A
broad
population
of
people
with
chronic
obstructive
pulmonary
disease
(COPD),
current
and
former
smokers
alike,
experienced
fewer
exacerbations
taking
a
first-in-class
biologic
targeting
interleukin
(IL)-33,
a
pair
of
double-blind
trials
showed.
In
OBERON
and
TITANIA,
the
addition
of
once-monthly
tozorakimab
injections
to
standard
inhaled
maintenance
therapy
resulted
in
fewer
moderate
or
severe
COPD
exacerbations.
Among
former
smokers,
the
annualized
rate
of
these
exacerbations
occurring
over
a
52-week
period
was
significantly
lower
with
tozorakimab
than
placebo
in
both
studies:
-
OBERON:
1.34
vs
1.90
events
(RR
0.71,
95%
CI
0.57-0.88) -
TITANIA:
1.37
vs
2.07
events
(RR
0.66,
95%
CI
0.55-0.80)
This
result
was
replicated
in
an
overall
population
of
former
and
current
smokers
in
the
two
trials:
-
OBERON:
1.41
vs
2.00
events
(RR
0.70,
95%
CI
0.58-0.85) -
TITANIA:
1.44
vs
2.03
events
(RR
0.71,
95%
CI
0.59-0.84)
“Tozorakimab,
a
first-in-class
biologic,
demonstrates
a
valuable
potential
therapeutic
agent
for
our
patients
with
COPD
who
continue
to
exacerbate
despite
guideline-based
therapy,”
said
Frank
Sciurba,
MD,
of
the
University
of
Pittsburgh,
presenting
the
two
trials
at
the
European
Respiratory
Society
(ERS)
Congress,
held
this
year
in
Barcelona,
Spain.
OBERON
and
TITANIA
were
simultaneously
published
in
the
New
England
Journal
of
Medicine.
These
phase
III
trials
now
position
tozorakimab
as
another
option
for
biologic
treatment
in
COPD.
With
its
unique
targeting
of
IL-33
—
setting
it
apart
from
IL-4/IL-13
blocker
dupilumab
(Dupixent)
and
IL-5-targeting
mepolizumab
(Nucala)
—
tozorakimab
potentially
adds
another
way
for
clinicians
to
tailor
therapies
to
patients
based
on
biologic
parameters.
Of
note,
OBERON
and
TITANIA
did
not
restrict
enrollment
by
blood
eosinophil
count,
unlike
the
trials
for
dupilumab
and
mepolizumab.
“With
tozorakimab,
we
really
move
more
upstream
towards
the
airway
epithelium,
and
kind
of
having
more
response
towards
these
innate
immune
challenges,
such
as
everything
that
we
inhale,
but
also
particulate
damage,”
commented
Lena
Uller,
PhD,
MSc,
of
Lund
University
in
Sweden.
“If
we
can
block
this
response,
we
could
have
an
effect
on
inflammation,
not
just
T2
inflammation,
but
bronchial
hyperactivity
and
exacerbation.
So
I
think
it’s
really,
really,
really
interesting
with
the
data
you
presented
with
tozorakimab
today,”
Uller
said
as
the
ERS
session
discussant.
Tozorakimab
is
a
monoclonal
antibody
that
inhibits
the
activity
of
IL-33,
which
can
act
on
multiple
inflammatory
pathways
and
is
implicated
in
the
pathogenesis
of
COPD.
Multiple
studies
have
shown
the
large
role
that
IL-33
plays
in
allergic
inflammation
by
driving
persistent
type
2
immune
responses;
IL-33
is
also
associated
with
increased
mucus
production
and
vascular
endothelial
permeability,
contributing
to
inflammation.
Maker
AstraZeneca
said
tozorakimab
is
under
priority
review
at
the
FDA
with
an
approval
decision
expected
in
early
2027.
Sciurba
addressed
an
audience
question
on
why
tozorakimab
succeeded
in
the
present
trials
whereas
other
IL-33
agents
have
failed
in
COPD.
“It
could
be
due
to
multiple
different
things,”
he
said
during
the
Q&A
portion
of
the
ERS
session.
“IL-33
is
a
very
complex
molecule.
It
has
multiple
conformational
states
and
where
the
antibody
binds
on
that
molecule plausibly
makes
a
difference,
and
that
very
well
may
have
been
the
case
with
this
molecule.”
Studies
are
ongoing
to
clarify
tozorakimab’s
mechanism
of
action
in
preventing
COPD
exacerbations,
the
trialists
noted.
OBERON
and
TITANIA
were
replicate
phase
III
trials,
conducted
at
separate
sites,
with
nearly
900
participants
each
(mean
age
67-68
years
across
study
arms,
around
65%
men).
Eligible
patients
were
adults
with
COPD
who
were
current
or
former
smokers
and
had
a
history
of
exacerbations
in
the
previous
year
despite
being
on
stable
inhaled
maintenance
therapy.
Patients
had
to
have
had
at
least
two
moderate
or
one
severe
recent
COPD
exacerbation.
Patients
with
clinically
significant
or
radiologically
evident
pulmonary
disease
other
than
COPD
were
ineligible,
including
those
with
asthma.
Sciurba
and
colleagues
had
trial
participants
randomized
to
add-on
subcutaneous
tozorakimab
(300
mg)
or
placebo
every
4
weeks
for
52
weeks.
In
both
trials,
the
primary
endpoint
counted
moderate
exacerbations
(resulting
in
treatment
with
systemic
glucocorticoids
for
at
least
3
days
or
antibiotics
or
both,
or
an
emergency
department
visit)
and
severe
ones
as
well
(those
leading
to
hospitalization
or
death).
Tozorakimab’s
efficacy
was
supported
by
1-year
improvements
in
prebronchodilator
forced
expiratory
volume
in
1
second
and
total
scores
on
the
Evaluating
Respiratory
Symptoms
in
COPD
assessment.
Another
key
secondary
endpoint,
change
in
the
St.
George’s
Respiratory
Questionnaire
total
score,
trended
in
favor
of
the
tozorakimab
group
without
reaching statistical significance.
As
for
safety,
adverse
events
occurred
in
a
similar
70.4%
with
tozorakimab
versus
77.2%
with
placebo
in
OBERON
and
80.1%
versus
79.8%,
respectively,
in
TITANIA.
Though
rare,
major
adverse
cardiovascular
events
were
numerically
more
frequent
with
tozorakimab
than
with
placebo
(0.4%
vs
0),
as
were
serious
adverse
events
that
resulted
in
death
(1.3%
vs
1.2%).
Monitoring
of
rare
safety
events
requires
longer
follow-up
and
a
larger
sample
than
was
available
in
OBERON
and
TITANIA,
the
investigators
acknowledged.
They
also
cautioned
that
adherence
to
inhaled
maintenance
therapy
was
not
monitored
systematically
in
these
trials,
nor
were
they
able
to
assess
efficacy
among
patients
who
had
never
smoked.
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