101. RFJC – NAVIGATOR

We’re back with another Rapid Fire Journal Club. Luke Hedrick and Dave Furfaro discuss the NAVIGATOR trial published in NEJM in 2021 evaluating tezepelumab for adults with asthma. Article and Reference We are talking today about the NAVIGATOR trial evaluating … Continue reading →

Episode Transcript

(00:16):
Hey, everyone. Thanks for tuning in. We are
back again with another rapid fire journal club
episode. As always, I'm joined by our associate
editor who is in charge of rapid fire
journal clubs, Luke Hedrick. Hey, Luke. How's it
going?
Hey, Dave. Happy to be here. I'm loving
these asthma guideline episodes. And,
as a a budding asthma aficionado myself, I

(00:37):
couldn't resist jumping and piggybacking off of that
with this paper today. Please. Yes. There's always
more to add. I'm glad that people have
been finding them helpful. We've been having a
blast recording them. For those who haven't listened,
we've been going through the GINA guideline
best practices in asthma therapy. And one of
those episodes, we're talking about biologic therapies, and
Luke wanted to talk about one of these
landmark trials today. So we are gonna be

(00:59):
discussing today the navigator trial from the New
England Journal of Medicine in 2021.
Luke, you are gonna be an expert in
all things inflammation and airways. Can you give
us a little background
of what preceded the navigator trial?
Oh, man. That's that's quite the bill. I
feel like the more I learn about the
inflammatory cascades, the more I realize I I

(01:20):
don't actually know what, like, t cells are,
but
I do my best.
Take it till you make it. Yeah.
So I think the relevant background here is
that there are multiple biological agents that are
being used for severe asthma,
all of which previously have targeted IgE
or type two cytokine signaling, so IL four,

(01:40):
IL five, IL 13.
These have revolutionized
asthma care, but there is an unmet need
for new therapies for patients with non allergic
or non eosinophilic
phenotypes.
So tezepelumab
is a monoclonal antibody that binds to thymic
stromal lymphopoietin
or TSLP,
which is a very upstream mediator of both

(02:01):
t two and non t two inflammatory
signaling.
Thanks, Luke. Yes. This is a complex set
of pathways that we're always trying to learn
and wrap our head around. I think that
is a great background. And the important thing
is to note that the landscape this trial
was coming into is that biologic
therapy for asthma did exist. Right? We were

(02:23):
already using
therapies that targeted IgE, like omalizumab.
We were using therapies that targeted some of
these cytokines you mentioned, IL five, commonly, mepilizumab,
benralizumab,
IL four, tapilumab. And we knew that IL
13 was playing a role in this, but
this was trying to get at an agent
or a a node a little bit higher

(02:44):
upstream
from all of these to see if it
could have an increased effect.
So in trying to answer this question, what
kind of study design and trial did they
choose to run?
Yeah. So this was a phase three, multicenter,
double blind, placebo controlled RCT in 18 different
countries
that ran from November 2017

(03:04):
to September 2020.
Yeah. Impressive. So this has all the right
words you're looking for, double blind placebo controlled
randomized 18 countries. Again, I have a lot
of generalizability
coming out of this study.
And anything we're thinking about treating asthma, there
are multiple type of outcomes that we can
look at to see if our therapy has
been effective. So what did they choose as

(03:26):
their primary outcome, and what did they choose
as their secondary outcomes?
Yeah. So they looked at a handful of
things. Their primary outcome was the annualized rate
of exacerbations,
which they
communicated as events per patient year. There were
some key secondary outcomes here, change in baseline
pre bronchodilator
FEV one,
symptoms, and quality of life via a variety

(03:48):
of scores.
They
which I really appreciated in their paper too,
also went ahead and defined what the minimum
clinically important difference was for all of these
studies as well.
That's great. Yeah. These are the meaningful outcomes
that we have come up in our episodes
so far. Rate of it, we know this
is an exacerbating disease and that people have
morbidity and mortality associated with their exacerbations. So

(04:11):
I think thinking about annualized rate of exacerbation
is certainly very appropriate. And then we get,
very, very clinically relevant for the patient symptoms
and quality of life and the very physiologic
change in FEV one. We've also talked in
our episodes about really the importance of phenotyping
in asthma. You mentioned already
that we are thinking about different cytokines, different

(04:31):
inflammatory pathways, and we have different measures that
can help us get a clue about which
patients with asthma
may have elevated inflammation, may have a role
from IgE or a rate role from eosinophils,
and this phenotyping in garter therapy. And so
the I know in this trial, they talked
about some subgroups to try to get at
a little bit of this phenotyping.

(04:53):
So can you tell us about the subgroups
that they predefined that we can then look
at later when our when we're talking about
the results?
Yeah. So they looked at patients with varying
levels of baseline absolute eosinophil count, FeNO or
that fractional exhaled nitric oxide,
and then perennial allergen sensitivity.
And so, again, getting at the idea that

(05:13):
the landscape that this paper was being published
into was one in which
a number of biologics did exist and were
being used. And so given how upstream
the mechanism of action that tesapilumab
has is,
the hope was that it might be effective
for folks who don't have t too high
inflammation that, you know, could have gotten a

(05:35):
biologic that was already in use.
And then one other neat thing they did
too just from a study design standpoint, is
some hierarchical testing.
They did that just because of how many
different analyses they were running. You always worry
about your type one error or your false
positive error rate going up just from running
a bunch of tests. And so they

(05:55):
looked first at the overall primary outcome and
then the primary outcome with low eosinophils, and
then they looked at key secondaries. And so
really trying to do things in a thoughtful
way to minimize the
effect on their outcomes just from the statistical
design. Yeah, that's great. I think they have
good preparation. We're going to be able to
have very meaningful results from this, and we're

(06:16):
going to be able to understand how these
baseline factors influence those results.
Another thing we've talked about in our asthma
series is really the importance of appropriate medical
therapy, how inhaled corticosteroids have become the cornerstone
of therapy. And so when we're thinking about
our inclusion criteria and our exclusion of who
these patients should be, we really wanna hone

(06:37):
in on what therapies they've been on, what
their current asthma looks like. So what were
the key inclusion and exclusion to get into
this trial?
Yeah. So from an inclusion standpoint,
relatively broad. It was patients aged 12 to
80
with asthma on either a medium or high
dose inhaled corticosteroid
or ICS
for at least twelve months before screening, and

(06:59):
then also had some kind of additional controller
medication like a LABA, some bronchodilator
for at least three months before consent,
which is a mealy mouth way of saying,
generally speaking, patients from 12 to 80 with
guideline appropriate medical therapy.
Those people also had to have had at
least two exacerbations
in the last twelve months, which they defined

(07:21):
as worsening symptoms that led to systemic steroids
for three or more days, an ED visit
leading to steroid use, or any hospital admission.
Fantastic. These people were on the therapy that
we were hoping to get and pretty frequent
exacerbators too. Exacerbations the last twelve months would
definitely raise my antenna if I was in
pulmonary clinic seeing the patient.
And who do they wanna exclude from this

(07:42):
trial to make sure we had the best
pure design?
Yeah. So in terms of exclusion criteria,
they excluded anyone who had their diagnosis for
less than twelve months.
And then on spirometry, there were a handful
of things they wanted to see. Anybody who
had a pre bronchodilator
FEV one of greater than eighty percent or
ninety percent for adolescents was excluded.

(08:03):
And then anyone who didn't show bronchodilator
response or that reversibility
on their PFTs within the last twelve months
was also excluded.
And then the last thing was just recent
alternative biologic use, which makes sense. These drugs
have super long half lives, and they wanted
to make sure that they were studying the
effect of the actual study drug and not
something else you may have taken recently.

(08:26):
Yeah. And this is really a pure test
of this. We can listen to our episodes
or think later about combination biologic therapies, but
that is not what they were trying to
look at this test. And then in excluding
some of the spirometry
factors, they really wanted to get at people
who they think can benefit from this therapy,
who are having significant burden of disease, and
are gonna be the most likely to have

(08:47):
a benefit
from additional therapy. Luke, your patented one line
summary of who we're gonna be getting into
this trial and who it applies to?
Yeah. So thinking about that table one, in
summary, these were middle aged, predominantly white and
female patients
with poorly controlled severe asthma despite high intensity
medical treatment.

(09:08):
About seventy five percent of them were on
high dose inhaled steroids and about ten percent
were actually on oral steroids.
The mean pre bronchodilator FEV1 was sixty two
percent predicted or so. And notably, about forty
percent had normal phenos and just under sixty
percent had a eosinophil count under 300.
The median IgE as well was about a

(09:29):
95.
And so not a little distinct from some
of the other patient populations and other trials.
Yeah. This is really important for this is
we're getting at a group with really poorly
controlled asthma. Some of them on standing oral
corticosteroids
that maybe we might not be predict the
most responders to this drug, right, or to

(09:50):
conventional biologic therapy. And so if we can
find something that's gonna help them, this is
gonna make a huge impact. And I'll just
add that in the design of this, they
really had specific monitoring
to make sure the distribution of those clinical
factors was staying stable as they recruited patient.
So twenty percent had to be on a
medium dose ICS, forty percent had to have
three exacerbations or more, and about fifty percent,

(10:13):
they got close, had to have that high
eosinophil count, leaving the rest to have a
low eosinophil count. And so I think just
a really thoughtful design and then recruitment of
patients into this trial.
So what kind of power do they wanna
see? What were they assuming was gonna be
the impact of this? And then how did
they do in recruiting their patients?
Yeah. So their power calculation got done assuming

(10:36):
a fifty percent relative reduction in the annualized
asthma exacerbation rate. And that needed
a little or excuse me, right around a
60 patients, which is pretty much what they
enrolled. So their n was a thousand and
sixty one,
that got stratified based on age, either adult
or adolescent, and then geographic region. So what

(10:56):
part of the globe, Asia Pacific, Central Eastern
Europe, etcetera.
And then they randomized them one to one
to tesapilumab
or placebo
as a sub q injection every four weeks
for fifty two weeks.
Fantastic.
I I'd like the power being 50% relative
reduction.
And when you just read that, it seems

(11:17):
like an astounding amount of effect you're gonna
think the drug's gonna happen.
Although, then you think about the inclusion, and
it was two exacerbations. So you're really going
from two to one, which is still very
clinically meaningful, but that's how I think that
they're getting the fact that they think this
is gonna work to at least prevent one
or both exacerbation
or more.
And then we had talked a little bit

(11:37):
before about what happens at the end of
this trial. I think they go through these
fifty two weeks, and a lot of these
studies have a defined post treatment protocol. Anything
you want to talk about there? Yeah. So
at fifty two weeks, they patients either entered
a twelve week post treatment follow-up period or
the long term extension study, which was called
destination.
And then one other just note about their

(11:59):
intervention too is that no changes were made
during the trial to their pre enrollment medications.
So they did not try to tweak their
inhaled steroid, their bronchodilator,
or for the folks who are on oral
steroids, they did not try to reduce those
during the study either.
It's great. Really getting at the impact of
our intervention.
And then you always love to see a
long term follow-up extension so that even if

(12:20):
this trial is meaningful, that you're gonna have
some longitudinal data. And it's great that even
for the people not in that, we have
at least three months of follow-up to see
how they were doing.
Alright. We have all our lead in done.
Let's get to the meat of the story.
So what was the efficacy outcomes that they
found in this trial?
Yeah. So this was a positive trial. The

(12:41):
annualized asthma exacerbation rate was point nine three
versus 2.1,
giving them a rate ratio of point four
four, a p value of less than point
o o one.
When they looked at that same outcome for
folks with an absolutely eosinophil count of under
300,
it was a smaller but still persistent effect.
So one point zero two versus one point

(13:02):
seven three with a rate ratio of 0.59.
That pattern of smaller but still present effects
bore out across
the absolute eosinophil count groupings, the whatever their
FeNO was
or whether they had perennial
allergen sensitivity.
That's great. Huge impact, right? We have our

(13:23):
rate ratio of 0.44
overall. And I think really getting at what
they wanted to see as well is that
even with an absolute use in a book
out less than that 300, we're still having
a very clinically meaningful impact on these patients
by nearly half in the rate of exacerbation
they had and persistent across all of those
subgroups.
What else? Any other additional Yeah. Now to

(13:44):
you? So from a spirometry standpoint, their pre
bronchodilator FEV one increased by about a quarter
of a liter in the intervention arm versus
point zero nine liters. That was also statistically
significant.
Interestingly, they saw that difference as early as
week two, and then that was stable throughout
the study.
And then thinking about a quality of life

(14:06):
standpoint as well,
across three different measures
of same patient reported symptom burden,
the
symptom burden was lower in the intervention arm
statistically,
but all three of them were less than
the minimum clinically important difference. And so unclear
how much the symptoms truly got better in
a meaningful way for patients.

(14:27):
Yeah. I love that. We've talked about this
before. The word significant becomes so loaded in
interpreting trials because this is just telling you,
yes, there is a statistical difference whether or
not you can tell patients this will make
them feel better. It remains up in question
given below that minimal clinical
important difference that we predefined.
And then two of the points that I'll

(14:49):
add to the findings for this, we're talking
about relevant overall very positive findings from this
trial. One sort of negative note is that
still about forty percent or more people in
the tesapilumab
arm had an exacerbation. So
these are frequent exacerbators. I think often patients
are not expecting a total cure all, but
it's important to note to them that

(15:10):
nearly half of people still had an exacerbation,
so they shouldn't expect that it's impossible that
this all goes away. But a really big
selling point is that the exacerbations that were
had on the treatment arm were less severe.
So they were less frequently required in a
mission or an ED visit, and that's a
huge impact on patient quality to just be
able to get steroids at home and not

(15:31):
have to be hospitalized
is a major selling point. And so I
talk to patients about this. It's the same
feel I give with the flu vaccine is,
yeah, you might still have an exacerbation, but
we think we're protecting
from having a severe exacerbation, and that's important.
Yeah. Absolutely. I think that's a theme in
so much of what we're doing in pulmonary
is ideally preventing

(15:51):
bad outcomes in general. But if you're gonna
have it trying to make it less severe
for you, that's true. Just like you said
in the flu vaccine, that's also true in
our smart therapy.
I'll that's a theme, I think, that emerges
in pulmonary, but especially in asthma.
Absolutely.
Alright. Anytime we are advising our patients about
a new medication, the first question I always
get are what are the side effects? Is

(16:12):
this safe? And people do get freaked out
by the word biologic. They get freaked out
by the sub q administration of the drug,
although more and more there are drugs that
are delivered that way. So what safety outcomes
where do we see that we can help
talk to our patient?
Yeah. So these were interesting to read. At
first glance, there was a little concerning, but
overall, this actually was quite safe and well

(16:33):
tolerated. So
seventy seven percent reported some kind of adverse
effect and nine point eight percent a serious
one with two percent of patients stopping therapy
due to one.
But these were all actually more common in
the placebo arm. And for whatever reason, the
placebo arm seemed like people were having more
side effects than the actual drug. The most
common ones that folks had were an upper

(16:54):
respiratory
tract infection,
a headache, or inflammation of the nasal passages,
nasopharyngitis.
In terms of more serious complications, the incidence
of severe infection and cancer were no different,
and
three point six percent of patients had an
injection site reaction in the drug arm. Nobody
had anaphylaxis, and there were no cases of

(17:15):
GBS. And so, again,
taking a step back, this was a safe
and well tolerated intervention.
Yeah. Fantastic. That's the bottom line. Very important
to be able to tell patients that. And
do sometimes tell them they might have an
upper respiratory
or at least symptoms that mimic an upper
respiratory that nasopharyngitis,
but really good to know that,
no serious adverse events. And, yeah, that's why

(17:37):
we run a placebo arm. Sometimes the adverse
events happen more in that arm and that,
you know, tells us something.
Alright. So what's our overall takeaway from the
navigator trial?
Yeah. So for me, when I take a
step back,
this paper showed that tesapelumab
significantly reduces asthma exacerbations
and markers of inflammation

(17:57):
and improves lung function, asthma control, and health
related quality of life regardless of someone's baseline
biomarkers.
Fantastic.
This is drug has become commonplace in our
armamentarium
for patients who are having asthma,
uncontrolled asthma even on maximum inhaler therapy, even
sometimes on oral therapy.

(18:18):
And we will go beyond this trial to
talk about how you choose which biologic pair
patient, not a topic for today, but great
that we know we have a an upstream
drug that can really influence these things.
Alright. Well, thank you, Luke. Appreciate you taking
us through this trial.
Yeah. Thanks for having me. This was fun.
Alright, everybody. We'll see you next time when
you tune in.