Assessment of Drug Resistance during Phase 2b Clinical Trials of Presatovir in Adults Naturally Infected with Respiratory Syncytial Virus

Abstract

Background: This study summarizes drug resistance analyses in 4 recent phase 2b trials of the respiratory syncytial virus (RSV) fusion inhibitor presatovir in naturally infected adults. Methods: Adult hematopoietic cell transplant (HCT) recipients, lung transplant recipients, or hospitalized patients with naturally acquired, laboratory-confirmed RSV infection were enrolled in 4 randomized, double-blind, placebo-controlled studies with study-specific presatovir dosing. Full-length RSV F sequences amplified from nasal swabs obtained at baseline and postbaseline were analyzed by population sequencing. Substitutions at RSV fusion inhibitor resistance-associated positions are reported. Results: Genotypic analyses were performed on 233 presatovir-treated and 149 placebo-treated subjects. RSV F variant V127A was present in 8 subjects at baseline. Population sequencing detected treatment-emergent substitutions in 10/89 (11.2%) HCT recipients with upper and 6/29 (20.7%) with lower respiratory tract infection, 1/35 (2.9%) lung transplant recipients, and 1/80 (1.3%) hospitalized patients treated with presatovir; placebo-treated subjects had no emergent resistance-associated substitutions. Subjects with substitutions at resistance-associated positions had smaller decreases in viral load during treatment relative to those without, but similar clinical outcomes. Conclusions: Subject population type and dosing regimen may have influenced RSV resistance development during presatovir treatment. Subjects with vs without genotypic resistance development had decreased virologic responses but comparable clinical outcomes.

Structural Insight into Paramyxovirus and Pneumovirus Entry Inhibition

“…Although the antiviral impact of presatovir was marginal in these trials, substitutions in signature resistance microdomains (i.e., at fusion peptide residues 127, 138, 140, and 141, at residues 399-401, and at residues 486-488) emerged in up to 11.2% of patients in treatment groups, but were absent from placebo-treated subjects [100]. Patients in which resistant viruses emerged experienced smaller reductions in viral load, but clinical outcome was similar to that in subjects without viral escape, indicating that resistant viruses replicate efficiently in vivo but do not cause enhanced disease.…”

Targeting the Respiratory Syncytial Virus N 0 -P Complex with Constrained α-Helical Peptides in Cells and Mice

“…Most of the antivirals under development aim at targeting the fusion protein (F), responsible for virus entry ( 28 , 29 ), or the enzymatic activities of L polymerase ( 30 – 32 ). Importantly, most of the studies focusing on these antivirals report the appearance of escape mutants upon selection pressure ( 33 – 39 ). The detection of novel specific targets is thus warranted to support the development of combination therapies to minimize the emergence of resistance.…”

“…(28,29), or the enzymatic activities of the L polymerase (30)(31)(32). Importantly, most of the studies focusing on these antivirals report the appearance of escape mutants upon selection pressure (33)(34)(35)(36)(37)(38)(39). Novel specific targets are thus warranted to support the development of combination therapies to minimize the emergence of resistance.…”

Anno 2021: Which antivirals for the coming decade?

“… 75 On the other hand, despite promising data from preclinical and preliminary clinical studies, 76 results from a recently completed Phase II clinical trial examining the efficacy of the pyrazolo[1,5-a]pyrimidines candidate presatovir (GS-5806; Gilead Sciences) revealed a lack of therapeutic benefit in adult hematopoietic cell transplant recipients 77 , 78 and low barrier to resistance. 79 While the clinical utility of RSV fusion inhibitors remains to be fully validated, the identification of new heterocyclic leads binding the viral surface F glycoprotein continues to be of interest to the medicinal chemistry community. A lead optimization strategy based on a machine learning algorithm led to novel compounds integrating the popular benzimidazole scaffold.…”