Biology Reference
In-Depth Information
about 125 pM, the effects on extrapulmonary PDE4 or cell functions should be
minor, with little impact on the favorable findings with inhaled GSK256066 on
the airway allergen responses in that trial. As a corollary, the effects of inhaled
GSK256066 in these asthmatics are explained by the compound's deposition in the
lungs.
In a recently disclosed study (Laazar et al.
2010
), inhaled GSK256066 at 25 or
87.5
m
gkg
1
per day was administered to patients with moderate COPD in a
double-blind, placebo-controlled, randomized, 4-week trial. Primary end points
were safety and efficacy; secondary end points included lung function, biomarkers
of inflammation, and pharmacokinetics. In this trial, which was not powered to
detect significant differences in lung function, inhaled GSK256066 at 25 or
87.5
m
gkg
1
per day reduced the lung residual volume (RV) by 141 and 367 ml,
respectively (significant for the higher dose group). These findings may indicate a
potential to reduce hyperinflation, considered a hallmark in COPD. Whether this
observation translates into improved exercise capacity remains to be explored.
Other lung volumes such as total lung capacity (TLC) or FRC followed more or
less the findings for RV and there was a trend for (postbronchodilator) FEV
1
to
dose-dependently increase (by 50 and 91 ml at 25 and 87.5
m
gkg
1
per day). In
induced sputum, trends for a reduction in total proteins, IL-8, and myeloperoxidase
(MPO) were reported. As requested for an inhaled compound, no relevant systemic
PDE4-related adverse events were observed.
The solubility of GSK256066 is rather low (
2
m
M), which along with one of
the specificities of this quinoline that is slow reversal of [
3
H] GSK256066 binding
from PDE4 (indicating a long drug-target residence time) may support long dura-
tion of action favoring once-daily administration.
The development of two earlier PDE4 inhibitors used in inhaled programs for
COPD and asthma (tofimilast, 10, and UK-500,001, 11, both from Pfizer) (Danto
et al.
2007a
,
b
; Vestbo et al.
2009
) has been discontinued for lacking or low efficacy
in 6-week clinical trials (Vestbo et al.
2009
).
In aggregate, while earlier endeavors with inhaled PDE4 inhibitors have been
disappointing, initial experience with GSK256066 is more promising. On the basis
of enzymatic, physicochemical, and pharmacokinetic parameters disclosed,
GSK256066 was specifically designed for inhaled administration by integrating
long pharmacological duration of action in the lungs with minimal systemic
exposure. With curiosity new results of long-term studies with GSK256066 and
comparable inhaled PDE4 inhibitors in asthma and COPD are awaited that may
finally allow to assess whether there would be a position (and if affirmative where)
of a well-designed inhaled PDE4 inhibitor in the management of these respiratory
ailments.
The rationale behind developing PDE4 inhibitors specifically designed for
topical administration to the skin in dermal indications was to improve the thera-
peutic index. While more than 30 years after Stawiski's seminal discovery that
topically administered Ro 20-1724 reduces plaque size in psoriasis (Stawiski et al.
1979
), no topical PDE4 inhibitor for this dermal indication has gained market
access perhaps the most progressed and recent development is Anacor's AN2728
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