Biology Reference
In-Depth Information
Fig. 15.3
Estimates of RSV infection. (
a
) Percent of cumulative subjects infected with RSV are
shown for ALN-RSV01 (
light blue line
) and placebo (
dark blue line
) with RSV infection deter-
mined by quantitative culture (plaque assay) (
p
= 0.0069), or (
b
) percent of cumulative subjects that
were uninfected with RSV are shown for ALN-RSV01 (
blue bar
) and placebo (
gray bar
) with
RSV infection determined by plaque assay (
p
< 0.01)
shedding duration, and clinical symptom scores showed favorable trends for ALN-
RSV01 but were not statistically significant due to insufficient powering of the
study for these end points. The antiviral effect was shown to be independent of
intranasal inflammatory cytokine concentrations, suggesting that the effect is medi-
ated by specific inhibition of RSV and not an indirect immune-stimulatory
mechanism.
Treatment with ALN-RSV01 was safe and well-tolerated. There were no severe
adverse events (SAE), and the incidence of adverse events (AEs) was similar
between subjects receiving ALN-RSV01 and placebo. There was no difference in
the level of i.n. cytokines (TNF-alpha, IFN-alpha, G-CSF, and IL-1RA) between
ALN-RSV01-treated subjects and placebo. Thus, this study determined that i.n.
administration of ALN-RSV01 was both safe and effective, demonstrating proof of
concept for the first time that ALN-RSV01 had antiviral activity in humans in an
experimental model of RSV infection. Based on the results from our Phase I studies
as well as allometric scaling from our preclinical toxicology studies, the dose of
ALN-RSV01 to be used for further clinical studies was chosen to be 0.6 mg/kg.
15.3.3
Phase 2 Studies in RSV-Infected Lung Transplant Patients
Lung transplant patients have increased susceptibility to infection with community
acquired viruses due to their immunosuppression and the fact that the transplanted
lung is in direct communication with the environment. Chronic graft dysfunction in
the transplanted lungs, as manifested by bronchiolitis obliterans syndrome (BOS),
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