98. Guidelines Series: GINA Guidelines – Biologics for Treatment of Asthma

Today, we continue our review of the Global Initiative for Asthma (GINA) guidelines on asthma. We’ve covered asthma diagnosis and phenotyping, and the initial approach to therapy. On today’s episode we’re talking about biologic therapies for asthma and will cover … Continue reading →

Episode Transcript

(00:16):
Hey everybody. Welcome back to Palm peeps. We
are very excited to be back again today
with another episode in our guideline series about
asthma.
And today I think is one of the
most interesting topics. One of the ones that
comes up the most for our pulmonary fellows
and certainly for our patients, which is the
use of biologic therapy for asthma patients, really
a game changing paradigm shift in therapies.

(00:38):
Christina, you are podcasting live from Cabo right
now. How are you? How's the vacation?
Doing great for I know. I think I'm
gonna put a plug in for we should
do, like, a live Palm Peeps podcast
next time in Cabo or somewhere tropical, but
really excited to be here. As you mentioned,
this is such a big area with biologics

(01:00):
for severe asthma treatment, not only for our
patients, but really for our trainees.
I know our our fellows will be joined
by probably and Tom a little bit later
today in the show as well. But such
an area that I think people wanna understand
more and really excited to
have a guest today who is an expert
in this area.
So with that, I'm gonna go ahead and
introduce our guest for today, who's doctor Megan

(01:22):
Conroy.
Megan completed her fellowship training at the Ohio
State University, where where she is currently an
assistant professor of medicine and is also the
associate program director for curriculum and quality
in the PCCM fellowship there. Megan's clinical area
of expertise involves asthma and biologic therapies,
and she was recently recognized for her work
in this area as a twenty twenty four

(01:42):
chest airway disorders network rising star. Such an
honor to have you on the show today,
Megan.
Thanks so much, Christina. I'm excited to be
here and looking forward to our discussion on
this today.
Yeah. Thanks, Megan. We really appreciate it. I
also wanted to make one point that you
pointed out to us and actually a couple
other people have mentioned as well is that
this has been our guideline series initiative. We

(02:05):
really wanna help fellows, residents, faculty
understand what the core recommendations are for different
disease processes.
But you pointed out that there is an
important distinction between what Gina does or what
gold does and what like a true guidelines
do. And that guidelines have a real set
of criteria. They have to use narrow PICO
questions to provide the guidance where Gina is

(02:26):
giving more sweeping guideline or report on how
we should manage asthma and severe asthma. And
so it has a little bit more flexibility
in that, which makes it a really helpful
tool, but just that thing to point out
for our listeners.
And with that, we will welcome back our
fellows who are leading this series. They've been
unbelievably
dedicated and successful at this thus far, but

(02:47):
Roopali and Tom from, Johns Hopkins joining us
again. Welcome back to the show.
Thanks, Dave. Excited to be here and back
delving into this topic that, as Monte mentioned,
is near and dear to our hearts and
our everyday clinical practice. So can't wait for
the discussion.
Good morning, everyone. Happy to be here.
Awesome.
And so with that, we will dive in.

(03:09):
First, our standard disclaimer, we are gonna be
talking about a bunch of different medical topics.
None of the things we discuss are for
specific medical advice in a specific case. The
opinions we discuss may not reflect those of
our employers.
And if we talk about patients, the patients
will either be fictionalized or they will have
had data changed to protect their identity.

(03:30):
For today, the roadmap is gonna be that
we're gonna cover the definition of biologic
therapies, and we're gonna talk about which patients
are suited for this or which patients have
this as an indication.
We'll talk about the different types of biologic
therapies that are available for asthma treatment, how
to choose the right one, and then the
real world impact of these therapies using the
GINA
guidelines as a frame of reference for all

(03:51):
of
this. So, Roopali, hopefully you can start us
off with a case.
Sure, Dave. So I had a patient come
to clinic. She's a 27 year old woman
who came to establish care with me in
clinic with a history of multiple hospitalizations
for exacerbations in the past year.
She had fortunately gotten lab work done before
she came to see me, and her lab
showed that she had elevated peripheral eosinophils

(04:14):
at 500,
high IgE levels in the hundreds as well,
and a positive allergic RAS panel for cats,
dogs, and various pollens suggesting she was sensitized
to some of these allergens.
She at that time was on a daily
low dose inhaled corticosteroid
with a long acting beta
agonist, but was still struggling to control her
symptoms. She was also reporting to me that

(04:35):
she had frequent bouts of what sounded like
sinusitis
requiring some antibiotic courses in the past. We
discussed a few things at that visit,
minimizing her exposures to these allergens. We uptight
treated her to a medium dose SMART, her
single maintenance and reliever therapy
with her ICS laba
during this visit. And we also started a
leukotriene antagonist to see if that might help.

(04:58):
I additionally sent her to the ear, nose,
and throat specialist to further explore her sinusitis
and possibly evaluate whether she could have any
comorbid conditions like nasal polyps.
Given her persistent symptoms and her type two
inflammation
per her phenotyping,
I started thinking about a biologic targeting some
of those type two pathways that might be
the next step in breaking the cycle of
exacerbation.

(05:19):
Megan, based on that case, when do you
typically start thinking about biologics for your patient?
Yeah. Thanks for that summary, Rapalini. I think
that's the exact type of case and the
right time to start thinking about these biologics
ahead of pulling that trigger.
And before talking really specifically about when we
start the biologics, I'd actually like to point
out several

(05:40):
really important notes that you made there in
your approach to this patient
before starting a biologic.
Particularly, you started to explore some of the
allergic sensitization
and considered some ways to maybe mitigate her
exposures.
You also thought about other cofactors like her
chronic rhinosinusitis
and work to control those symptoms. And I
agree, I'll also engage a multidisciplinary

(06:02):
team like otolaryngologists
and allergists when I've got these complex cases
that are difficult to control.
One really key aspect that I think we
take for granted, both in our clinical case
discussions and our real world care, so it's
worth calling it out, is the very simple
but very important
nature of assessing our inhaler technique for our

(06:24):
patients.
And this really comes back and brings us
back to a key distinction,
between difficult to control asthma and severe asthma,
because not all difficult to control asthma is
truly severe.
So some estimates suggest that probably about twenty
percent of patients with asthma are difficult to
control,
but only about five percent of patients with

(06:46):
asthma have severe asthma.
So what's really happening in that other fifteen
percent?
Most commonly, that's the impact of other uncontrolled
cofactors like gastroesophageal
reflux, chronic sinusitis,
nasal polyps, untreated sleep apnea, post nasal drip,
smoking, anything, vaping, THC, cigarettes,

(07:08):
frequent allergen exposures, and other cofactors that can
drive poor asthma control.
And when we address these other entities, a
lot of times, the asthma comes under control.
And also in that fifteen percent, that difference
between twenty percent difficult to control and only
five percent of being severe
are patients who aren't taking their inhalers correctly
or as often as they should. So while

(07:28):
seemingly simple, not these complex biologic drugs, it
takes time and intention
and, importantly, knowledge of how to use these
inhaler devices
to be able to teach our patients to
use them and to check-in over time.
Just like anything else you learn in fellowship
and beyond, our knowledge can degrade over time,
and so I recommend continually reassessing

(07:50):
how your patients are taking their inhalers to
make sure that what you have prescribed is
actually getting into their airways.
I joke with my patients, like, I give
you a pill, you swallow it. I'm pretty
sure it's in your body, but it's not
the same with inhalers because these are hard
medications to take. And so it's an important
point to note and an important aspect in
the assessment of whether or not a patient

(08:12):
has severe asthma because all the medical decision
making you describe, Repali, totally appropriate.
And the last key is delivering that medicine
into the patient.
So I'll come to biologic therapy in patients
who really, despite optimizing all of the comorbidities
that can impact their asthma control
and ensuring that they're getting and taking their
combination controller inhalers correctly

(08:34):
through that stepwise care
who continue to have poor asthma control as
evidenced by at least two exacerbations in one
year requiring oral corticosteroids
or any patient who requires daily oral corticosteroids
to control their asthma.
Now, thankfully, these biologics are quite effective medications,
but they're also costly.

(08:54):
They're not entirely without side effects,
and we don't really have clearly defined off
ramps of stopping these medications after we start
using them. So it is prudent to ensure
that you've got holistic care alongside your step
ups in care towards biologics
because it's important to know that really not
all of those twenty percent of patients with

(09:16):
difficult to control asthma should be on biologic
therapy.
Thanks, Megan. That was so wonderful to walk
through, and we're probably such a great case
to bring up as well. I think a
lot of those listening today probably have the
opportunity to take care of a patient very
similar to the patient that you cared for
in clinic. And, Megan, thank you for bringing
up such an important point. Right? It's a
basic point as you mentioned, but so important

(09:38):
is what are our patients actually taking? Right?
Are they getting their medications,
filled on time? Are they actually taking them?
As you said, you can assess, can they
swallow the pill? But are they actually getting
the inhaler
technique down right? And they are they actually
getting the medication delivered to where it needs
to be in such an important thing to
do, I think, both in the clinic and
in the inpatient setting. I was recently on

(09:59):
service and we had a patient who got
a new type of inhaler prescribed to her,
which was on our pharmacy formulary.
And I'll say that the entire team had
some difficulties in trying to figure out how
to use the inhaler correctly for her. It
was, like, the clicking and the coordination was
really difficult. It was, like, I even struggled
with it a bit. So I was like,
I can understand how this is really happening

(10:20):
in real world. Fortunately, we were able to
get it fixed for her and we did
some great teaching that we all benefited from,
but such an important pot topic to think
about.
And I wanna even take a step step
back, really looking forward to all of the
things that you were mentioning, Megan, that we'll
get to at during this episode. But taking
a step back and talking and reminding ourselves
about this type two inflammatory

(10:41):
pathway or phenotype. And we brought this up
in our first asthma series a few weeks
ago. And you may have remembered, we talk
about some of that for type two inflammation.
Some of the key players were eosinophils,
biomarkers could be high eosinophils as well as
high fractional
X held nitric oxide.
Trigger types for allergens, steroid responsiveness, we said

(11:01):
is usually high in this phenotype
and treatment included in held corticosteroids.
And then we briefly brought up biologics and
preview this episode when we talked about that.
But unlike bronchodilators
or systemic corticosteroids,
biologics
target key immune system components,
which really are so great and fantastic though,
because they can offer additional therapeutics for patients

(11:22):
whose asthma has been difficult to control.
And, Tom, I'd love if you can walk
us through a little bit more so list
listeners today can understand
the type two inflammation pathway.
Yeah, absolutely. Thinking about
these different inflammatory mediators is a little bit
of a throwback to immunology from medical school
with the reappearance of cytokines and interleukins and

(11:44):
things of that sort. But we can think
of these biologics as blocking key players
in this type two inflammatory
cascade. There's actually a lot of really great
review articles that you could just do a
quick Google search for that have nice pictures
of where these different biologics target.
The key ones that we're thinking about with
our biologic therapies

(12:05):
are
IgE, which is involved in the allergic response,
as well as mast cell activation,
IL five, which is involved in the production
and survival
of the eosinophils.
IL four and IL 13,
these contribute to airway, hyper responsiveness, mucus production,
and can potentiate IgE synthesis.

(12:27):
And then also much higher up the pathway
is a molecule called TSLP.
This is an upstream pathway that affects multiple
downstream pathways
and, plays an important role in some of
our different types of biologics.
Thanks, Tom, for walking us through that and

(12:48):
giving us a little reminder of some of
the pathways we discussed and we'll make sure
that we share some images with folks so
they have a good reference.
Now that we understand the targets, I wanna
make sure that we talk to the biologics
systematically about when we're gonna be thinking about
them, about how they work and how we
can apply them for our patients. And so
to do this, kind of wanna set the
stage. Megan brought us some great points that

(13:08):
difficult to control asthma and severe asthma have
different definitions. They're not exactly the same. And
so, Rupali, I was hoping you could tell
us what GINA says about how we should
be thinking about our patients for who should
be on biologic therapy and when we should
be considering them.
Yeah. Thanks, Dave. According to the GINA guide
2024,
biologics should be considered for patients with severe

(13:30):
asthma who meet a few different criteria. So
one, they remain uncontrolled,
their asthma despite high dose
inhaled corticosteroids
combined with long acting beta agonist.
Two,
these patients have frequent exacerbations that, like Megan
mentioned, require systemic steroids or hospitalizations.
And three, there shows some evidence of type

(13:52):
two inflammation as we've been talking about. This
includes elevated eosinophils. One fifty is often the
lower threshold for cutoff.
Increased fractional exhaled nitric oxide, like we discussed
in our previous episodes, or asthma symptoms that
seem to be allergen driven.
So in summary, we should be thinking about
using biologics in patients with severe uncontrolled

(14:12):
asthma despite being optimized on medium or high
dose ICS LAVA treatment
with
usually more than one to two exacerbations in
whom we see clear markers of type two
inflammation.
The GINA guide also highlights the importance of
intervening early with these biologics
because in the long run, they can help
minimize steroid exposure and actually

(14:35):
optimize long term lung function decline and prevent
that from happening. So according to the GINA
guide 2024, I think about biologics
in that subset of patients who maybe meet
those three criteria
after, as Megan had mentioned, we ensure that
they're using their inhalers correctly and are actually
getting the medicines that are prescribed to them.

(14:56):
Also, thanks so much, Rupali. A great framework
for the rest of our show today. And
I think really turning to try to understand
almost like a matching pair now. Right? Which
biologic,
what does it target and which patient population
is this gonna be best suited for? And
so glad to have Megan on. I Megan
and I have the opportunity to work together
on the chest t and t committee. And
Boston, Megan actually had the brainchild to one

(15:18):
of the live questions for the chest challenge
was actually matching biologics
with their,
target pathway as well as indications. So for
those listening today, we won't reuse it as
a question for, chest
twenty twenty five, but just anything anything in
pulmonary critical care medicine can be used for
patients and real world as well as for

(15:38):
chest challenge and medical trivia. But, Megan, based
off of that, tell us a little bit
more DA approved biologic therapies that are available
currently.
Yeah. Sure. So the first longest standing approved
biologic is omalizumab.
This is known under the brand name of
Xolair, and this is an anti IgE monoclonal
antibody. And this is approved for use in

(15:59):
allergic asthma among other indications.
Next on the scene is mepilizumab,
known under the brand name of Nucala.
This is for use in eosinophilic
asthma and is an anti IL five monoclonal
antibody.
There's also an IV medication.
It's less frequently used because it's IV and
not subcutaneous called reslizumab.

(16:19):
This is under the brand name Syncair, and
this is also for use in eosinophilic asthma
as an anti IL five.
Benralizumab,
known under the brand name of Fasenra, is
an anti IL five receptor
monoclonal antibody, also for use in eosinophilic asthma.
Dupilumab,
known under the brand name of Dupixent,

(16:40):
targets the
IL four receptor alpha subunit, which is a
receptor subunit also shared by IL 13. So
it targets both IL four and IL 13
by targeting that alpha subunit.
And that's approved for use in eosinophilic and
allergic asthma among other indications.
Also recently in October 2024, got an indication

(17:02):
for use in COPD
with eosinophilia.
So dupilumab with use not just in asthma
in the pulmonary world.
And then new newest on the scene as
of 2021
is tezapelumab,
which is known under the brand name of
Tezbire.
And this is an anti TSLP or that
thymic stromal lymphopoietin
upstream

(17:23):
mediator
that is for use in both t two
high asthma
and can be used in t two low
asthma phenotypes, and this is the first and
only drug that we can use there.
Thanks, Megan, for walking us through that. And
also just to just to to our listeners,
you don't have to be an expert at
pronouncing all these names to be an expert
pulmonologist.
So, you know, and no pressure there. Manya,

(17:45):
I was hoping you could help us with
the link between phenotyping
and picking a biologic. I love that in
pulmonary and critical care medicine, we're moving a
lot toward more towards phenotyping,
personalized medicine. I think these medications
are an indication of that, especially when they're,
we're using them. Like, as you mentioned, dupilumab
and COPD now when we have an eosinophilic
component.

(18:06):
But when you're talking to a patient, how
much are you focusing on the target pathway,
measuring biologic measures of that target pathway versus
other clinical factors that you gather from examining
or talking to the patient to hit the
right drug?
Yeah, absolutely. I think it's really a combination
of the both.
It's a difficult task if we say pick

(18:27):
the one best biologic for any given patient
in front of you. It's a trick question.
There may not be only one. And and
in general, I would say that I really
will approach
choice for a patient, both by considering all
of the totality of data of what do
I have to say is the predominant
driving inflammatory pathway in this patient,

(18:47):
which also involves knowing other comorbidities
that are big factors for this patient.
So if they have other comorbidities that might
be impacted by biologics,
I conceptualize this as
another
area of evidence of the systemic manifestations
of that inflammatory
pathway.
So patients who have concomitant food allergies,

(19:10):
IgE mediated food allergies may be a predominant
allergic phenotype. Those who have chronic rhinosinusitis
and nasal polyposis
may have good effects from IL five or
IL four targets.
For eczema, really with the IL four target,
and it's same for eosinophilic esophagitis.
These are entities that
some of these drugs carry independent FDA labeling

(19:30):
for. So our dermatology colleagues and our GI
colleagues and our ENT colleagues are prescribing these
for those indications.
And if you've got a patient with severe
asthma and some of these other diseases,
it seems to me that's probably helpful in
establishing
a more confident
inflammatory
endotyping for that patient. That's really kind of

(19:50):
the question we're getting at when we say
pick which biologic is best is what pathway
do you think predominates
in driving this patient's asthma?
So, you know, as some concrete examples, I
might choose omalizumab,
not just for a patient whose total IgE
is high and who I find sensitization
to a perennial aeroallergen,
so that's the biomarker data, But really in

(20:13):
that patient whose asthma by clinical history is
truly driven by exposure to these sensitized antigens.
Other factors that should play a role are
things like whether or not a patient is
on chronic oral corticosteroids.
This is maybe one of the most important
things to play into a decision, to choose
a drug that has evidence
to assist in reducing oral corticosteroid dosing,

(20:35):
which we have in
dupilumab,
mepelizumab,
benralizumab,
and omalizumab,
but tesapolumab
does not have evidence to reduce oral corticosteroid
use.
And so for many patients, several of these
biologics could be a reasonable choice.
And without any head to head randomized controlled
trials,
there is very low certainty of evidence to

(20:57):
definitively guide you one way or another. To
reframe this difficulty,
I'll say there are really multiple reasonable choices.
And if at first you don't succeed,
you
have additional options that you can try as
a second line, which compared to twenty years
ago is a really exciting space to be
in in severe asthma, and quite honestly is
a part of why I do this work.

(21:20):
Thanks, Megan. That was fantastic and a great
way for us to think
how to match a certain patient's certain phenotype
with a biologic.
So Jason summarized, once the patient has clear
asthma and optimal treatment with evidence of type
two inflammation, the next step is really to
choose the right biologic. The genome guide does
give some specific indicators for some of these

(21:42):
biologics,
which lends to patients qualifying for these drugs,
which as you mentioned is part of choosing
the right biologic as well. So omalizumab,
as you mentioned, for allergic asthma with high
IgE levels ranging from 30 to 700 affecting
dosing
for the IL five blockers that you mentioned,
the meprelizumab,
brasolizumab, benralizumab
or the eosinophilic asthma with different cutoffs of

(22:03):
EO cutoffs that range from one fifty to
400, depending on which drug is chosen.
Depilumab, when there's eosinophilic
asthma with comorbidities,
like you had mentioned, nasal polyps, eosinophilic esophagitis,
atopic dermatitis.
And then as we mentioned,
tislepilizumab
for broader severe asthma, even when the biomarker

(22:24):
thresholds aren't met and potentially be prescribed
in that setting.
So, Megan, I know we have gone over
all of the FDA approved biologics at this
time. We went over what the GINA guide
recommends as your day to day practice, but
are there situations when even these strict categories
are not something that you abide by and
when you have to think outside of them?

(22:44):
And how do you think about navigating
the biologic selection a little bit more?
Yeah. And, really, these categories that are described
in the JINA guide derive from
the FDA approval for these medications,
which is, of course, from the inclusion criteria
and the randomized trials
that prove their utility for use.
And not really deviating strongly from any of

(23:07):
these categories, right, because this is the area
in which they are proven to use the
patients that you're predicting to have the best
response for. But, really, as mentioned before, there
may be
multiple reasonable options for a patient. They might
fall into a couple of these strict categories.
And, really, when that happens, I think choosing
between them, it really may be subtle aspects

(23:28):
that push you one way or another,
necessarily dev deep deviating deeply outside of these
categories.
But I think probably the biggest example where
you might be pushed outside of that, unfortunately,
there are some examples of insurance formularies pushing
you out. So certain systems that you work
in might say you have to try
omalizumab
first before you can try a second drug.

(23:49):
If the patient doesn't fit criteria for allergic
asthma
with an IgE and a weight within dosing,
don't do it. Right? It doesn't make sense
to deviate
based on an insurance formulary or insurance guidance
for a patient that's not gonna respond to
this to this medication there. One nice thing
that the GINA guide does, not only in
these categories,

(24:10):
they also give some nice algorithms that try
to overlay some of the factors that might
predict better response to a drug. So things
like a higher FeNO,
higher absolute eosinophil counts. And, again, this really
comes to evidence of
strong
endotyping that is the predominant inflammatory pathway driving
asthma for those patients. So it makes sense
that if you're more deeply within that, you

(24:31):
have higher levels in that inflammation, you're gonna
respond a little bit better. And so it
can make it so clear as mud, but
sometimes it can give you some of the
nuance to to push one way or another.
Thanks so much, Megan. Yeah. I think so
such an important point, as you said, that
looking at the patient in front of us,
and sometimes we can have restrictions, as you
said, based off of insurance, but really trying

(24:53):
to make the best decision that you think
for a patient and really comes down to,
I know, a shared decision making. I think
one of the things that we're hoping to
do today is help those listening today really
understand
kind of practical implications of choosing the biologic
for someone. And one of that we haven't
really discussed yet, but hoping you could get
into more is really this dosing frequency

(25:14):
as well as route of administration. I know
the majority are subcutaneously
administered, but one intravenously,
which I know can really make a big
difference in real world use.
So hoping that you can walk us through
a little bit to more on how you
think about that and how you start to
talk about this with your patients, as well
as sorry, I'm gonna repeat that sentence.

(25:34):
Hoping Megan, that you can talk to us
a little bit more about how you incorporate
this route of administration, as well as frequency
with your patients when you're talking with them
in clinic?
Yeah. Absolutely. First, I'd say route of administration
is a big driver in my practice, the
subcutaneous versus intravenous.
My practice is honestly 100
on the subcutaneous

(25:54):
administration.
I don't know that I've ever prescribed
reslizumab
as the IV version, and that's really because
of ease of use. Since the pandemic, these
subcutaneous medications, we can use all of them
now by self administration
at home.
And, overall, that is the route that my
patients prefer because it's just so much easier.
In our clinic, we've got protocols for patients

(26:16):
to get their first one to three doses
in the clinic with a nurse. We partner
with clinical pharmacists to get them more medication
training, and then the patients are able to
take this at home, and they do really
well managing it on their own.
Pragmatically, sometimes there's reason to administer it in
a health care facility, so things like infusion
centers. And this comes down, honestly, to insurance

(26:38):
or strong patient preference.
If you deliver an infusion center, oftentimes, that's
processed through medical benefits compared to a home
administration is processed through pharmacy benefits.
So when we talk about disparities in access,
sometimes, if someone has limited pharmacy benefits but
good medical benefits,
this can be the difference between whether or
not they can get access to the medication,

(26:59):
and so exploring both venues can be helpful.
Frequency of administration does come up. We can
span every two weeks to every eight weeks
at longest between these medications.
And And when you're able to give it
at home, every two weeks may not be
that big of a deal if you're not
needing to drive or come into a health
care facility.
But maybe for needle phobic patients, so patients

(27:20):
young on the younger end, perhaps, who are
maybe just transitioning from pediatric care, I experienced
might have a little bit more needle phobia,
or some patients whose job or lifestyle
takes them traveling away from home
frequently.
Longer time between administrations
may make it more feasible to use these
medications because they require refrigeration, and it's not

(27:41):
like you get and they're delivered on a
monthly basis, usually. If you're traveling for four
weeks at a time, it can be very
difficult to get properly store and take those
medications,
say, people who are working internationally or traveling
internationally in retirement.
So sometimes working with patients on the frequency
and the route of administration there, be at
home or an infusion center, it really needs

(28:03):
to be personalized to be able to fit
into their life.
That's great. Thanks for going over all those,
Megan. And I think it really shows us
how we can personalize.
There's so many options out there now, fortunately,
and different
routes and timing that we can personalize our
care. Just to summarize for our listeners, a
quick rundown of the different dosing we're talking

(28:23):
about here for these drugs.
Omalizumab,
this is dosed every two to four weeks,
making sure that you're paying attention to the
patient's weight and their IgE levels because the
dosing is dependent upon those.
Mebelizumab
is dosed every four weeks as a subcutaneous
administration.
Rizaluzumab

(28:44):
is every four weeks, and that's the IV
formulation that we've mentioned.
Benralizumab
is every four weeks initially, and that is
spaced out every eight weeks.
Depilumab
is every two weeks and tezapilumab
is every four weeks. It's definitely part of
the shared decision making conversation.
These
schedules of these different drugs can be tailored

(29:07):
to meet the patient's preferences,
what their logistics are with both coming to
clinic and with their insurance,
and ultimately trying our best to ensure appearance
and the efficacy of these medications.
Great. Thanks, Tom and Meghan, for talking to
us through some of the practicalities,
some of the dosing schedule, some of the
consideration for our patients, and how we're gonna

(29:29):
actually use them. Meghan, like you mentioned, the
needle phobic. I always have this story of
one patient who came to me and hadn't
started her biologic because she was so nervous
about doing the sub q injection. And then
we get her first one observed, and she
was like, oh my goodness. That was it?
Like, I this was a totally nothing. And
then she responded very well.
So, Megan, one of the themes of the
conversation we've had is that there are multiple

(29:51):
right answers in this case. Sometimes when you
have a patient who has severe asthma for
biologic, which is nice, gives us a lot
of flexibility,
but that also can be difficult for people
who are just starting out, who are like
learning how to choose which drug. So what
do you do for a patient
that meets criteria for multiple
of these drugs? Say they have both elevated

(30:11):
IgE
and an elevated eosinophil level to target. How
do you prioritize between these things? Is your
choice end up being driven more by the
biomarker level,
by the patient's symptoms or comorbidities,
or by their preference? How do you go
through that?
So I'd say it's really a combination of
biomarkers and clinical history.

(30:32):
As for preferences, it's kind of rare for
my patients to come in with preform preferences
on these medications. And so while it's definitely
a conversation, definitely an example of where I
think providing a recommendation to the patient is
key.
So for the type of patient you describe,
where they have both IgE and eosinophils,
they may honestly be a candidate for any
of the available
biologics by FDA labeling. Then it comes to

(30:54):
history combined with those biomarkers. So running through
some scenarios that might push me one way
or another. I might choose omalizumab
in a patient here where both clinical history
is is really predominantly one of exposure to
that sensitized allergen
resulting in worsening of symptoms. So thinking of
a patient example of someone who, say, their
family got a dog and asthma control went

(31:15):
off the rails thereafter.
Immunotherapy might play a role here, but no
improvement with that or even concurrently, I might
I would start Xolair then. And in this
scenario, you can have a really great response,
and I've got patients who can even be
around their dogs then. Certainly, an ideal scenario
would be mitigating and not having a dog,
but this is what happens in real life.
In a patient who has some sensitizations

(31:36):
that aren't clear by history to really be
a driver of their asthma symptoms, maybe they've
got some mild IgE
elevation, and they've gotten absolute eosinophil count, that's
maybe borderline for
considering it to be an eosinophil driver, say
maybe at that 150, or sometimes you check
it and it's below that. That's a patient
where I might lean towards tezapelumab.
So here I'm describing several sort of borderline

(31:58):
phenotyping where it's not, I don't feel confident
that this is T2 high inflammation
driven. Maybe pauc granulocytic or neutrophilic drivers as
well, but I can't quantify those by biomarkers
as easily in clinical practice.
Even T2 patient, T2 high patients do really
well with targeting TSLP.
And that's why the GINA guidelines suggest that
with higher E and O and higher eosinophils,

(32:20):
they'll predict a better response to tesaprelumab because
that's true. But you'll also see adequate response
in patients with T2 low.
So take another patient. Say they've got a
variety of allergic sensitizations
and confident eosinophilia.
They're on repeated checks closer to or over
that 300 absolute eosinophil count. That's a patient
where I'd likely learn lean towards dupilumab

(32:41):
because this targets both eosinophilic
and allergic pathways.
Say this is a patient who also has
nasal polyps or who I have suspicion for
aspirin exacerbated respiratory disease, those subsets of patients
do really well on dupilumab.
So in combining biomarkers and the clinical history,
it really comes to more help confidently
categorize patients.

(33:02):
And if they appear to be t too
high and it's predominantly allergic or predominantly eosinophilic,
that might drive you to choose your target.
If they got a little bit of everything
or they're clearly t too low, that might
push you towards TSLP.
And
no matter what you choose, it's really recommended
that you give a four to six month
trial of these medications once you start it

(33:22):
before you you call failure or success. And
so what do we call success in these
scenarios? And, really, this and it's helpful in
setting expectations with patients on this too.
What I'm looking for is a 50% reduction
in flares
and or a 50% reduction in oral corticosteroid
use in a daily fashion.
A cherry on top that I'm always hoping

(33:43):
for is improved daily control, improved lung function,
or improved asthma related quality of life, but
you can't promise this universally. So this is
not our first test of success. But when
we land on the right drug, if we
start it early, particularly in patients with shorter
disease duration, who have lower BMI, who are
not in the most extremes of disease severity,

(34:04):
we've got a good chance of actually seeing
clinical remission
of asthma symptoms
while still on treatment.
And database analysis suggests in about twenty percent
of patients, we can get to that sort
of clinical remission on treatment in asthma with
these drugs. So it's really exciting to respond
and also an argument that maybe if you're
not getting the right one first,

(34:25):
might be reasonable to keep
trying.
That was so awesome, Megan. Thank you for
going through with that. And I think one
of my key takeaway so far is what
you just mentioned where you actually said recommending
to have a four to six month trial
before you can define success or failure. I
know we've been consulted by teams and, like,
a patient an inpatient has been on biologic

(34:47):
for a month, and they're not necessarily having
any improvement. Which one should we switch to
next? And it's kinda like they they need
more time. So I think that thank you
so much for mentioning that and really liked
how you also added other things that mark
success with 50% reduction in flare or 50%
reduction in oral corticosteroid
use. So that was, fantastic, and thank you
for bringing that up. And I think what

(35:07):
we've said so far was biologic can depend
on a few different things, but three things
that we've mentioned so far throughout the show
today are really the patient's asthma phenotype,
biomarker levels such as EOs, IgE, as well
as allergic testing,
and associated comorbidity
associated comorbidities.
And GINA twenty twenty four recommends matching the

(35:28):
biologic to the specific patient.
And Roopali, I know you and Tom know
it's hard for me to remember things sometimes,
but you you try to bring up new
tools that can help you remember some of
this. And, obviously, we'll post a fantastic infographic
that you and Tom have worked on really
hard. But, Rupali, walk us through a way
that you like to remember
some of the biologics

(35:48):
and
take us back to your patient's case?
Definitely, Monty. Thank you so much, and thank
you, Megan, again for that fantastic summary. As
Monty mentioned, we will have an infographic linked
to this episode with all the information we
provided here. So we don't, for those of
you who have a hard time memorizing all
this information, it will be laid out for
us simply. Monty, we can refer to it

(36:09):
when we need it. But if we'd like
an even simpler memory tool, something I reach
for in the clinic, just when I'm trying
to quickly think of patients and biologic
preferences as well as what they may qualify
for. Here's a little memory device that I
use. So it's a little rhyme. So OMA
avoids allergies,
Mepho mutes, Resly reduces, Edbenroblast

(36:29):
Eos,
Doopy destroys stuffy polyps and swallowing EoE, and
Tezi tackles tough asthma for all. So that's
just as a quick way to help you
remember some of the indications as well as
what the drugs might be used for and
how patients can qualify for those drugs. Because
as Megan mentioned, the qualifications are often based
on the clinical trial inclusion criteria,

(36:49):
and that is very nicely laid out in
our infographic as well. So just getting back
to my patient's case for a moment.
In my patient's case, the ear, nose, throat
doctor reached out to me and let me
know that in clinic, they have been able
to scope my patient, and she had severe
nasal polyposis
that was discovered. So in this scenario, she'd
already been on o oral corticosteroids

(37:10):
for some time, so we chose together to
start her on DUPIXENT and then plan to
bring her black to clinic to monitor both
her asthma symptoms as well as her sinusitis
symptoms thereafter.
So it was a really nice case of
multidisciplinary
care and working together to get her started
on the right biologic for her.
And, Paula, you're the queen of mnemonics. I

(37:31):
feel like your mnemonics are range far and
wide, and it's always really helpful. Thanks for
sharing that one. So you mentioned something there
is that you brought this patient back to
clinic to monitor. Obviously, we're gonna be watching
these patients closely. And in our first two
episodes, we did talk a lot about how
important reassessment is in the therapy of asthma
patients. So, Megan, hoping you can help us
again of what type of monitoring we're doing

(37:53):
with these patients. What are we looking for
when they come back to clinic? Are we
checking any lab levels? Have are checking PFTs
or symptoms? What should we be looking at?
Yeah. Absolutely. So anytime that we're starting,
biologic,
as noted, you wanna give a four to
six month trial to really monitor response.
The primary outcome in the randomized trials that
put these medications into practice was a reduction

(38:14):
in annualized exacerbations.
So it takes a while to see that
effect by not
having exacerbations.
Right?
So I generally will recommend seeing a patient
back within about three months of starting that
biologic.
You want to assess for side effects, check
on initial benefits. You may trend their asthma
control scores, make sure that they're doing okay

(38:34):
with the medication, not having any other surprises.
You'll wanna follow them really still at that
four to six month time frame then to
really check on their response.
And, again, I'd categorize success for biologic in
seeing that 50% reduction in exacerbations or 50%
reduction in daily steroids. And anything short of
that,
think of as suboptimal.
So if we're still at that at about

(38:55):
the six month period of time and not
reaching those, you might consider changing to another
drug.
And, really,
how they responded to one drug can become
helpful data point in what you would choose
second.
As for monitoring, beyond clinical monitoring, for these
specialty medications, considering the special that they are
specialty medications, there's actually very little that we
need to be following.

(39:17):
Within those first six months, I would recommend
repeating spirometry.
Many of these drugs have evidence of improvement
of FEV1,
often around 140 milliliters.
While this is not a patient centered outcome
or a way that I would solely validate
use of the biologics,
It can be a nice objective metric and
one that insurances can take as a rationale
to continue paying for the therapies.

(39:38):
For omalizumab,
you need to be sure that your patient
has an up to date epinephrine
autoinjector
because omalizumab
has a black box warning for anaphylaxis.
This is relatively rare, and especially if they've
tolerated their first three doses in clinic, they're
likely to do very well at home, but
it is important to make sure they have
that up to date.
For dupilumab,

(39:58):
you are going to want to monitor eosinophilic
levels, particularly within the first sixteen weeks of
therapy,
and for patients who start at a higher
eosinophil level at baseline, particularly like around 600,
because there are rare hypereosinophilic
syndromes that can come up as a reaction
to this medication
that might necessitate stopping or consider using one

(40:20):
of those anti IL fives
to obliterate some of those eosinophils
if that happens.
For any patient who's on oral corticosteroids and
you're tapering those doses because of their response
to biologics, that's another space in which you're
gonna need to have close clinical monitoring
to avoid abrupt withdrawal and look for adrenal
insufficiency.
Otherwise, you don't really need to follow a

(40:41):
lot of biomarkers with these biologics because it's
not going to change your management.
You're really looking for clinical response and looking
for the opportunity
to down titrate
other controller medications,
trying to avoid
long term
risks of side effects from some of those
medications.
Megan, can I ask you a follow-up for
that dupilumab question?

(41:02):
I know you have to monitor for these
hyperacinophilic.
What did you expect
to see for patients in those first sixteen
weeks? Should eosinophils
go up at first and then down? Like,
what trends are normal, and then what trends
are concerning aside from eosinophils just skyrocketing?
Yeah. You're after starting dupilumab, you might see
a slight increase in eosinophils. So say somebody

(41:22):
starts out at 300 and they go to
400 or four fifty, like, that's not a
concerning level. But if you have a patient
whose eosinophils come up to over 1,500,
I think the highest I've seen is 4,500.
That is definitely
out
of the ordinary.
You're, of course, gonna wanna look for additional
causes of that eosinophilia, which you probably did

(41:44):
before starting these medications,
but certainly is concerning for a hypereasinophilic
reaction.
Oftentimes,
when patients have those hypereasinophilic
reactions, which again is rare, I haven't seen
a ton of it thankfully,
they may actually have, like, clinical worsening as
evidenced by systemic eosinophilic
penetration there
as you do with hyper eosinophilic syndromes with

(42:06):
eGPA
that you see increased clinical manifestations
with in line with those increased eosinophils. Particularly,
if you start dupilumab and the patient's saying
I'm doing worse, really make sure you're checking
those eosinophils.
Thanks so much for sharing, Megan. And I
anticipate
several of our fellows will probably just have
this last section, like, on repeat in fellows
clinic when we're thinking about which biologic to

(42:28):
choose and things that we should be thinking
about. And I think a purpose of today,
we wanted to just highlight biologics
based off the Gina twenty twenty four
guide and really showing steroid sparing strategies and
how biologics play a central role in this.
And even talking about how they can be
so transformative for many of the patients that
we get to care for, but I know
that there's also some challenges in being able

(42:50):
to have biologics prescribed for all patients. And,
Tom, I know we ran into some of
these issues in your clinic recently and hoping
you could share a little bit more about
that with us today.
Yeah. Thanks, Christina. Definitely.
I've realized
just in the time I've been in pulmonary
fellows clinic that we really do run into
cost and access
as significant barriers to prescribing some of these.

(43:12):
As Megan alluded to earlier, insurance can sometimes
limit the coverage
for many of these different medications.
There are fortunately some patient assistance programs that
can help.
And GINA twenty twenty four really emphasizes the
need for equitable access to these biologics
globally,
particularly because severe asthma disproportionately

(43:33):
affects underserved populations.
So it's something
we really need to work hard on and
think about.
Yeah. Thanks, Tom and Meaghan, for all that
great useful information on how we can actually
be approaching our patients in clinic.
Just to get back to our case, based
on what Meaghan had recommended, my patient was
able to return to clinic three months and

(43:55):
six months after starting the DUPIXENT feeling much
improved. She reported no exacerbations,
no need for oral corticosteroids.
Her ears, we had measured. They were stable.
There was importantly no evidence of Piper Earsenic
Filic Syndrome. We were actually able at that
point to down titrate her inhaled corticosteroid
because she was feeling
better on the biologic.

(44:17):
However, at that visit, she did share with
me that she was newly pregnant.
Now, Megan, I know it's clear that we've
made huge strides with type two targeted biologics,
but I wanna ask you about a few
special patient populations.
The first is pregnant patients, and the second
is patients who may not fit the typical
type two asthma phenotype.
We know there have been some newer publications

(44:38):
and applications of these biologics in these populations.
Could you just share with us your insights
and your approach to consideration of biologic therapy
in these special patient populations?
Yeah. Absolutely. And asthma control in pregnancy,
certainly, maybe a whole episode in its own.
As we experience across all parts of medicine,
and unfortunately, the same is true for biologics,

(44:58):
pregnancy is an exclusion criteria, randomized controlled trials,
and where pregnant patients are protected from research
as opposed to being protected by research. And
we unfortunately also have limited post market data
in a lot of these drugs. So omalizumab,
which we've had since late nineties, early '2
thousands, has the most data in pregnancy. There's
two larger observational studies, they include one hundred

(45:19):
and eighty eight and two fifty women respectively,
and concluded they found no evidence of increased
risk for major congenital
anomalies
compared to women who were unexposed to omalizumab
who have severe
moderate to severe asthma.
There are pregnancy registries
that enrolled for mepelizumab,
benrelizumab,

(45:39):
and dupilumab,
and they've closed to enrollment.
While I haven't seen formal individual reports of
those data, a recent study that reported over
1,500 events reported to a global
pharmacovigilance
database
does suggest some differences
in these biologics,
first with regards to spontaneous fetal death, suggested

(46:00):
lower reports for benrelizumab,
and some more reports for dupilumab,
omalizumab,
and mepilizumab,
though those three drugs did show lower reports
for preterm birth,
pregnancy, and delivery complications
later in term.
Still, there's a
significant paucity of data in this space, and
FDA guidance is that there's insufficient

(46:21):
evidence to inform on drug associated risks in
pregnancy.
There are animal studies both in mice and
monkeys, and a lot of these monkeys, they
gave nine times, five times the dose that
we give in humans and found
no evidence of fetal harm in those animal
studies, which is reassuring,
but still really a lack of clinical data
in pregnancy in our patients.

(46:42):
Tezapilumab
is the newest drug on the market since
2021
and has not had a registry, so there's
no data reported for that in pregnancy.
So this is really a vacuum
of clinical evidence.
In that vacuum, there was an interesting physician
paper
came out this year that reports expert consensus
on the use of biologics in pregnancy. This

(47:03):
was a modified Delphi study, and they had
141
panelists across 32 countries.
And they came to some reassuring consensus here.
So they agreed the importance of risk benefit
discussions with patients and shared decision making when
thinking about continuing biologics in pregnancy.
They felt that biologics do not need to
be stopped while patients are trying to conceive

(47:24):
and that these can be continued throughout pregnancy.
They even went so far actually to have
agreement that biologics can be initiated during pregnancy
as long as it's in line with national
prescribing data,
and particularly for patients with frequent exacerbations,
so four or more in a twelve month
period.
And that kinda comes back to the risk

(47:45):
and benefit. Right? The risk of very poorly
controlled asthma in pregnancy is pretty high.
In patients who have asthma related admissions to
the hospital or the ICU or the presence
of steroid side effects, they agreed there should
be a lower threshold for starting biologics in
pregnancy. Again, very high risk associated with those
things.
And the asthma biologics can both be initiated

(48:05):
and continued while breastfeeding
postpartum.
Of note, among those consensus, there was no
consensus on the use of tesaprelumab
during pregnancy and breastfeeding because of the complete
lack of data for this, but there was
consensus for the other available biologics.
And, personally, this fits my practice.
I do think it prudent
to discuss with any patient of childbearing age

(48:26):
who you are starting on biologic
therapy in shared decision making
to really emphasize the difficulty in the space
of possible and unknown risks to feed us
with the known benefits of asthma control in
pregnancy.
And so anytime I'm starting this in a
a person of childbearing age, I will

(48:46):
kind of unsolicited,
bring this up as we are starting it.
And that's actually gone well. One of my
most severely uncontrolled patients
that that started this conversation with was very
thankful down the line that we had discussed
it
at initiation because it came up later. And
that patient felt confident in making her choice
to continue her biologic through her pregnancy

(49:08):
and carried to term and a healthy toddler.
Growing now now and can see really good
outcomes. But, again, these are case reports and
individual anecdotes and not large levels of data.
When we think about your
second patient population, the sort of t two
low asthma severe asthma patients,
This is a really important

(49:29):
gap that was met with the approval of
tesapelumab,
and this is really the only biologic that
we can use in this patient population.
And they can have really great responses, so
it's been a nice hole to fill, but
still only one choice.
There are more biologics in the pipeline. The
one that seems most on the cusp is
depemocumab,
and apologies on, again,

(49:50):
showing the
difficulty in pronunciate pronouncing these things. This is
an ultra long acting twice yearly anti IL
five.
And just saw it actually last month at
March of twenty twenty five, this is under
review in the FDA. So we may hear
sometime soon that this may become another option.
And when we think about a lot of
these difficulties, right, these are spaces where we

(50:10):
say there's not a whole lot of data.
There's not a whole lot of data. I
can't count how many times I've already said,
it's hard to pick between these. And this
is a guideline episode. Right? So we've got
ATS and ERS guidelines that came out in
2019, and 2019 was still on the cusp.
There's been a lot of progress since that
time. And in those guidelines, they say we
should use anti IgE. We should use anti
IL-five and anti IL-four biologics for treating severe

(50:32):
asthma in adults, but it doesn't give us
guidance between them.
So the Jena Guide provides some helpful frameworks,
but we still arrive at multiple choices. And
in an attempt to really provide some evidence
based guidelines
to further assist in these biologic choices, the
American College of Chest Physicians
did convene an international panel of experts.
And we've been working for the last few

(50:52):
years to bring about the first guidelines for
the use of of biologics in asthma.
While we are under our final hopefully final
revisions, I'm hopeful that these will be published
within the year. And given that there's no
head to head trials, unfortunately, this is low
very low certainty of evidence
and really leads to only conditional recommendations.
But I do think that this still fills

(51:14):
a necessary vacuum, vacuum of space with some
necessary analysis
and evidence
to nudge between two options or to really
validate a reasonable choice between two.
Thanks so much, Megan. And I know we're
all looking forward to the release of those
guidelines that you've been able to be a
part of. And going back to something that

(51:36):
you said earlier, definitely, I think we need
to have a an entire episode on asthma
management in pregnancy. I think a common inpatient
consult that our fellows get and a lot
of important things to really
consider. And I feel like I don't want
this show to end. I know that we've
done had such a great discussion over the
last hour, and I feel like we can
keep going.
Before I headed to FERC, probably just one

(51:57):
final thing learning from today, I think you
all have realized that, there's more than one
way to say a biologic name. But I
think, Meaghan, that one of the most important
takeaways as you said today, there there could
definitely be more than one biologic that's appropriate
for a patient, but really
understanding which pathway or phenotype predominates things.
But I think with that for such an

(52:18):
informative discussion, but we'll hand it back to
you to close out for today.
Yeah. What a great discussion episode. Thank you
so much again, Megan, for coming on. Thank
you, Tom, for Roopali for steer steering this.
And thank you all for listening. Join us
for our next asthma episode will be the
case review, trying to address some questions that
we haven't talked about in our first three.
But thank you all very much. This episode

(52:39):
was written, produced, and edited by myself, Rupali
Sud, Tom Dipentilio,
and Christina Montemayor. And the audio is original
music by Eric Rogers, and we'll see you
next time.