Merck & Co., Inc., 2000 Galloping Hill Rd, Kenilworth, NJ 07033, USA.
Certara, 100 Overlook Center STE 101, Princeton, NJ 08540, USA.
EBioMedicine. 2021 Nov;73:103651. doi: 10.1016/j.ebiom.2021.103651. Epub 2021 Nov 11.
Neutralizing mAbs can prevent communicable viral diseases. MK-1654 is a respiratory syncytial virus (RSV) F glycoprotein neutralizing monoclonal antibody (mAb) under development to prevent RSV infection in infants. Development and validation of methods to predict efficacious doses of neutralizing antibodies across patient populations exposed to a time-varying force of infection (i.e., seasonal variation) are necessary.
Five decades of clinical trial literature were leveraged to build a model-based meta-analysis (MBMA) describing the relationship between RSV serum neutralizing activity (SNA) and clinical endpoints. The MBMA was validated by backward translation to animal challenge experiments and forward translation to predict results of a recent RSV mAb trial. MBMA predictions were evaluated against a human trial of 70 participants who received either placebo or one of four dose-levels of MK-1654 and were challenged with RSV [NCT04086472]. The MBMA was used to perform clinical trial simulations and predict efficacy of MK-1654 in the infant target population.
The MBMA established a quantitative relationship between RSV SNA and clinical endpoints. This relationship was quantitatively consistent with animal model challenge experiments and results of a recently published clinical trial. Additionally, SNA elicited by increasing doses of MK-1654 in humans reduced RSV symptomatic infection rates with a quantitative relationship that approximated the MBMA. The MBMA indicated a high probability that a single dose of ≥ 75 mg of MK-1654 will result in prophylactic efficacy (> 75% for 5 months) in infants.
An MBMA approach can predict efficacy of neutralizing antibodies against RSV and potentially other respiratory pathogens.
中和单抗可预防传染性病毒疾病。MK-1654 是一种正在开发的呼吸道合胞病毒 (RSV) F 糖蛋白中和单克隆抗体 (mAb)，旨在预防婴儿 RSV 感染。需要开发和验证预测在暴露于不断变化的感染力（即季节性变化）的患者群体中有效中和抗体剂量的方法。
利用五十年的临床试验文献，建立了一个描述 RSV 血清中和活性 (SNA) 与临床终点之间关系的基于模型的荟萃分析 (MBMA)。通过向后翻译为动物挑战实验和向前翻译为预测最近 RSV mAb 试验的结果来验证 MBMA。MBMA 预测结果与 70 名参与者的人体试验进行了比较，这些参与者接受了安慰剂或 MK-1654 的四个剂量水平之一，并接受了 RSV 挑战 [NCT04086472]。使用 MBMA 进行临床试验模拟，并预测 MK-1654 在婴儿目标人群中的疗效。
MBMA 建立了 RSV SNA 与临床终点之间的定量关系。这种关系与动物模型挑战实验和最近发表的临床试验结果在定量上是一致的。此外，人类中 MK-1654 剂量增加引起的 SNA 降低了 RSV 症状感染率，其定量关系与 MBMA 相近。MBMA 表明，较高剂量（≥75mg）的单剂量 MK-1654 很可能在婴儿中产生预防疗效（5 个月内>75%）。
MBMA 方法可预测针对 RSV 中和抗体的疗效，并且可能针对其他呼吸道病原体。
