Nebulised ALX-0171 for RSV lower respiratory tract infection in hospitalised children: a double blind, randomised, placebo-controlled Phase 2b trial

Background Respiratory syncytial virus (RSV) is the most common cause of severe lower respiratory tract infection, with a high global health burden. There are no effective treatments available. ALX-0171 is a novel trivalent Nanobody® with RSV antiviral properties. We assessed the safety and antiviral activity of nebulised ALX-0171 in hospitalised children with RSV lower respiratory tract infection. Methods Previously healthy children aged 28 days to <24 months, hospitalised with RSV acute severe lower respiratory tract infection, were enrolled to a double blind, randomised, placebo-controlled, dose ranging study of nebulised ALX-0171 once daily for three days. Web based randomisation assigned participants to three dose levels of ALX-0171 (3, 6, 9mg/kg). A sequential safety part (Cohorts 1, 2, 3, n=12 per ascending dose, 3 ALX: 1 Placebo, first block size 12, subsequently 4) was followed by a parallel part (Cohort 4, parallel, 1:1:1:1 ALX 3, 6, 9mg/kg, placebo, blocks of 8 by restricted randomisation) to a total of 180. Study drug blinding was by two consecutive nebulisations (each either ALX-0171 or placebo) depending on assigned treatment group. Analysis was by modified intention to treat (mITT, participants receiving at least one dose of study drug). Primary outcome was to evaluate time to below quantifiable limit of RSV measured by plaque assay on mid-turbinate nasal swabs. Safety, clinical activity, pharmacokinetics and immunogenicity were secondary outcomes. This trial is registered with Eudra CT, 2016-001651-49 Findings 175 children (median age 4.8 months (iqr 2.0, 10.8)), received at least one dose of study drug (mITT population) commencing at a mean 3.3 days (1.1 sd) from symptom onset. Time-to-below quantifiable limit (BQL) in plaque assay RSV load was significantly faster for nALX-0171 3mg/kg (N=45, median 14.2 hours (iqr 5.0-28.0)), 6mg/kg (N= 43, 5.1 (4.7-28.5)) and 9mg/kg (N=45, 5.1 (4.6-5.9)) (all p<0.001), when compared to placebo (N=42, 46.1 (25.2-116.7)). RT-qPCR had a longer median (25,75) time to BQL than plaque assay: placebo (N=35) 95.9 hours (26.7-P75 not estimable), all nALX-0171 (N=118) 49.4 hours (25.1-351.4). Fifteen participants experienced 15 Serious Adverse Events (4/40 (12.5%) placebo, 4/45 (8.9%) 3mg/kg, 3/44 (6.8%) 6mg/kg, 3/46 (6.5%) 9mg/kg), leading to study drug discontinuation in three infants (two 3mg/kg and one 6mg/kg ALX-0171). Thirteen SAE were related to worsening respiratory status and none were considered study drug related. Serum concentrations of ALX-0171 on Day 2 exceeded the concentration estimated to give full RSV neutralisation in the lung at 6 and 9mg/kg doses. Clinical outcomes were not improved by ALX-1071 (N=133) compared with placebo (N=42): Time to clinical response (SpO2 >92% and adequate feeding) (ALX-0171 median 43.8 hours (25,75; 21.7, 68.5), Placebo 47.9 hours (22.5, 76.4). Change in Global Severity Score post dose day 2 (ALX-0171 median -4.0 (min, max; -12,3), placebo -4.0 (-11,4)). Treatment-emergent anti-drug antibodies were detected at Day 14 in 34.1% (46/135) of nALX-0171 and 25.6% (10/39) of the placebo-treated children. Interpretation Antivirals against RSV may be unable to improve clinical course once RSV lower respiratory tract infection is established. Future studies of RSV antivirals should focus on earlier intervention and more precise measurement of objective outcomes before the onset of significant lower respiratory tract inflammation. Funding The study was funded by Ablynx N.V. (Belgium), now a Sanofi company.