A Phase 2b, Randomized, Double-blind, Placebo-Controlled Multicenter Study Evaluating Antiviral Effects, Pharmacokinetics, Safety, and Tolerability of Presatovir in Hematopoietic Cell Transplant Recipients with Respiratory Syncytial Virus Infection of the Lower Respiratory Tract

Abstract

Background: Presatovir significantly reduced nasal viral load, signs, and symptoms of respiratory syncytial virus (RSV) infection in a human challenge study. We evaluated presatovir in hematopoietic-cell transplant (HCT) recipients with RSV lower respiratory tract infection (LRTI).

Methods: Patients with confirmed RSV in upper and lower respiratory tract and new chest X-ray abnormalities were randomized (1:1), stratified by supplemental oxygen and ribavirin use, to receive oral presatovir 200 mg or placebo every 4 days for 5 doses. The primary endpoint was time-weighted average change in nasal RSV viral load through day 9. Secondary endpoints included supplemental oxygen-free days, incident respiratory failure requiring mechanical ventilation, and all-cause mortality.

Results: From January 31, 2015, to March 20, 2017, 60 patients from 17 centers were randomized (31 presatovir, 29 placebo); 59 received study treatment (50 allogeneic, 9 autologous HCT). In the efficacy population (29 presatovir, 28 placebo), presatovir treatment did not significantly reduce time-weighted average change in viral load (-1.12 vs -1.09 log10 copies/mL; treatment difference -0.02 log10 copies/mL, 95% confidence interval: -.62, .57; P = .94), median supplemental oxygen-free days (26 vs 28 days, P = .84), incident respiratory failure (10.3 vs 10.7%, P = .98), or all-cause mortality (0 vs 7.1%, P = .19) versus placebo. Adverse events were similar between arms (presatovir 80%, placebo 79%). Resistance-associated substitutions in RSV fusion protein emerged in 6/29 presatovir-treated patients.

Conclusions: Presatovir treatment was well tolerated in HCT patients with RSV LRTI but did not improve virologic or clinical outcomes versus placebo.

Clinical trials registration: www.clinicaltrials.gov, NCT02254421; EudraCT, #2014-002475-29.

Keywords: Presatovir; hematopoietic cell transplant; lower respiratory tract infection; respiratory syncytial virus.

Figure 1.

Patient disposition from screening through analysis. The adverse events leading to discontinuation of study drug were acute liver injury with cholestasis in 1 presatovir-treated patient; and sepsis and respiratory failure, bacterial infection and pancytopenia, and leukopenia in 1 placebo-treated patient each. ^aIncludes the patient who withdrew consent without completing study treatment. ^bIncludes the patient who died before completing study treatment. ^c1 patient in each group did not have detectable RSV RNA on day 1. Abbreviations: LRT, lower respiratory tract; RSV, respiratory syncytial virus.

Figure 2.

Presatovir treatment did not significantly reduce respiratory syncytial virus (RSV) RNA relative to placebo. Panel (A) shows median nasal RSV RNA and panel (B) shows median change from baseline in nasal RSV RNA at each study visit in patients treated with presatovir (solid circles and lines) vs placebo (open circles, dashed lines) in the efficacy population. Error bars represent the interquartile range. Numbers below the graph are n at each time point.