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

Abstract

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.)

Structural Insight into Paramyxovirus and Pneumovirus Entry Inhibition

“…Primary efficacy end point of the model was typically shed virus load in nasal swab samples, secondary end points included total mucus weight produced during the acute infection period and symptom scores. Currently available trial outcome data show that three of the entry inhibitor candidates tested, presatovir (GS-5806) [94], RV521 [95], and JNJ-53718678 [96], reduced viral burden, shortened disease duration, and/or alleviated secondary clinical signs.…”

Leveraging 3D Model Systems to Understand Viral Interactions with the Respiratory Mucosa

“…Meaningful human- and donor-specific data can be captured through emergent culture systems in lieu of challenge experiments, which are hindered by the severity of the agent being tested and participant acquisition [ 103 , 104 ]. For example, work by Peretz et al showed that cultures responded to sex hormones according to the sex of the primary cell donor.…”

A COVID‐19 human viral challenge model. Learning from experience

“…In conclusion, a safe and reproducible human experimental model of RSV infection and disease was developed, and the developmental process may parallel potential COVID‐19 HVCM development in several ways. The RSV HVCM has already proven its worth in quickly establishing important human therapeutic efficacy and in speeding the development of experimental interventions which are now being conducted in high‐risk populations 45 . Additionally, the RSV HVCM has provided the first evidence of RSV vaccine efficacy in producing sterilising immunity and disease severity reductions 46 …”