A Randomized, Placebo-Controlled, Respiratory Syncytial Virus Human Challenge Study of the Antiviral Efficacy, Safety, and Pharmacokinetics of RV521, an Inhibitor of the RSV-F Protein.
Effective treatments for respiratory syncytial virus (RSV) infection are lacking. Here, we report a human proof-of-concept study for RV521, a small-molecule antiviral inhibitor of the RSV-F protein. In this randomized, double-blind, placebo-controlled trial, healthy adults were challenged with RSV-A Memphis-37b. After infection was confirmed (or 5 days after challenge virus inoculation), subjects received RV521 (350 mg or 200 mg) or placebo orally every 12 h for 5 days. The primary endpoint was area under the curve (AUC) for viral load, as assessed by reverse transcriptase quantitative PCR (RT-qPCR) of nasal wash samples. The primary efficacy analysis set included subjects successfully infected with RSV who received ≥1 dose of study drug. A total of 66 subjects were enrolled (n = 22 per group); 53 were included in the primary analysis set (RV521 350 mg: n = 16; 200 mg: n = 18; placebo: n = 19). The mean AUC of RT-qPCR-assessed RSV viral load (log10 PFU equivalents [PFUe]/ml · h) was significantly lower with RV521 350 mg (185.26; standard error [SE], 31.17; P = 0.002) and 200 mg (224.35; SE, 37.60; P = 0.007) versus placebo (501.39; SE, 86.57). Disease severity improved with RV521 350 mg and 200 mg versus placebo (P = 0.002 and P = 0.009, respectively, for AUC total symptom score [score × hours]). Daily nasal mucus weight was significantly reduced (P = 0.010 and P = 0.038 for RV521 350 mg and 200 mg, respectively, versus placebo). All treatment-emergent adverse events were grade 1 or 2. No subjects discontinued due to adverse events. There was no evidence of clinically significant viral resistance, and only three variants were detected. RV521 effectively reduced RSV viral load and disease severity in humans and was well tolerated. (This study has been registered at ClinicalTrials.gov under registration no. NCT03258502.).
DeVincenzo J
，Tait D
，Efthimiou J
，Mori J
，Kim YI
，Thomas E
，Wilson L
，Harland R
，Mathews N
，Cockerill S
，Powell K
，Littler E
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Nebulised ALX-0171 for respiratory syncytial virus lower respiratory tract infection in hospitalised children: a double-blind, randomised, placebo-controlled, phase 2b trial.
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 antiviral properties against RSV. We aimed to assess the safety and antiviral activity of nebulised ALX-0171 in children admitted to hospital with RSV lower respiratory tract infection.
This double-blind, randomised, placebo-controlled, phase 2b trial was done in 50 hospital paediatric departments across 16 countries. Previously healthy children aged between 28 days to younger than 24 months who were admitted to hospital with RSV acute severe lower respiratory tract infection were randomly assigned in three sequential safety cohorts (3:1) to receive nebulised ALX-0171 (cohort 1 received 3 mg/kg, cohort 2 received 6 mg/kg, and cohort 3 received 9 mg/kg) or placebo once daily for 3 days using web-based randomisation in the sequential safety part (first block size 12, subsequently four). In a parallel part of the study, participants (cohort 4) were randomly assigned (parallel 1:1:1:1) to receive nebulised ALX-0171 3 mg/kg, 6 mg/kg, 9 mg/kg, or placebo (blocks of eight by restricted randomisation). Study drug masking was by two consecutive nebulisations (each either ALX-0171 or placebo) depending on assigned treatment group. The primary outcome was to evaluate time for the RSV viral load to drop to below quantifiable limit, measured by plaque assay on mid-turbinate nasal swabs. Safety, clinical efficacy, pharmacokinetics, viral load by RT-qPCR, and immunogenicity were secondary outcomes. Analysis, including of the primary outcome, was by modified intention to treat (participants receiving at least one dose of study drug as assigned), and safety was assessed in all children who received at least one administration of study drug, as treated. This trial is registered with EudraCT, 2016-001651-49.
Between Jan 10, 2017, and April 26, 2018, 175 children (median age 4·8 months [IQR 2·0-10·8]), received at least one dose of study drug (45 received 3 mg/kg of ALX-0171, 43 received 6 mg/kg of ALX-0171, 45 received 9 mg/kg of ALX-0171, and 42 received placebo; the modified intention-to-treat population) commencing at a mean 3·3 days (SD 1·1) from symptom onset. Median time for the viral load to drop to below quantifiable limit on plaque assay was significantly faster for the 3 mg/kg group (median 14·2 h [IQR 5·0-28·0]), 6 mg/kg group (5·1 h [4·7-28·5]), and 9 mg/kg group (5·1 h [4·6-5·9]) than the placebo group (46·1 h [25·2-116·7]; hazard ratio [HR] all ALX-0171 groups vs placebo 2·6 [1·7-3·9]; p<0·0001). Median time for the viral load to drop below quantification limit with RT-qPCR was 95·9 h (IQR 26·7 to not estimable) for the placebo group (n=35) versus 49·4 h (25·1 to 351·4) for all ALX-0171 groups (n=118). Clinical outcomes were not improved by ALX-0171 compared with placebo, with no difference in time to clinical response (oxygen saturation >92% for 4 h in room air and adequate oral feeding) in ALX-0171 groups and the placebo group (median 43·8 h [IQR 21·7-68·5] vs 47·9 h [22·5-76·4]; HR 1·1 [95% CI 0·8-1·6]) or change in the global severity score from baseline to 5 h post-dose on day 2 (-4 [IQR -6 to -2] vs -4 [-6 to -1]; difference in least-squares mean -0·45 [95% CI -1·39 to 0·49]). Serum concentrations of ALX-0171 on day 2 exceeded the concentration estimated to give full RSV neutralisation in the lung at 6 mg/kg and 9 mg/kg doses. Treatment-emergent antidrug antibodies were detected at day 14 in 46 (34%) of 135 patients who received ALX-0171 and ten (26%) of 39 patients who received placebo. Serious adverse events were reported in five (13%) of 40 children in the placebo group and ten (7%) of 135 children in all ALX-0171 groups, leading to study drug discontinuation in three children (two in the 3 mg/kg group and one in the 6 mg/kg group). 13 of 15 serious adverse events (three of four in the 3 mg/kg group, two of three in the 6 mg/kg group, three of three in the 9 mg/kg group, and five of five in the placebo group) were related to worsening respiratory status, and none were considered to be related to the study drug.
Antivirals against RSV might 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.
Ablynx, a Sanofi Company.
Cunningham S
，Piedra PA
，Martinon-Torres F
，Szymanski H
，Brackeva B
，Dombrecht E
，Detalle L
，Fleurinck C
，RESPIRE study group
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EDP-938, a Respiratory Syncytial Virus Inhibitor, in a Human Virus Challenge.
Respiratory syncytial virus (RSV) infection causes substantial morbidity and mortality among infants, older adults, and immunocompromised adults. EDP-938, a nonfusion replication inhibitor of RSV, acts by modulating the viral nucleoprotein.
In a two-part, phase 2a, randomized, double-blind, placebo-controlled challenge trial, we assigned participants who had been inoculated with RSV-A Memphis 37b to receive EDP-938 or placebo. Different doses of EDP-938 were assessed. Nasal-wash samples were obtained from day 2 until day 12 for assessments. Clinical symptoms were assessed by the participants, and pharmacokinetic profiles were obtained. The primary end point was the area under the curve (AUC) for the RSV viral load, as measured by reverse-transcriptase-quantitative polymerase-chain-reaction assay. The key secondary end point was the AUC for the total symptom score.
In part 1 of the trial, 115 participants were assigned to receive EDP-938 (600 mg once daily [600-mg once-daily group] or 300 mg twice daily after a 500-mg loading dose [300-mg twice-daily group]) or placebo. In part 2, a total of 63 participants were assigned to receive EDP-938 (300 mg once daily after a 600-mg loading dose [300-mg once-daily group] or 200 mg twice daily after a 400-mg loading dose [200-mg twice-daily group]) or placebo. In part 1, the AUC for the mean viral load (hours × log10 copies per milliliter) was 204.0 in the 600-mg once-daily group, 217.7 in the 300-mg twice-daily group, and 790.2 in the placebo group. The AUC for the mean total symptom score (hours × score, with higher values indicating greater severity) was 124.5 in the 600-mg once-daily group, 181.8 in the 300-mg twice-daily group, and 478.8 in the placebo group. The results in part 2 followed a pattern similar to that in part 1: the AUC for the mean viral load was 173.9 in the 300-mg once-daily group, 196.2 in the 200-mg twice-daily group, and 879.0 in the placebo group, and the AUC for the mean total symptom score was 99.3, 89.6, and 432.2, respectively. In both parts, mucus production was more than 70% lower in each EDP-938 group than in the placebo group. The four EDP-938 regimens had a safety profile similar to that of placebo. Across all dosing regimens, the EDP-938 median time to maximum concentration ranged from 4 to 5 hours, and the geometric mean half-life ranged from 13.7 to 14.5 hours.
All EDP-938 regimens were superior to placebo with regard to lowering of the viral load, total symptom scores, and mucus weight without apparent safety concerns. (ClinicalTrials.gov number, NCT03691623.).
Ahmad A
，Eze K
，Noulin N
，Horvathova V
，Murray B
，Baillet M
，Grey L
，Mori J
，Adda N
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ResearchGate
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