Evaluation of the safety, tolerability and pharmacokinetics of ALN-RSV01, a novel RNAi antiviral therapeutic directed against respiratory syncytial virus (RSV)

• Published in: Antiviral research Vol. 77; no. 3; pp. 225 - 231
• Main Authors: DeVincenzo, John, Cehelsky, Jeffrey E., Alvarez, Rene, Elbashir, Sayda, Harborth, Jens, Toudjarska, Iva, Nechev, Lubomir, Murugaiah, Veeravagu, Vliet, Andre Van, Vaishnaw, Akshay K., Meyers, Rachel
• Format: Journal Article
• Language: English
• Published: Amsterdam Elsevier B.V 01.03.2008; Elsevier
• Subjects: Administration, Intranasal; Adolescent; Adult; ALN-RSV01; Antibiotics. Antiinfectious agents. Antiparasitic agents; Antiviral; Antiviral agents; Antiviral Agents - administration & dosage; Antiviral Agents - adverse effects; Antiviral Agents - pharmacokinetics; Biological and medical sciences; Humans; Male; Medical sciences; Middle Aged; Pharmacology. Drug treatments; Respiratory syncytial virus; Respiratory Syncytial Viruses - drug effects; RNA interference; RNA, Small Interfering - administration & dosage; RNA, Small Interfering - adverse effects; RNA, Small Interfering - pharmacokinetics; RNA-induced silencing complex; Small interfering RNA; Viral Proteins - antagonists & inhibitors; Small interfering RNA; ALN-RSV01; Antiviral; Respiratory syncytial virus; RNA interference; RNA-induced silencing complex; Human; Human respiratory syncytial virus; Pneumovirinae; Healthy subject; RNA; Toxicity; siRNA; Intranasal administration; Paramyxoviridae; Dose activity relation; Virus; Gene silencing; Mononegavirales; Treatment; Pneumovirus; Pharmacokinetics
• ISSN: 0166-3542; 1872-9096
• DOI: 10.1016/j.antiviral.2007.11.009

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 150 mg 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.