Backer Vibeke, Sjöbring Ulf, Sonne Jesper, Weiss Anne, Hostrup Morten, Johansen Helle Krogh, Becker Victoria, Sonne David P, Balchen Torben, Jellingsø Mads, Sommer Morten Otto Alexander
Department of Otorhinolaryngology, Rigshospitalet, Blegdamsvej 9, 2100 Copenhagen, Denmark.
Center for Physical Activity Research, Rigshospitalet, Ole Maaløes vej 24, 2200 Copenhagen, Denmark.
Lancet Reg Health Eur. 2021 May;4:100084. doi: 10.1016/j.lanepe.2021.100084. Epub 2021 Apr 6.
Coronavirus disease 19 (COVID-19) is spreading globally and treatment options remain limited. A formulation of niclosamide, a potent anti-SARS-CoV-2 agent and a broad-spectrum antiviral treatment candidate, optimized for inhalation and intranasal administration (UNI91104) was developed.
We conducted a randomized, placebo-controlled, double-blind, single-centre, dose-ascending Phase 1 trial to assess the safety of UNI91104 in Denmark (NCT04576312). Healthy volunteers were randomly assigned to a ascending single dose in cohort 1-4 and five doses over 2.5 days in cohort 5. Inclusion criteria included a minimum 80% of predicted lung function. Exclusion criteria included severe, clinically significant allergies and current acute or chronic condition especially airway diseases. Safety was evaluated through adverse events (AEs) and pulmonary function tests including forced expiratory volume in one second (FEV1) and fractional exhaled nitric oxide (FeNO) tests. The primary endpoints were defined as the frequency of reported AEs and the change of safety variables relative to pre-dose. Data from all enroled healthy volunteers receiving any amount of IMP was included in the primary analyses. The pharmacokinetics of UNI91104 was determined.
The trial was conducted between 29 June 2020 and 08 August 2020. Thirty-four healthy volunteers received UNI91104 and ten placebo. No serious AEs or discontinuation were reported. Mild irritation in the upper respiratory tract following inhalation of UNI91104 was reported as most frequent AE (45 events in 26 healthy volunteers, 59% of all healthy volunteers). Nasal application was well-tolerated. There was no evidence of difference in the change of mean levels of pulmonary function tests between active and placebo group across all cohorts. Five healthy volunteers (11.4%) (1 on placebo) had signs of increased transient FeNO and 4 on active (9.1%) experienced asymptomatic drops in FEV1, which resolved spontaneously or were reversible with a β2-agonist. Niclosamide exhibited dose-proportional pharmacokinetics following inhalation and intranasal administration.
UNI91104, a promising candidate for inhalation and intranasal therapy against COVID-19 and other viral respiratory tract infections is well-tolerated in healthy volunteers and warrants further testing in patient trials.
The study was funded by Innovationsfonden Denmark and UNION therapeutics.
新型冠状病毒肺炎（COVID-19）正在全球蔓延，治疗选择仍然有限。开发了一种氯硝柳胺制剂（UNI91104），它是一种有效的抗SARS-CoV-2药物和广谱抗病毒治疗候选药物，针对吸入和鼻内给药进行了优化。
我们在丹麦进行了一项随机、安慰剂对照、双盲、单中心、剂量递增的1期试验，以评估UNI91104的安全性（NCT04576312）。健康志愿者在第1-4组中被随机分配接受递增单剂量，在第5组中在2.5天内接受5剂。纳入标准包括至少80%的预测肺功能。排除标准包括严重的、具有临床意义的过敏以及当前的急性或慢性疾病，尤其是气道疾病。通过不良事件（AE）和肺功能测试评估安全性，包括一秒用力呼气量（FEV1）和呼出一氧化氮分数（FeNO）测试。主要终点定义为报告的AE频率以及相对于给药前安全变量的变化。所有接受任何剂量研究药物的入选健康志愿者的数据都纳入了主要分析。测定了UNI91104的药代动力学。
该试验于2020年6月29日至2020年8月8日进行。34名健康志愿者接受了UNI91104，10名接受了安慰剂。未报告严重AE或停药情况。吸入UNI91104后上呼吸道轻度刺激是最常见的AE（26名健康志愿者中有45起事件，占所有健康志愿者的59%）。鼻内给药耐受性良好。在所有队列中，活性组和安慰剂组之间肺功能测试平均水平变化没有差异的证据。5名健康志愿者（11.4%）（1名接受安慰剂）有短暂FeNO升高的迹象，4名接受活性药物的志愿者（9.1%）出现无症状的FEV1下降，这些情况自发缓解或用β2激动剂可逆。氯硝柳胺在吸入和鼻内给药后表现出剂量比例药代动力学。
UNI91104是一种有前景的吸入和鼻内治疗COVID-19及其他病毒性呼吸道感染的候选药物，在健康志愿者中耐受性良好，值得在患者试验中进一步测试。
该研究由丹麦创新基金和联合治疗公司资助。
