Biology Reference
In-Depth Information
is the leading cause of death beyond the first year of lung transplantation [
29,
30
] .
Typically, patients with BOS present with cough and progressive shortness of breath.
Severity of BOS is determined by the extent of decline in a patient's lung function
as determined by pulmonary function testing and is graded on a scale of 0-3 [
31
] .
RSV infection after lung transplantation has been shown to be an independent risk
factor for the development of new or progressive BOS and acute rejection [
32-
36
] .
We hypothesized that treating RSV-infected lung transplant patients with ALN-
RSV01 would prevent the development of new or progressive BOS. To test this
hypothesis, we performed two Phase 2 studies in lung transplant patients infected
with RSV.
The first Phase 2a study, ALN-RSV01-106, was performed in adult lung trans-
plant patients infected with RSV [
37
]. In this multicenter, multinational, double-
blind, randomized, placebo-controlled study, 24 RSV-infected lung transplant
patients (randomized 2:1, ALN-RSV01 to placebo) were administered ALN-RSV01
at 0.6 mg/kg or placebo once daily by nebulization for 3 days, in addition to the
hospital's standard-of-care. Enrolled patients were stratified by ribavirin use to
avoid an imbalance of this antiviral medication in two the treatment arms. The pri-
mary end point was safety and tolerability. Secondary clinical end points of the
study included RSV infection characteristics (duration of viral shedding, viral clear-
ance, and overall viral load) and patient-reported symptom scores through day 14 as
well as pulmonary function parameters and BOS grade measured at day 90.
ALN-RSV01 was safe and well-tolerated. There was no difference between the
treatment groups in the incidence of respiratory AEs or serum cytokine measure-
ments. There were no drug-related SAEs, deaths, or discontinuations. Two indepen-
dent clinical outcomes indicated a possible therapeutic effect of ALN-RSV01. First,
the clinical symptom score (comprised of 16 symptom categories) showed improve-
ment starting on day 1 in ALN-RSV01-treated patients, including a statistically
significant difference in mean daily total symptom score from days 0 to 14 (
p
= 0.037)
and cumulative daily total symptom score compared to the placebo group (
p
= 0.035).
These effects were independent of treatment with ribavirin or high-dose steroids.
Secondly, the incidence of new or progressive BOS (primary end point) was
significantly decreased by 87.5% in the ALN-RSV01-treated subjects compared to
placebo (
p
= 0.027) (Table
15.1
). Supporting data was also seen in the number of
subjects that had a forced expiratory volume in 1 second (FEV1) < 80% of baseline
at day 90, which trended lower in the ALN-RSV01 group compared to placebo
(12.5 vs. 37.5%,
p
-value NS). No difference in any of the viral parameters could be
detected, likely due to the small numbers of patient in the study as well as the imbal-
ance in the baseline mean viral loads between the ALN-RSV01 and placebo groups.
In addition, studies indicate that adults have both lower RSV titers (up to 1,000-fold
lower) and a shorter duration of viral shedding than infants, which may lead to
greater variability in viral data and contribute to the potential difficulty of showing
antiviral efficacy in adult patient populations [
38,
39
] .
To confirm these encouraging results, a larger Phase 2b randomized, multicenter,
multinational, double-blind, placebo-controlled study in RSV-infected lung trans-
plant patients was commenced (ALN-RSV01-109) in February 2010 at 33 transplant
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