NVP-DFV890

NVP-DFV890 (DFV-890; NLRP3 拮抗剂 2 (化合物 102) 是一种 NLRP3 拮抗剂。NLRP3 拮抗剂 2 可用于骨关节炎研究。 DFV890是一种新型、口服、强效且选择性的低分子量NLRP3炎症小体抑制剂。它通过直接与NLRP3蛋白结合，将其锁定在非活性构象，从而阻止NLRP3炎症小体响应危险信号而组装。这种阻断作用抑制了促炎细胞因子IL-1β和IL-18的成熟与分泌，并防止细胞焦亡的发生。鉴于其在调节先天免疫反应中的关键作用，DFV890在一项2a期随机临床试验（NCT04382053）中被作为COVID-19肺炎的潜在治疗药物进行研究，因为该疾病中失调的NLRP3激活会导致细胞因子风暴和冠状病毒相关急性呼吸窘迫综合征。在这项研究中，患有COVID-19肺炎且呼吸功能受损的住院患者被随机分配接受DFV890 50 mg每日两次联合标准治疗或单独标准治疗，持续14天。虽然主要终点（第14天APACHE II评分的改善）未能达到，但与单独标准治疗相比，DFV890治疗与更快的SARS-CoV-2清除、数值上更优的临床状态改善以及更少的致死事件相关。该药物耐受性良好，未发现意外安全性信号。其在其他NLRP3相关炎症性疾病（如冷炎素相关周期性综合征和骨关节炎）中的潜力值得进一步研究。[1]

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Trial registration: ClinicalTrials.gov, NCT04382053. [1]
Background: Coronavirus-associated acute respiratory distress syndrome (CARDS) has limited effective therapy to date. NLRP3 inflammasome activation induced by SARS-CoV-2 in COVID-19 contributes to cytokine storm.
Methods: This randomised, multinational study enrolled hospitalised patients (18-80 years) with COVID-19-associated pneumonia and impaired respiratory function. Eligible patients were randomised (1:1) via Interactive Response Technology to DFV890 + standard-of-care (SoC) or SoC alone for 14 days. Primary endpoint was APACHE II score at Day 14 or on day-of-discharge (whichever-came-first) with worst-case imputation for death. Other key assessments included clinical status, CRP levels, SARS-CoV-2 detection, other inflammatory markers, in-hospital outcomes, and safety.
Findings: Between May 27, 2020 and December 24, 2020, 143 patients (31 clinical sites, 12 countries) were randomly assigned to DFV890 + SoC (n = 71) or SoC alone (n = 72). Primary endpoint to establish clinical efficacy of DFV890 vs. SoC, based on combined APACHE II score, was not met; LSM (SE), 8·7 (1.06) vs. 8·6 (1.05); p = 0.467. More patients treated with DFV890 vs. SoC showed ≥ 1-level improvement in clinical status (84.3% vs. 73.6% at Day 14), earlier clearance of SARS-CoV-2 (76.4% vs. 57.4% at Day 7), and mechanical ventilation-free survival (85.7% vs. 80.6% through Day 28), and there were fewer fatal events in DFV890 group (8.6% vs. 11.1% through Day 28). DFV890 was well tolerated with no unexpected safety signals.
Interpretation: DFV890 did not meet statistical significance for superiority vs. SoC in primary endpoint of combined APACHE II score at Day 14. However, early SARS-CoV-2 clearance, improved clinical status and in-hospital outcomes, and fewer fatal events occurred with DFV890 vs. SoC, and it may be considered as a protective therapy for CARDS.