title: Activity of Oral ALS-008176 in a Respiratory Syncytial Virus Challenge Study.
abstract: BACKGROUND Respiratory syncytial virus (RSV) infection is a cause of substantial morbidity and mortality. There is no known effective therapy. METHODS We conducted a randomized, double-blind, clinical trial in healthy adults inoculated with RSV. Participants received the oral nucleoside analogue ALS-008176 or placebo 12 hours after confirmation of RSV infection or 6 days after inoculation. Treatment was administered every 12 hours for 5 days. Viral load, disease severity, resistance, and safety were measured throughout the 28-day study period, with measurement beginning before inoculation. The primary end point was the area under the curve (AUC) for viral load, which was assessed immediately before administration of the first dose through the 12th day after inoculation in participants infected with RSV. RESULTS A total of 62 participants received placebo or one of three ALS-008176 dosing regimens: 1 loading dose of 750 mg followed by 9 maintenance doses of 500 mg (group 1), 1 loading dose of 750 mg followed by 9 maintenance doses of 150 mg (group 2), or 10 doses of 375 mg (group 3). In the 35 infected participants (23 of whom were treated with ALS-008176), the AUCs for viral load for groups 1, 2, and 3 and the placebo group were 59.9, 73.7, 133.4, and 500.9 log10 plaque-forming-unit equivalents × hours per milliliter, respectively (P≤0.001). The time to nondetectability on polymerase-chain-reaction assay (P<0.001), the peak viral load (P≤0.001), the AUC for symptom score (P<0.05), and the AUC for mucus weight were lower in all groups receiving ALS-008176 than in the placebo group. Antiviral activity was greatest in the two groups that received a loading dose--viral clearance was accelerated (P≤0.05), and the AUC for viral load decreased by 85 to 88% as compared with the placebo group. Within this small trial, no viral rebound or resistance was identified. There were no serious adverse events, and there was no need for premature discontinuation of the study drug. CONCLUSIONS In this RSV challenge study, more rapid RSV clearance and a greater reduction of viral load, with accompanying improvements in the severity of clinical disease, were observed in the groups treated with ALS-008176 than in the placebo group. (Funded by Alios BioPharma; ClinicalTrials.gov number, NCT02094365.).
authors.affiliation: From the Departments of Pediatrics, Microbiology, Immunology, and Biochemistry, University of Tennessee College of Medicine, and the Children's Foundation Research Institute at Le Bonheur Children's Hospital - both in Memphis (J.P.D.); Alios BioPharma, South San Francisco (M.W.M., J.A.S., C.W., S.C., Q.Z., L.B., L.M.B., J.F.); Retroscreen Virology, London (H.F., R.L.-W.); d3 Medicine, Parsippany, NJ (P.S.); and the University at Buffalo School of Pharmacy and Pharmaceutical Sciences, Buffalo, NY (P.S.).
authors.forename: John P
authors.initials: JP
authors.lastname: DeVincenzo
authors.forename: Matthew W
authors.initials: MW
authors.lastname: McClure
authors.forename: Julian A
authors.initials: JA
authors.lastname: Symons
authors.forename: Hosnieh
authors.initials: H
authors.lastname: Fathi
authors.forename: Christopher
authors.initials: C
authors.lastname: Westland
authors.forename: Sushmita
authors.initials: S
authors.lastname: Chanda
authors.forename: Rob
authors.initials: R
authors.lastname: Lambkin-Williams
authors.forename: Patrick
authors.initials: P
authors.lastname: Smith
authors.forename: Qingling
authors.initials: Q
authors.lastname: Zhang
authors.forename: Leo
authors.initials: L
authors.lastname: Beigelman
authors.forename: Lawrence M
authors.initials: LM
authors.lastname: Blatt
authors.forename: John
authors.initials: J
authors.lastname: Fry
mesh_terms: D000284:Administration, Oral; D000293:Adolescent; D000328:Adult; D000998:Antiviral Agents / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics; D019540:Area Under Curve; D003841:Deoxycytidine / Q000008:administration & dosage / Q000009:adverse effects / Q000031:analogs & derivatives* / Q000493:pharmacokinetics; D004311:Double-Blind Method; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D009093:Mucus; D018357:Respiratory Syncytial Virus Infections / Q000188:drug therapy* / Q000821:virology; D012136:Respiratory Syncytial Viruses / Q000302:isolation & purification / Q000502:physiology; D019562:Viral Load / Q000187:drug effects; D014779:Virus Replication / Q000187:drug effects; D055815:Young Adult
chemical_list: D000998:Antiviral Agents; D003841:Deoxycytidine; C000597470:4'-chloromethyl-2'-deoxy-3',5'-di-O-isobutyryl-2'-fluorocytidine