individuals over a 1-month efficacy assessment period. Here we present additional results, including the 7-month follow-up period (months 2-8), providing additional insights about the potential for efficacy in pre-exposure prophylaxis settings.
This was a randomised, double-blind, placebo-controlled trial done in the USA, Romania, and Moldova in 2020-2021, before the emergence of omicron (B.1.1.529) and omicron-lineage variants. Uninfected and unvaccinated household contacts of infected individuals, judged by the investigator to be in good health, were randomly assigned (1:1) to receive 1200 mg CAS + IMD or placebo by subcutaneous injection according to a central randomisation scheme provided by an interactive web response system; randomisation was stratified per site by the test results of a local diagnostic assay for SARS-CoV-2 and age group at baseline. COVID-19 vaccines were prohibited before randomisation, but participants were allowed to receive COVID-19 vaccination during the follow-up period. Participants who developed COVID-19 symptoms during the follow-up period underwent RT-PCR testing. Prespecified endpoints included the proportion of previously uninfected and baseline-seronegative participants (seronegative-modified full analysis set) who had RT-PCR-confirmed COVID-19 in the follow-up period (post-hoc for the timepoints of months 2-5 and 6-8 only) and underwent seroconversion (ie, became seropositive, considered a proxy for any SARS-CoV-2 infections [symptomatic and asymptomatic]; prespecified up to day 57, post-hoc for all timepoints thereafter). We also assessed the incidence of treatment-emergent adverse events. This study is registered with ClinicalTrials.gov, NCT04452318.
From July 13, 2020, to Oct 4, 2021, 2317 participants who were RT-PCR-negative for SARS-CoV-2 were randomly assigned, of whom 1683 (841 assigned to CAS + IMD and 842 assigned to placebo) were seronegative at baseline. During the entirety of the 8-month study, CAS + IMD reduced the risk of COVID-19 by 81·2% (nominal p<0·0001) versus placebo (prespecified analysis). During the 7-month follow-up period, protection was greatest during months 2-5, with a 100% relative risk reduction in COVID-19 (nominal p<0·0001; post-hoc analysis). Efficacy waned during months 6-8 (post-hoc analysis). Seroconversion occurred in 38 (4·5%) of 841 participants in the CAS + IMD group and in 181 (21·5%) of 842 in the placebo group during the 8-month study (79·0% relative risk reduction vs placebo; nominal p<0·0001). Six participants in the placebo group were hospitalised due to COVID-19 versus none who received CAS + IMD. Serious treatment-emergent adverse events (including COVID-19) were reported in 24 (1·7%) of 1439 participants receiving CAS + IMD and in 23 (1·6%) of 1428 receiving placebo. Five deaths were reported, none of which were due to COVID-19 or related to the study drugs.
CAS + IMD is not authorised in any US region as of Jan 24, 2022, because data show that CAS + IMD is not active against omicron-lineage variants. In this study, done before the emergence of omicron-lineage variants, a single subcutaneous 1200 mg dose of CAS + IMD protected against COVID-19 for up to 5 months of community exposure to susceptible strains of SARS-CoV-2 in the pre-exposure prophylaxis setting, in addition to the post-exposure prophylaxis setting that was previously shown.
Regeneron Pharmaceuticals, F Hoffmann-La Roche, US National Institute of Allergy and Infectious Diseases, US National Institutes of Health.
对于未产生或预计无法产生足够免疫应答以完全接种 COVID-19 疫苗的患者人群，存在对 COVID-19 的预防需求。我们之前报告称，单剂 1200mg 的 casirivimab 和 imdevimab （CAS+IMD）联合单抗在 1 个月的疗效评估期内预防了一般健康的 SARS-CoV-2 感染个体的家庭接触者中 81.4%的有症状 SARS-CoV-2 感染。在此，我们提供了更多结果，包括 7 个月的随访期（第 2-8 个月），提供了关于在暴露前预防环境中潜在疗效的更多见解。
这是一项在 2020-2021 年于美国、罗马尼亚和摩尔多瓦进行的随机、双盲、安慰剂对照试验，研究开始前尚未出现 omicron（B.1.1.529）和 omicron 谱系变异。未感染和未接种疫苗的感染个体的家庭接触者，经研究者判断健康状况良好，按照中央随机分配方案，根据当地 SARS-CoV-2 诊断检测的结果和基线时的年龄组，按 1：1 随机分配接受 1200mg CAS+IMD 或安慰剂皮下注射；随机分配按每个地点分层，疫苗接种前禁止使用 COVID-19 疫苗，但允许参与者在随访期间接种 COVID-19 疫苗。随访期间出现 COVID-19 症状的参与者接受 RT-PCR 检测。预先指定的终点包括在随访期间（仅事后分析第 2-5 个月和第 6-8 个月）未感染和基线血清阴性（血清阴性修正全分析集）的参与者中，有多少人通过 RT-PCR 确认 COVID-19，以及发生血清转化（即，变为血清阳性，被认为是任何 SARS-CoV-2 感染的替代指标[有症状和无症状]；预先设定至第 57 天，此后所有时间点均为事后分析）。我们还评估了治疗出现的不良事件的发生率。本研究在 ClinicalTrials.gov 注册，编号为 NCT04452318。
从 2020 年 7 月 13 日至 2021 年 10 月 4 日，共有 2317 名 SARS-CoV-2 检测为阴性的参与者被随机分配，其中 1683 名（841 名分配至 CAS+IMD 组，842 名分配至安慰剂组）基线时血清阴性。在整个 8 个月的研究期间，与安慰剂相比，CAS+IMD 降低了 81.2%的 COVID-19 风险（名义 p<0.0001）（预先指定的分析）。在 7 个月的随访期间，保护作用在第 2-5 个月最大，COVID-19 的相对风险降低了 100%（名义 p<0.0001；事后分析）。在第 6-8 个月，保护作用减弱（事后分析）。在 CAS+IMD 组的 841 名参与者中，有 38 名（4.5%）发生血清转化，而在安慰剂组的 842 名参与者中有 181 名（21.5%）发生血清转化（与安慰剂相比，风险降低 79.0%；名义 p<0.0001）。安慰剂组中有 6 名参与者因 COVID-19 住院，而接受 CAS+IMD 的参与者中无一例住院。接受 CAS+IMD 的 1439 名参与者中有 24 名（1.7%）和接受安慰剂的 1428 名参与者中有 23 名（1.6%）报告了严重的治疗出现的不良事件（包括 COVID-19）。报告了 5 例死亡，均与 COVID-19 无关，也与研究药物无关。
截至 2022 年 1 月 24 日，CAS+IMD 尚未在美国任何地区获得授权，因为数据表明 CAS+IMD 对 omicron 谱系变异无效。在这项研究中，在 omicron 谱系变异出现之前进行，在社区接触易感 SARS-CoV-2 株的暴露前预防环境中，单剂 1200mg 的 CAS+IMD 保护作用长达 5 个月，除了之前显示的暴露后预防环境外。
Regeneron 制药公司、罗氏、美国国立过敏和传染病研究所、美国国立卫生研究院。
