Safety, tolerability, and pharmacokinetics of radavirsen (AVI‐7100), an antisense oligonucleotide targeting influenza a M1/M2 translation

Abstract

AIMSThe aims of the present study were to assess the safety, tolerability and pharmacokinetics of radavirsen following single ascending doses and multiple doses given as intravenous infusions in healthy adults. METHODSA phase I safety and pharmacokinetic study of radavirsen was performed in healthy volunteers. The study was divided into two parts. The first was a single-ascending-dose study of five cohorts of eight subjects each, randomized 6:2 to receive single intravenous doses of radavirsen ranging from 0.5 mg kg -1 to 8 mg kg -1 or placebo. The second was a multiple-dose study of 16 subjects randomized 12:4 to receive 8 mg kg -1 or placebo once daily for 5 days. RESULTSA total of 66 subjects were screened, and 56 subjects were dosed between 2013 and 2015. At least one adverse event occurred in 31/42 (74%) who received radavirsen, and 13/14 (93%) receiving placebo. The most common adverse events were headache and proteinuria, and were similar in incidence and severity among those receiving radavirsen or placebo. Single-dose pharmacokinetics demonstrated relatively linear and dose-proportional increases in maximal concentration and in area under the concentration-time curve from zero to 24 h (AUC 0-24 ). At 8 mg kg -1 in the multiple-dose cohort, the day 4 geometric mean AUC 0-24 was 57.9 μg*h ml -1 . CONCLUSIONSingle infusions of radavirsen up to 8 mg kg -1 , and multi-dosing at 8 mg kg -1 once daily for 5 days, appear to be safe and well tolerated in healthy subjects. The multi-dose day 4 AUC 0-24 in the present study was comparable with that associated with protection from viral infection in a preclinical ferret influenza model. Further evaluation of radavirsen for the treatment of influenza infections is warranted. British Journal of Clinical PharmacologyBr J Clin Pharmacol (2018) 84 25-34 25

Zoonotic Potential of Influenza A Viruses: A Comprehensive Overview

“…The sialidase activity of NA is exerted by specific and highly conserved aa residues (active sites). These aa residues are differentiated into 8 catalytic- and 11 framework residues ( Table 4 ) [ 287 , 288 , 289 ]. The catalytic residues interact directly with the substrate while the framework residues stabilize the catalytic residues.…”

“…Currently, further inhibitors are under investigation in late-phase clinical trials: (i) VX-787, an orally active inhibitor of PB2; (ii) S-033188, an orally active PA inhibitor; and (iii) AVI-7100, intravenously active, small interfering antisense RNA constructs, targeting influenza M1/M2 translation [ 277 , 278 , 287 ]. More recently, Scheuch et al showed that intranasally administered d,l -lysine-acetylsalicylate-glycine (LASAG), an anti-inflammatory derivative of Aspirin, resulted in a significantly faster alleviation of influenza symptoms, more rapid decline in viral shedding, and decreased risk of viral spread [ 306 ].…”

In vivoandin vitrostudies of antisense oligonucleotides – a review

“…106 For example, plasma half-lives for positively charged PMO used for the treatment of Marburg virus approximated 3 hours for humans and nonhuman primates. 108,110 A study conducted by Amantana et al 109 has shown rapid distribution to tissues of PMOs administered intravenously, with the initial distribution half-life ranging from 0.40 to 1.56 hours, while the elimination half-live did not exceed 9 hours. The highest ASOs concentration was detected in the kidney and liver with lower concentrations observed in the lungs, spleen, heart, and brain.…”

A Review of Therapeutics in Clinical Development for Respiratory Syncytial Virus and Influenza in Children

“…14 AVI-700 (radavirsen) is an antisense oligonucleotide that targets mRNA and inhibits viral translation of the M1 matrix protein and M2 ion channel in influenza A. 72 A Phase I trial has been completed, and no additional trials are registered to date. 14…”