Chavez-Tapia Norberto, Sayeed Muneeba Ahsan, Luxmi Shobha, Kasper Douglas J, Xue Fenchao, Shen Yang, Fan Weiliang, Yuan Wei, Du Bin
Obesity and Digestive Disease Unit, Medica Sur Clinic and Foundation, Mexico City, Mexico.
Sindh Infectious Diseases Hospital and Research Centre, Dow University of Health Sciences, Karachi, Sindh, Pakistan.
J Intensive Med. 2024 Sep 12;5(1):70-78. doi: 10.1016/j.jointm.2024.07.003. eCollection 2025 Jan.
Receptor-interacting protein kinase 1 (RIPK1), a serine/threonine protein kinase, is mainly activated by pro-inflammatory cytokines and pathogens, including severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), and its activation could result in apoptosis, necroptosis, or inflammation. This study was conducted to evaluate the safety and efficacy of a potent and selective inhibitor of RIPK1, SIR1-365, in hospitalized patients with severe coronavirus disease 2019 (COVID-19).
This multicenter, randomized, double-blind, phase 1b study screened patients from December 18, 2020 until November 27, 2021. Adults hospitalized with severe COVID-19 (diagnosed ≤2 weeks before screening) were randomized 1:1 to receive oral placebo or SIR1-365 100 mg three times daily for ≤14 consecutive days, with standard-of-care. The primary objective was to evaluate SIR1-365 safety and tolerability. Secondary objectives included an assessment of SIR1-365 efficacy. Descriptive statistics were used to summarize safety. The study was not powered for efficacy testing. Relevant inferential statistical tests were used to aid interpretation of differences in clinical efficacy.
Forty-five patients were randomized, 42 were treated. Eighteen patients experienced treatment-emergent adverse events (TEAEs) and 7 patients were ≥ grade 3. Fewer SIR1-365-treated . placebo-treated patients experienced TEAEs (30.4% 57.9%) and serious TEAEs (13.0% 26.3%) within 28 days of the first dose. There were no serious treatment-related TEAEs or deaths. Compare to placebo, SIR1-365 significantly increased arterial oxygenation from baseline to day 7 (least-squares mean change [standard error]: 109.4 [26.4] -24.2 [23.6]; =0.0095), significantly reduced hospitalization duration after treatment (mean±standard deviation: [4.7±3.7] days . [8.6±5.6] days; =0.0145) and respiratory failure incidence (8.3% . 38.1%; two-sided =0.0291) during the study, and numerically shortened the time to clinical improvement in World Health Organization ordinal scale (median: 5.0 days 9.0 days, =0.0766).
SIR1-365 was well tolerated and demonstrated a trend toward quicker recovery than placebo in hospitalized patients with severe COVID-19. ClinicalTrials.gov number: NCT04622332.
受体相互作用蛋白激酶1（RIPK1）是一种丝氨酸/苏氨酸蛋白激酶，主要由促炎细胞因子和病原体激活，包括严重急性呼吸综合征冠状病毒2（SARS-CoV-2），其激活可导致细胞凋亡、坏死性凋亡或炎症。本研究旨在评估一种强效且选择性的RIPK1抑制剂SIR1-365对2019年冠状病毒病（COVID-19）住院重症患者的安全性和有效性。
这项多中心、随机、双盲、1b期研究于2020年12月18日至2021年11月27日筛选患者。确诊为重症COVID-19（筛查前诊断≤2周）的住院成人患者按1:1随机分组，接受口服安慰剂或SIR1-365 100 mg，每日3次，连续服用≤14天，并接受标准治疗。主要目的是评估SIR1-365的安全性和耐受性。次要目的包括评估SIR1-365的有效性。采用描述性统计来总结安全性。该研究未进行效力测试。使用相关的推断性统计检验来辅助解释临床疗效的差异。
45例患者被随机分组，42例接受治疗。18例患者发生治疗中出现的不良事件（TEAE），7例患者为3级及以上。与安慰剂治疗的患者相比，SIR1-365治疗的患者在首剂给药后28天内发生TEAE（30.4%对57.9%）和严重TEAE（13.0%对26.3%）的较少。没有与治疗相关的严重TEAE或死亡。与安慰剂相比，SIR1-365从基线到第7天显著提高了动脉氧合（最小二乘均值变化[标准误]：109.4[26.4]对-24.2[23.6]；P=0.0095），显著缩短了治疗后的住院时间（均值±标准差：[4.7±3.7]天对[8.6±5.6]天；P=0.0145）以及研究期间呼吸衰竭的发生率（8.3%对38.1%；双侧P=0.0291），并且在数值上缩短了世界卫生组织序贯量表中临床改善的时间（中位数：5.0天对9.0天，P=0.0766）。
SIR1-365耐受性良好，在重症COVID-19住院患者中显示出比安慰剂更快恢复的趋势。ClinicalTrials.gov编号：NCT04622332。
