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

DeVincenzo, John P.; Cehelsky, Jeffrey; Alvarez, Rene; Elbashir, Sayda M.; Harborth, Jens; Toudjarska, Iva; Nechev, Lubomir V.; Murugaiah, Veeravagu; Vliet, André van; Vaishnaw, Akshay; Meyers, Rachel

doi:10.1016/j.antiviral.2007.11.009

Cited by 221 publications

(162 citation statements)

References 19 publications

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“…On the other hand, the duration of dosing of ALN-RSV01 was possibly suboptimal to achieve maximal reductions in viral load or RSV disease measures in infected subjects. Previous phase 1 studies of ALN-RSV01 had evaluated its safety with intranasal dosing in a 5-day dosing scheme (16). Therefore, due to regulatory considerations, we also evaluated a 5-day dosing regimen in this proof-of-concept study.…”

Section: Discussionmentioning

confidence: 99%

“…d, study day; h, hours; i.n., intranasal; RSV, inoculation with RSV, with quantity of inoculum administered to subjects in each cohort indicated in the boxes labeled "Cohort 1" and "Cohorts 2-6"; Rx, dosing with ALN-RSV01 or placebo. Cohorts 1-6 consisted of 8,8,18,16,24, and 14 subjects, respectively. Three subjects (1 active, 2 placebo) were withdrawn from cohort 6 due to foodrelated gastroenteritis having received one study drug dose and without receiving RSV inoculation.…”

Section: Discussionmentioning

confidence: 99%

“…Upon intranasal delivery to the lungs of mice, ALN-RSV01 reduces lung RSV concentration by 3-4 Logs compared to mismatched siRNA controls when administered before RSV inoculation and by 2-3 Logs when given 1-2 days following inoculation (15). ALN-RSV01 was safe when administered intranasally to healthy volunteers at doses up to 150 mg daily for 5 days (16). Healthy adults can be experimentally infected with RSV, causing a self-limited upper respiratory illness (17).…”

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confidence: 99%

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A randomized, double-blind, placebo-controlled study of an RNAi-based therapy directed against respiratory syncytial virus

DeVincenzo

Lambkin‐Williams

Wilkinson

et al. 2010

Proc. Natl. Acad. Sci. U.S.A.

387

293

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RNA interference (RNAi) is a natural mechanism regulating protein expression that is mediated by small interfering RNAs (siRNA). Harnessing RNAi has potential to treat human disease; however, clinical evidence for the effectiveness of this therapeutic approach is lacking. ALN-RSV01 is an siRNA directed against the mRNA of the respiratory syncytial virus (RSV) nucleocapsid (N) protein and has substantial antiviral activity in a murine model of RSV infection. We tested the antiviral activity of ALN-RSV01 in adults experimentally infected with wild-type RSV. Eighty-eight healthy subjects were enrolled into a randomized, double-blind, placebocontrolled trial. A nasal spray of ALN-RSV01 or saline placebo was administered daily for 2 days before and for 3 days after RSV inoculation. RSV was measured serially in nasal washes using several different viral assays. Intranasal ALN-RSV01 was well tolerated, exhibiting a safety profile similar to saline placebo. The proportion of culture-defined RSV infections was 71.4 and 44.2% in placebo and ALN-RSV01 recipients, respectively (P = 0.009), representing a 38% decrease in the number of infected and a 95% increase in the number of uninfected subjects. The acquisition of infection over time was significantly lower in ALN-RSV01 recipients (P = 0.007 and P = 0.03, viral culture and PCR, respectively). Multiple logistic regression analysis showed that the ALN-RSV01 antiviral effect was independent of other factors, including preexisting RSV antibody and intranasal proinflammatory cytokine concentrations. ALN-RSV01 has significant antiviral activity against human RSV infection, thus establishing a unique proof-of-concept for an RNAi therapeutic in humans and providing the basis for further evaluation in naturally infected children and adults.antiviral | RNA interference | small interfering RNA | RSV R NA interference (RNAi) is a highly conserved natural cellular mechanism of posttranscriptional regulation observed in eukaryotic cell types (1), including mammalian cells (2, 3). Specifically, RNAi is mediated through the RNA-induced silencing complex (RISC) and involves the targeted cleavage of messenger RNA by the complementary, antisense strand of a double-stranded, small interfering RNA (siRNA) resulting in suppressed expression of the corresponding protein. The discovery of RNAi raises the possibility that this cellular pathway can be harnessed as a unique approach to treat human disease. This possibility has been underscored recently by many in vivo studies of RNAi as treatment in a wide range of animal models of disease, including hypercholesterolemia (4, 5), viral hepatitis (6), Huntington's disease (7,8), and cancers (9). However, definitive evidence is lacking from well-controlled studies for the effectiveness of an RNAi therapeutic against any human disease.Respiratory syncytial virus (RSV) is the most common cause of infant hospitalization in the United States, producing ≈10-fold higher mortality rates than influenza in this population (10). RSV also produces significant m...

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

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A randomized, double-blind, placebo-controlled study of an RNAi-based therapy directed against respiratory syncytial virus

DeVincenzo

Lambkin‐Williams

Wilkinson

et al. 2010

Proc. Natl. Acad. Sci. U.S.A.

387

293

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“…A second lot of RSV M37 was acquired by Alnylam Pharmaceuticals to test the efficacy of a small interfering RNA (siRNA) directed against the mRNA of RSV N protein [35]. Although a trend was seen in the ALN-RSV01-treated group toward a lower viral load, the study was not powered to detect a statistically significant difference.…”

Section: Challenge Models Enable Proof-of-concept For Rsv Antiviral Dmentioning

confidence: 99%

Controlled human infection with RSV: The opportunities of experimental challenge

Habibi

Chiu

2017

Vaccine

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“…So far, the therapeutic potential of siRNA has been demonstrated successfully both in vitro and in vivo (Shim and Kwon 2010) while a number of siRNA-based therapy clinical trials have been initiated, including therapeutics directed against inherited skin disorder (Leachman, Hickerson et al 2009), solid tumor (Davis, Zuckerman et al 2010), respiratory syncytial virus (RSV) infection (DeVincenzo, Cehelsky et al 2008;DeVincenzo, LambkinWilliams et al 2010) and age-related macular degeneration (AMD) (Kaiser, Symons et al 2010). Until now however, there are no pDNA or siRNA-based therapeutic products approved by the FDA; the lack of an efficient and safe delivery system being the major hurdle to limit the clinical application of nucleic acids.…”

Section: Introductionmentioning

confidence: 99%

Endosomal Escape Pathways for Non-Viral Nucleic Acid Delivery Systems

Liang¹,

Lam²

2012

Molecular Regulation of Endocytosis

122

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

Cited by 221 publications

References 19 publications

A randomized, double-blind, placebo-controlled study of an RNAi-based therapy directed against respiratory syncytial virus

A randomized, double-blind, placebo-controlled study of an RNAi-based therapy directed against respiratory syncytial virus

Controlled human infection with RSV: The opportunities of experimental challenge

Endosomal Escape Pathways for Non-Viral Nucleic Acid Delivery Systems

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