Daily Mosnodenvir as Dengue Prophylaxis in a Controlled Human Infection Model.

No antiviral prophylaxis or treatment options are available.

目前尚无可用的抗病毒预防或治疗方案。

Methods

In a phase 2a, double-blind, randomized trial, we assigned healthy adults to receive oral mosnodenvir once daily as a low dose (40-mg loading dose followed by 10-mg maintenance dose), medium dose (200 mg followed by 50 mg), or high dose (600 mg followed by 200 mg) or matched placebo.

在一项2a期、双盲、随机试验中，我们安排健康成人每日口服mosnodenvir，分别作为低剂量（首剂40mg后维持剂量10mg）、中剂量（首剂200mg后维持剂量50mg）或高剂量（首剂600mg后维持剂量200mg）组，或匹配安慰剂组。

Loading doses were given for 5 days and maintenance doses for 21 days.

首剂给药持续5天，维持剂量给药持续21天。

In a controlled human infection model, participants received subcutaneous inoculation of an underattenuated dengue virus serotype 3 (DENV-3) strain (rDEN3Δ30) on the day of the first maintenance dose (day 1).

在一项受控的人类感染模型中，参与者在首次维持剂量当天（第1天）接受了减毒不足的登革热病毒3型（DENV-3）株（rDEN3Δ30）的皮下接种。

The primary efficacy end point was the DENV-3 RNA load, assessed as the log10 area under the concentration-time curve from day 1 (immediately before inoculation) through day 29 (AUCD1-29).

主要疗效终点是DENV-3 RNA载量，评估为从第1天（接种前立即）至第29天的浓度-时间曲线下面积的对数10（AUCD1-29）。

The high-dose and placebo groups were compared in the primary end-point analysis.

在主要终点分析中，比较了高剂量组和安慰剂组。

Safety, pharmacokinetic features, and virologic and serologic features were evaluated through day 85.

通过第85天评估了安全性、药代动力学特征以及病毒学和血清学特征。

Results

The percentage of participants without signs of DENV-3 infection was 0% (0 of 6 participants) with the low dose of mosnodenvir, 17% (1 of 6) with the medium dose, and 60% (6 of 10) with the high dose, as compared with 0% (0 of 7) with placebo.

使用莫索德尼韦低剂量的参与者中，无登革热病毒3型（DENV-3）感染迹象的比例为0%（0/6），中剂量为17%（1/6），高剂量为60%（6/10），与安慰剂组的0%（0/7）相比。

High-dose mosnodenvir led to a significantly lower DENV-3 RNA load, assessed as the log10 AUCD1-29, than placebo (two-sided P<0.001 by tobit analysis of variance).

高剂量莫索德尼韦导致登革热病毒3型（DENV-3）RNA载量显著降低，以log10 AUCD1-29评估，与安慰剂相比差异具有统计学意义（通过tobit方差分析的双侧P<0.001）。

In this small trial, mosnodenvir did not result in any serious adverse events.

在这项小型试验中，莫索德尼韦并未导致任何严重不良事件。

Plasma concentrations of mosnodenvir increased from day -5 to day 1 and were maintained through day 21.

莫索德尼韦的血浆浓度从第-5天增加到第1天，并在第21天保持稳定。

Among participants with available NS4B sequencing data, emerging amino acid variations in the NS4B region of the rDEN3Δ30 genome were detected in 14 of 14 mosnodenvir recipients and none of 7 placebo recipients.

在有可用NS4B测序数据的参与者中，检测到14名mosnodenvir接受者中有14名在rDEN3Δ30基因组的NS4B区域出现了新的氨基酸变异，而7名安慰剂接受者中没有检测到。

Conclusions

In a controlled human infection model, a high daily dose of oral mosnodenvir led to a significantly lower DENV-3 RNA load than placebo.

在一种受控的人类感染模型中，高剂量的口服mosnodenvir导致DENV-3 RNA载量显著低于安慰剂。

Mosnodenvir did not result in any serious adverse events.

Mosnodenvir未导致任何严重不良事件。

(Funded by the National Institute of Allergy and Infectious Diseases and Johnson & Johnson; ClinicalTrials.gov number, NCT05048875.).

(该研究由国家过敏和传染病研究所以及强生公司资助；ClinicalTrials.gov编号，NCT05048875。)