Phase 1 First‐in‐Human, Single‐ and Multiple‐Ascending Dose, and Food Effect Studies to Assess the Safety, Tolerability, and Pharmacokinetics of Presatovir for the Treatment of Respiratory Syncytial Virus Infection

Abstract

Respiratory syncytial virus (RSV)-associated respiratory tract infection is a leading cause of hospitalizations in infants for which no effective treatment exists. RSV infection is also an important cause of respiratory disease in adults and immunocompromised patients. Presatovir (GS-5806) is an orally bioavailable antiviral agent that inhibits fusion of RSV with host cell membranes. Here, results from 2 phase 1 studies that evaluated safety, tolerability, and pharmacokinetics of presatovir in healthy adults following administration of single and multiple (7 days) once- or twice-daily ascending doses (first-in-human study) and in the presence or absence of food (food effect study) are described. Presatovir exhibited favorable safety and pharmacokinetic profiles that supported once-daily dosing. Presatovir exposure increased in an approximately dose-proportional manner across the evaluated dose range (single doses 25-300 mg; multiple doses 10-75 mg once daily for 7 days). Administration of presatovir with a high-fat meal did not alter exposure, supporting administration without regard to a meal in further clinical studies. These data were subsequently used to inform presatovir dosing regimens in a phase 2a challenge study of adults experimentally infected with RSV. Collectively, results from phase 1 evaluations and a phase 2a challenge study support further clinical investigation of presatovir for the treatment of RSV infection.

Small molecule inhibits respiratory syncytial virus entry and infection by blocking the interaction of the viral fusion protein with the cell membrane

“…GS-5806 is the only RSV fusion inhibitor that has reached the late phase of clinical trials. It was efficacious in the treatment of healthy adults who were challenged with RSV (22,38,39). In vitro, GS-5806 exhibited a potent antiviral activity against RSV infection (EC 50 = 0.35 nM) and showed various levels of cytotoxicity in different cell lines (40).…”

RNA respiratory viral infections in solid organ transplant recipients: Guidelines from the American Society of Transplantation Infectious Diseases Community of Practice

“…Small mol ecule drugs including oral RSV entry inhibitor Presatovir (GS-5806) are under investigation. 84,96,97 Inhaled DAS181 is a recombinant fu sion protein that has shown promise in inhibiting PIV replication. 87 In addition, adoptive Tcell therapy including the generation of PIV specific 98 and hMPV 99 Tcells in healthy donors is an emerging therapeutic modality.…”

Respiratory syncytial virus in hematopoietic cell transplant recipients and patients with hematologic malignancies

“…Presatovir is an oral RSV fusion inhibitor with selective anti-RSV activity in vitro . In a phase I, first-in-human, single- and multiple-ascending dose study, 98 presatovir had an excellent safety profile, despite having an extended half-life. The oral bioavailability was also good, regardless of prandial state.…”

“…The oral bioavailability was also good, regardless of prandial state. 98 Although clinical trials on RSV infections in transplant recipients have been challenging due to low recruitment, 71 two phase II trials on presatovir in HCT recipients with RSV infections were recently completed 99,100 ( ClinicalTrials.gov number NCT02254408 ). To overcome potential low recruitment, 189 HCT recipients with RSV infections limited to the upper respiratory tract were recruited from a total of 43 centers in nine countries over 2.5 years.…”