Bonavia Aurelio, Levi Micha, Rouha Harald, Badarau Adriana, Terstappen Jonne, Watson Shayne, Anderson Aparna B, White Joleen T, Ananworanich Jintanat, Taylor Dale, Radivojevic Andrijana, Shaffer Michael, Stamm Luisa M, Dunne Michael W
Bill & Melinda Gates Medical Research Institute, Cambridge, MA, USA.
Arsanis Biosciences, Vienna, Austria.
BMC Infect Dis. 2024 Dec 3;24(1):1378. doi: 10.1186/s12879-024-10120-w.
Respiratory syncytial virus (RSV) is a leading cause of lower respiratory tract disease among infants and young children worldwide, especially in low- and middle-income countries (LMICs). RSM01 is a novel, highly potent, half-life-extended anti-RSV monoclonal antibody (mAb) candidate primarily being developed for LMICs. Here we present the preclinical characterisation and results of a phase 1 trial of RSM01.
Preclinical characterisation of RSM01 was conducted using in-vitro neutralization assays and cotton rat models. In the first-in-human, double-blind, phase 1 trial, 56 healthy adults were randomised 6:1 within dose cohorts to receive a single dose of RSM01 (n = 48) or placebo (n = 8): 300 mg intravenously (IV), 300 mg intramuscularly (IM) or 1000 mg IV (parallel cohorts), 3000 mg IV, and an expansion cohort of 600 mg IM. Systemic solicited adverse events (AEs) were assessed through day 7; unsolicited AEs were collected through day 151. Pharmacokinetics and anti-drug antibodies (ADA) to RSM01 were assessed using immunoassays. A population pharmacokinetics model predicted paediatric pharmacokinetics parameters using allometric scaling and age-specific population weight statistics of North American and African infants.
RSM01 exhibited highly potent neutralizing activity in the single ng/mL range (0.7-6.4) against diverse RSV-A and RSV-B isolates in vitro. RSM01 also demonstrated prophylactic efficacy in cotton rat models with both RSV subtypes. In the phase 1 clinical trial, the most common unsolicited AEs were COVID-19 (2/48), headache (2/48), and nausea (2/48), all in RSM01-treated participants. The only systemic solicited AEs reported were headache (5/48) and tiredness (2/48) in participants receiving RSM01. No serious AEs or deaths were reported. The half-life of RSM01 was 78 days with dose-proportional increases in T and AUC after IV administration. Among RSM01-treated participants, 2/48 were ADA positive at baseline, and 1/48 seroconverted to ADA-positive post-baseline.
RSM01 is a highly potent, half-life-extended, RSV-neutralising mAb candidate that was shown to be well tolerated in healthy adults. The rate of ADA to RSM01 was low. The long half-life of RSM01 and pharmacokinetics profile support further development of RSM01 as a potential single dose per season prophylaxis to prevent RSV disease in infants.
Clinicaltrials.gov NCT05118386, Nov 12, 2021.
呼吸道合胞病毒（RSV）是全球婴幼儿下呼吸道疾病的主要病因，在低收入和中等收入国家（LMICs）尤为如此。RSM01是一种新型、高效、半衰期延长的抗RSV单克隆抗体（mAb）候选药物，主要针对LMICs开发。在此，我们展示了RSM01的临床前特征及1期试验结果。
使用体外中和试验和棉鼠模型对RSM01进行临床前特征分析。在首次人体双盲1期试验中，56名健康成年人在剂量组内按6:1随机分组，接受单剂量RSM01（n = 48）或安慰剂（n = 8）：静脉注射（IV）300 mg、肌肉注射（IM）300 mg或静脉注射1000 mg（平行组）、静脉注射3000 mg，以及一个600 mg肌肉注射的扩展组。在第7天评估系统性预期不良事件（AE）；在第151天收集非预期AE。使用免疫测定法评估RSM01的药代动力学和抗药抗体（ADA）。群体药代动力学模型使用北美和非洲婴儿的异速生长标度和特定年龄群体体重统计数据预测儿科药代动力学参数。
RSM01在体外对多种RSV-A和RSV-B分离株在单ng/mL范围（0.7 - 6.4）内表现出高效中和活性。RSM01在两种RSV亚型的棉鼠模型中也显示出预防效果。在1期临床试验中，最常见的非预期AE是COVID-19（2/48）、头痛（2/48）和恶心（2/48），均发生在接受RSM01治疗的参与者中。报告的唯一系统性预期AE是接受RSM01的参与者中的头痛（5/48）和疲劳（2/48）。未报告严重AE或死亡。RSM01的半衰期为78天，静脉注射后T和AUC随剂量成比例增加。在接受RSM01治疗的参与者中，2/48在基线时ADA呈阳性，1/48在基线后血清转化为ADA阳性。
RSM01是一种高效、半衰期延长的RSV中和mAb候选药物，在健康成年人中显示出良好的耐受性。RSM01的ADA发生率较低。RSM01的长半衰期和药代动力学特征支持其作为预防婴儿RSV疾病的潜在单季单剂量预防药物进一步开发。
Clinicaltrials.gov NCT05118386，2021年11月12日。
