Written in Blood
Featured research from recent issues of Blood
Paper Spotlight
New Target Holds
Potential for Treatment
of Common Anemia
Lexaptepid, an antihepcidin therapy, may be
the first viable treatment
option for patients with
anemia of inflammation,
according to the results
of an experimental study
published recently in Blood.
Hepcidin is a principal
regulator of iron homeostasis and has therefore been a
target for novel therapeutics
to treat iron disorders such
as anemia. In the small
study, use of lexaptepid
resulted in clinically relevant
hepcidin inhibition in a group
of healthy subjects with
an inflammation-induced
reduction in serum iron.
“We think that a hepcidin-targeted therapy, such
as the one investigated in
our study, will be a valuable addition to the current treatment options,”
lead study author Lucas
van Eijk, MD, of Radboud
University Medical Center
in Nijmegen, Netherlands,
told ASH Clinical News.
20
ASH Clinical News
Novel Target May Be
a Breakthrough for
Anemia of Inflammation Treatment
During inflammation,
inflammatory cytokines
stimulate the production
of hepcidin by the liver.
Hepcidin leads to the
internalization and degradation of the cellular
iron exporter ferroportin,
which is expressed on
liver cells and reticuloendothelial cells that
store iron and on duodenal cells that absorb
dietary iron. When ferroportin is reduced in the
cell membrane of those
cells, less iron is released
into the bloodstream
and circulating iron levels
decrease — meaning that
less iron is available for
erythropoiesis in the
bone marrow. Inflammation-induced production
of hepcidin ultimately
leads to iron restriction
of the bone marrow, con-
tributing to the development of anemia.
Currently, anemia of
inflammation is treated
with erythropoietin or
intravenous iron supplementation. However,
these treatments are not
always successful.
In contrast, the
hepcidin-targeted therapy
lexaptepid should result
in the release of iron from
reticulo-endothelial cells,
making it more available
for the production of
erythrocytes by the bone
marrow — helping to ameliorate the condition.
Evaluating Efficacy
Dr. van Eijk and colleagues designed this
randomized, doubleblind, placebo-controlled
trial to evaluate lexaptepid in humans. The study
included 24 healthy men
who were given 2 ng/kg
purified standard reference Escherichia coli (E
coli.) endotoxin to induce
a controlled state of inflammation. The subjects
were randomly assigned
to receive a 15-minute
1.2 mg/kg infusion of
placebo or lexaptepid half
an hour later.
Subjects in both groups
experienced a marked
induction of serum iron in
the first hours after E coli
administration. Thereafter, subjects in the placebo group saw a decline
in serum iron as hepcidin
concentrations increased.
In contrast, those subjects
given lexaptepid had a
prolonged increase in
serum iron concentration,
peaking at six hours posttreatment administration.
At nine hours postadministration, serum
iron had increased by
15.9 µmol/L from baseline in subjects assigned
lexaptepid compared with
a decrease in serum iron
of 8.3 µmol/L in subjects assigned placebo
(p<0.0001).
Interestingly, data
showed that 24 hours to
48 hours after treatment
serum iron concentrations
were lower in subjects
treated with lexaptepid
than in subjects who received placebo.
“We suspect that the
prolonged and strongly
elevated serum iron
concentrations may have
stimulated hepcidin production to overcome the
effect of lexaptepid, eventually resulting in hepcidininduced hypoferremia,” the
researchers wrote.
As a secondary endpoint, the researchers also
evaluated the effect of
lexaptepid on the innate
immune response. They
observed that all subjects
experienced a similar lipopolysaccharide-induced
inflammatory response.
Flu-like symptoms, body
temperature, C-reactive
protein, leukocyte counts,
and cytokine concentrations were similar between subjects given the
investigational drug and
those assigned placebo.
“Based on the pharmacology of lexaptepid,
we expect patients who
are iron-replete but who
do not respond well to
erythropoietin to respond
best to lexaptepid,” Dr.
van Eijk said. “This could
be patients with chronic
kidney disease, patients
with cancer-related
anemia, or patients with
rheumatic disorders.”
According to Dr. van
Eijk, lexaptepid could
also represent the first
specific treatment for
iron-refractory iron deficiency anemia (IRIDA), a
rare condition caused by
genetic mutations leading
to inappropriately high
hepcidin production.
Now that this study has
provided proof of concept,
the researchers plan to
evaluate the effect of
lexaptepid in patients with
anemia of inflammation. At
F