title: Evaluation of the safety, tolerability and pharmacokinetics of ALN-RSV01, a novel RNAi antiviral therapeutic directed against respiratory syncytial virus (RSV).
abstract: Small interfering RNAs (siRNAs) work through RNA interference (RNAi), the natural RNA inhibitory pathway, to down-regulate protein production by inhibiting targeted mRNA in a sequence-specific manner. ALN-RSV01 is an siRNA directed against the mRNA encoding the N-protein of respiratory syncytial virus (RSV) that exhibits specific in vitro and in vivo anti-RSV activity. The results of two safety and tolerability studies with ALN-RSV01 involving 101 healthy adults (65 active, 36 placebo, single- and multiple dose, observer-blind, randomized dose-escalation) are described. Intranasal administration of ALN-RSV01 was well tolerated over a dose range up through 150mg as a single dose and for five daily doses. Adverse events were similar in frequency and severity to placebo (normal saline) and were transient, mild to moderate, with no dose-dependent trend. The frequency or severity of adverse events did not increase with increasing ALN-RSV01 exposure. All subjects completed all treatments and assessments with no early withdrawals or serious adverse events. Physical examinations, vital signs, ECGs and laboratory tests were normal. Systemic bioavailability of ALN-RSV01 was minimal. ALN-RSV01 appears safe and well tolerated when delivered intranasally and is a promising therapeutic candidate for further clinical development.
authors.affiliation: Department of Pediatrics, University of Tennessee Health Science Center, 50 North Dunlap, Memphis, TN 38103, USA. jdevincenzo@utmem.edu
authors.forename: John
authors.initials: J
authors.lastname: DeVincenzo
authors.forename: Jeffrey E
authors.initials: JE
authors.lastname: Cehelsky
authors.forename: Rene
authors.initials: R
authors.lastname: Alvarez
authors.forename: Sayda
authors.initials: S
authors.lastname: Elbashir
authors.forename: Jens
authors.initials: J
authors.lastname: Harborth
authors.forename: Iva
authors.initials: I
authors.lastname: Toudjarska
authors.forename: Lubomir
authors.initials: L
authors.lastname: Nechev
authors.forename: Veeravagu
authors.initials: V
authors.lastname: Murugaiah
authors.forename: Andre
authors.initials: A
authors.lastname: Van Vliet
authors.forename: Akshay K
authors.initials: AK
authors.lastname: Vaishnaw
authors.forename: Rachel
authors.initials: R
authors.lastname: Meyers
mesh_terms: D000281:Administration, Intranasal; D000293:Adolescent; D000328:Adult; D000998:Antiviral Agents / Q000008:administration & dosage / Q000009:adverse effects* / Q000493:pharmacokinetics*; D006801:Humans; D008297:Male; D008875:Middle Aged; D034741:RNA, Small Interfering / Q000008:administration & dosage / Q000009:adverse effects* / Q000493:pharmacokinetics*; D012136:Respiratory Syncytial Viruses / Q000187:drug effects*; D014764:Viral Proteins / Q000037:antagonists & inhibitors*
chemical_list: D000998:Antiviral Agents; D034741:RNA, Small Interfering; D014764:Viral Proteins