The Basics of Biologics (Recording)

This webinar was recorded on April 10, 2025

While ordinary drugs will always have a place in healthcare, biologics are, in many ways, the future of medicine. Scientists are using biotechnology to target diseases more precisely and effectively, and often with fewer side effects. Research continues to refine this technology and develop new treatments for new conditions.

Speaker:

Jared Darveaux, MD Internist – Internal Medicine – Allergy & Immunology

Dr. Jared Darveaux is an Allergy/Immunology specialist. He serves as the Department Chair of Adult Allergy/Immunology as well as the Medical Director of Pharmacy for Emplify by Gundersen Health System in Onalaska, Wisconsin. Dr. Darveaux earned his undergraduate degree in biology from St. John’s University in Collegeville, Minnesota, and his medical degree from the University of North Dakota School of Medicine and Health Sciences in Grand Forks, North Dakota. He completed his Internal Medicine residency at the UNDSMHS and Allergy & Immunology fellowship at the University of Wisconsin Hospital and Clinics in Madison. He currently serves as a member of several committees for the ACAAI including the Asthma Committee, and the Abstract Review Committee, and is vice-chair of the Biologics and Pharmacology Committee. Additionally, he serves as a member of the AAAAI Immunotherapy, Allergen Standardization and Allergy Diagnostics Committee. Board certified by the American Board of Internal Medicine and the American Board of Allergy and Immunology, Dr. Darveaux’s medical interests include asthma, allergic rhinitis, and other atopic conditions with a special interest in biologic medications.

This Advances webinar is in partnership with the American College of Allergy, Asthma & Immunology. ACAAI offers CMEs for physicians for this webinar. If you are a member of ACAAI, you can obtain CME through the member portal for Advances webinars.

All attendees will be offered a certificate of attendance. No other continuing education credit is provided.

CME is available through ACAAI for this webinar.

Sponsored by the American College of Allergy, Asthma and Immunology

Transcript: While this transcript is believed to be accurate, errors sometimes occur. It remains your responsibility to evaluate the accuracy and completeness of the information in this transcript. This transcript is not intended to substitute for professional medical advice.

Ruthie Marker: Good afternoon, everyone. We’re going to be starting shortly, just going to give everyone a chance to join before we start today’s presentation.

Hello, everyone and thank you for joining us today. My name is Ruthie Marker. I’m the education program manager of the allergy and asthma network, and I’m thrilled to welcome you to today’s presentation. We have an exciting session, and I’m delighted to introduce today’s presenter, Dr. Jared Darbo, with his extensive knowledge and experience in allergy and immunology. We’re in for an enlightening and instructive session before we start today’s program, we do have a few housekeeping items to review.

First, all of our participants will remain on mute during the webinar. We will record today’s session and upload it to our website within a few days. You can find all of our recorded webinars at allergyasthanetwork.org. Please scroll down to the bottom of the page to access those recording webinars and any upcoming events our webinar will run for 1 h, including a dedicated question and answer session. We will address as many questions as possible. At the end, however, you are welcome to submit those questions at any time during the presentation. Using the Q. And a box located at the bottom of your screen. a team member will be actively monitoring the chat for any questions, or should you need any assistance, we will strive to answer as many questions as possible before we conclude today’s session.

This advances, webinar is sponsored in partnership with the American College of Allergy, asthma, and immunology. ACAAI offers cmes for physicians, and attendance credits for all others. You can create a free ACAAI account, and obtain a Cme. Or or attendance credit through their member portal for advances. Webinars. all attendees will receive a certificate of attendance. No other continuing education, credit is provided. A few days after this webinar, you will receive an email with supplemental information in a link to download the certificate of attendance. We will also be adding the link to the certificate attendance in the chat. So keep an eye on that.

So let’s go ahead and get started. Today’s presentation is titled the Basics of Biologics, while ordinary drugs will always have a place in healthcare. Biologics are in many ways the future of medicine. Scientists are using biotechnology to target diseases more precisely, effectively and offer often with fewer side effects.

Research continues to refine this technology and develop new treatments for new conditions. It is my pleasure to introduce today’s speaker, Dr. Jared Darveaux. Dr. Jared Darveaux, is a specialist in allergy and immunology. He serves as the department chair of adult allergy and immunology, and the medical director of Pharmacy for amplify at Gundersen health system in Onalask, Wisconsin, Dr. Darveaux earned his undergraduate degree in Biology from St. John’s University in Collegeville, Minnesota. He completed his Medical degree and his Internal Medicine Residency at the University of North Dakota School of Medicine and Health Sciences and Grand Forks, North Dakota. He then went on to complete his allergy and immunology fellowship at the University of Wisconsin Hospital and Clinics in Madison. Currently he is a member, and serves on several committees for the ACAAI, including the asthma Committee and Abstract Review Committee, and he is the vice chair of the Biologics and Pharmacological Committee. Additionally, he participates as a member of the ACAAI Immunology, Allergen, Standardization and Allergy Diagnostic Committee. He’s Board certified by the American Board of Internal Medicine and the American Board of Allergy and Immunology. Dr. Darveaux’s medical interests include asthma, allergic rhinitis, and other atopic conditions, with a particular focus on biologic medications. So with that, thank you for being here again, Dr. Darveaux, I will turn it over to you.

Jared Darveaux, MD: Great. Thank you, Ruthie, and thanks for everyone for tuning in to today’s lecture. We’ll get started here. This is a slide on my disclosures. So we’ll move on to the objectives. So we’re going to talk about biologics today. And in particular, since most of today’s biologics and our specialty are directed towards type 2, inflammation. We’re going to hit heavily on understanding type 2, inflammation and its relevance in atopic disease.

We’re going to talk about the use of biomarkers in these type 2 diseases and how to use them to help select biologic medications and then evaluate the currently approved biologic medications for common diseases that are seen within our specialty. Talk about how they work their mechanisms of action, and how to select an appropriate biologic for your patient.

So in general, biologics are medications that are derived from living organisms. So these are usually proteins or genes. And as any of you know who have prescribed biologic medications, or maybe you’re taking them yourselves. These are really just revolutionized, the care of atopic conditions. They can be absolutely life changing so many times. These are antibodies that are targeted at specific inflammatory pathways and so for that reason they can be very safe and effective, and they can even slow or halt disease, progression in some cases or lead to disease remission depending on which one you’re talking about.

I’ll draw your attention over to the left side of the screen, and you’ll see just kind of a refresher on naming of biologics. The suffix Mab means that it’s a monoclonal antibody, and then kind of the prefix before that indicates what type of monoclonal antibody it is so for Murine. It has an O for chimeric, it has. Xi. So Zimab Zumab would be a humanized antibody, and then human antibody, and then receptor fusion. So these are the current biologics for atopic diseases, and at least these are the ones that are used most heavily in allergy and immunology practices. So you can see that some of these medications just have one indication. Some of these medications have multiple indications and can be used across several different atopic disease processes.
We’re going to talk about each one of these a little bit in in more detail, and in particular related to the diseases that that they treat. So. There are several ways to kind of categorize biologic medications, or to think about how we use them. One of them is to think of them as kind of upstream versus downstream targeted medications to target those mediators of inflammation within the T. 2 or the type. 2 inflammation. We have medications that target the interleukin 5 or interleukin 5 receptors. So they’re really effective for eosinophilic conditions. Ige, the allergic antibody is a target for these, il. 4 and 13, we’ll talk about Tslp stands for thymic Stromo lymphopoietin interleukin 31 is a contributor to symptoms of itch so we use that in atopic dermatitis. And there are, of course, other medications or other parts of these inflammatory pathways that are under investigation currently.

And so as we’re learning more about these different, both upstream and downstream mediators and how they interact with different cell types. We can then use that information to select or try to develop medications that offer very targeted therapies to not only inhibit that inflammatory pathway, but also to minimize the possibility of side effects. And so some of these. This is from a journal article from 2017. You’ll recognize many of these as being approved for treatment already in several different atopic diseases but anything from things like immunoglobulins, cytokines, receptor antagonists being more downstream mediators of inflammation. We also have things like alarmins. We mentioned Tslp a minute ago and these are kind of more of the upstream mediators of disease. So let’s talk about this. Now, I kind of have a love hate relationship with these types of diagrams. They really offer a great way to understand cell and cell interactions and different communications with different cytokines and interleukins.

And that’s great for us to understand those pathways so that we learn how these targeted medications work. But despite looking really complex, it is. But it’s probably an oversimplification of what’s actually going on in a biological system. But when we’re talking about type 2. Inflammation. This is originally called th 2 inflammation, because it was the predominant type of inflammation from th 2 cells, we know that we can get that inflammation from th 2 cells. But there are other pathways where you can get type 2. Inflammation without it being a purely allergic pathway. So there’s different cell types involved in this type of inflammation. Th 2 cells we mentioned but mast cells and Basophils, Eosinophils innate lymphoid type. 2 cells. We’ll talk about those and then epithelial cells and antigen presenting cells. So I’m going to draw your attention over to the diagram on the right here. So in the classic pathway, when we’re thinking about type 2 inflammation, we have an Allergen that’s presented to a th 2 cell that activates the th 2 cell, and then the th 2 cell starts producing cytokines and interleukins.

Of course, that’s how the immune system communicates the type of inflammation it wants to create right. And so in the case of type 2, disease or allergic disease, th, 2 cells produce interleukins, 4 and 13. These are 2 heavily used interleukins in this process and they have several different downstream effects. They cause b cells to isotype switch and start producing more allergic antibodies. So Ige antibody. It also causes mast cells to increase the amount of ige receptors on their surface, so they’re more likely to be degranulated and cause allergic reactions.

There are other downstream or downstream effects related to interleukin. 13 on the epithelial barrier. So epithelial cells increase mucus production or producing cells and also T cells produce or th 2 cells produce interleukin. 5. And we know interleukin 5 to be one of the major contributors to eosinophil development and activation. So that’s kind of the classic way. We think about that, and you can have the same type of inflammation in other ways as well. So you can have epithelial derived cytokines like the Alarmins we talked about before. So that includes interleukin and 2533, and Tslp, and that can activate a group of cells called these innate lymphoid type 2 cells. Now, they’re called that because under the microscope they look like a lymphocyte, they’re shaped like a lymphocyte. But they don’t have a specific T cell receptor like a th 2 cell does.

But once they’re activated, they produce similar cytokine profiles and interleukin profiles that th 2 cells do so it produces things like interleukin. 13. That you know from whichever pathway it comes from can cause airway, smooth muscle, hyperreactivity, and it also produces interleukin, 5. Which can boost eosinophil development and activation like we talked about before. So looking at this and so that was kind of using the respiratory airway as an example on the left. Here we see a similar cytokine profile. When we talk about other type, 2 diseases like eczema, so interleukins 2533, and tslp. These alarmins can get released in the skin cells, and then they can activate dendritic cells. Dendritic cells interact with th 2 cells through ox, 40 through receptors called ox, 40 and ox, 40 ligand, and then that can activate the th 2 cells to produce the different interleukins that we were talking about on the previous slide. The alarmin group can be activated by allergens through interactions with the respiratory epithelium. But it can also more generically be activated from things like viruses, bacterias, pollutants. Anything that really damages or irritates the lining of the respiratory tract can cause release of these alarmins, and when it does, as we talked about on the previous slide. It can activate these innate lymphoid type, 2 cells. And so that’s how you can get this allergic type inflammation, even in the absence of allergic triggers.

So what do we do with all this? You know, the inflammatory process as we’re seeing is complex, it’s interactive. It’s redundant. There’s a lot of different cell types that produce the same interleukins. There’s different cell types that have the same receptors. And so that’s probably what accounts for the variability and responses to general medications, maybe non-biologic or biologic medications from one patient to another. So how do we decide what’s gonna work for? Who?
Well, that’s where we hope to use biomarkers. So in general, if you’re not familiar with biomarkers, these are traceable substances used to examine organ function and other aspects of health. So we’ve been using biomarkers for a long time. Hemoglobin a 1 c is a great biomarker for diabetes in Aids patients, we use CD 4 T cell counts if someone comes into an emergency room with chest pain. We order troponins to see if they’re having a heart attack. And so in the context of allergic disease, the best biomarkers are used to determine the presence or absence of a disease used to tell the disease, severity, and progression. You can use it as a target for therapy, and you can use it to decide whether they’re having a good response to therapy or not.

And it actually helps to guide about the subject survivability or prognostic factors. So just using asthma as an example. Here we kind of think of asthma as phenotypes and endotypes. So we have kind of the asthma syndrome which is characterized by airflow obstruction and bronchial hyperresponsiveness. And so we can kind of categorize this asthma syndrome through use of spirometry. Spirometry, isn’t a biomarker, but then you have patients that say, well, I only get asthma when I have an infection, or I only have asthma when I’m at grandma’s house and visiting, and she’s got cats in the house. And so then that’s kind of the phenotype that we’re observing. So that’s where we say people have allergic asthma exercise induced asthma infection, related asthma. endotypes tie a pathophysiologic mechanism to the phenotype that we’re observing. And so this is where we use the biomarkers. So we use things like ige, either specific to allergens or total ige. We use Eno exhaled nitric oxide and peripheral or sputum eosinophils to better characterize the type of asthma that we’re treating, and that can help us better select a biologic.

So what kind of biomarkers do we have available? Not a lot to be honest with you. I mean, we’ve used ige for asthma, and we use it in diagnosing food. Allergy, we know that Ige by itself is not particularly effective in treating eosinophilic esophagitis or guiding therapies in eosinophilic esophagitis. We know that eosinophils are elevated in the airways of asthmatics and can help us categorize eosinophilic asthmatics, but also it’s used in diagnosis of eosinophilic esophagitis and other Eosinophil related conditions exhaled. Nitric oxide is a good marker of th 2 type, inflammation or T. 2. Inflammation in the lower airway. It’s being studied in chronic rhinosinusitis with nasal polyposis, but isn’t widely used. Currently there’s some evidence that using specific Ige to Igg. 4 ratios are potentially useful for management of eosinophilic esophagitis and food allergies. Periostin isn’t widely, clinically available, but it’s another epithelial derived cytokine that’s been studied in different atopic conditions, including asthma, eoe and atopic dermatitis. And then, of course, we use eosinophils, and we can well, we can use eosinophil proteins and inflammatory mediators to monitor disease that’s being studied in the use of management of eosinophilicitis.

And you’ll notice that some of these biomarkers are common among a lot of different allergic diseases, so it can be difficult to decide which one is going to be most useful for my patient. So let’s start out by talking about biologics and asthma, we’ll start with the oldest one. Omalizumab omalizumab is a monoclonal antibody that targets the Fc. Portion of Ige. So it prevents the allergic antibody from binding to the surface of the mast cell, and then that helps to prevent degranulation and reduces allergic contribution to asthma disease. So when they were learning about this medication where they were developing this medication. They knew that Ige might be a good biomarker, because most patients with asthma have allergic sensitization, and we know that patients with asthma that also have allergies. The allergies are a contributor to that type of inflammation. Mast cells produce histamine that causes worsening of symptoms. But activated mast cells also produce other inflammatory mediators as well.

Now we know that also ige levels correlate with asthma severity both in adults and children, and so that made it a natural target for this disease and so for using omalizumab. The patient selection, when they designed the clinical trials initially, was based on their total ige levels, and they had to have allergic sensitization to a perennial Allergen. And that makes sense, because we know that Omalizumab binds to Ige. But as far as using that information as a biomarker to predict whether people were going to respond to that, it didn’t work very well. And so they started looking for other biomarkers that would better predict a response to omalizumab. So this is a study from 2013 where they started looking at some of these other biomarkers we were talking about. So they took patients, and they put them into either a placebo arm or a treatment with omalizumab arm, and they were looking at exacerbation, frequency, and they started looking at who was more likely to respond. Based on these biomarkers we see up here so exhaled nitric oxide, Eosinophil, peripheral eosinophil levels and periostin. And they categorize these people into low biomarker groups and high biomarker groups.

And you can see that the patients that had high biomarkers, higher Enos, higher eosinophil levels, higher periostin levels were much more likely to have prevention of exacerbations compared to the low biomarker group. And so although Ige is used in dosing and insurance approval. It maybe isn’t the best biomarker to use to decide whether someone is going to respond to treatment with omalizumab. So how well does omalizumab work in asthma? Well, in the right patients, it works really well, so it helps to reduce the frequency of symptoms. It helps reduce medication, rescue medication, use. It reduces exacerbation, frequency. It improves lung function, and it allows for reduction in inhaled steroid dose without loss of control of asthma these graphs on the right are from a study from Dr. Bill Bussey, looking at inner city children with moderate to severe asthma. Majority, had moderate to severe asthma, and on the top side we have days without symptoms, and really they were looking to see if Omalizumab attenuated the seasonal pattern that children often experience in the spring with allergies and in the fall with infections and you can see days without symptoms improved with Omalizumab over placebo. Number of exacerbations also improved. And you don’t see that bump that you typically or at least not as prompt prominent of a bump that you see in the spring and the fall months and also patients were able to use overall use lower inhaled corticosteroids to maintain control compared to the placebo group.

All right. So let’s move on to Eosinophils. We know that Eosinophils are heavily involved in the majority of patients with asthma. If you look at pathology or histology slides in the lungs of asthmatic patients. You’ll often see eosinophilic infiltration Eosinophils boost the T 2 response, but it can also cause they can be elevated in the allergic side of things. But we talked about. They can also be elevated in patients that don’t have any allergic contribution. And once they’re activated, they release their own inflammatory proteins that contribute to asthma exacerbations. So you can see elevated Eosinophils both peripherally and in the airway. But it’s a lot easier to collect a blood draw than it is to induce sputum or collect sputum through bronchoscopy. So we usually use peripheral Eosinophilia as the biomarker in this case.

So what do we know about Eosinophils. We know that the higher the Eosinophil levels, the more likely the patient is to have more severe asthma, the more likely they have persistent airflow obstruction, and they have increased risk of exacerbations. And we know that reducing Eosinophil levels is linked to clinical improvement. So this is kind of an older study. This is from 2,002, and this was a study where they looked at patients with moderate to severe asthma, and they categorized them into 2 strategies as far as treatment they had. The Bts stands for British Thoracic Society, and that’s essentially like the stepwise approach that we use for stepping up or stepping down asthma care in the Us. Like in the Gina guidelines or the Nhlbi guidelines. So they put them into 2 groups, and they had one group just manage, based on the standard of care from the British Thoracic Society guidelines. The other group they made adjustments to medications based on normalization of the sputum Eosinophil count and what they saw was the patients that were managed based on their sputum Eosinophil level were much less likely to have exacerbations compared to the standard of care about a 3, rd the number of exacerbations compared to just the standard stepwise approach. And you might say, Okay, well, that’s probably because these people we know that Eosinophils are really sensitive to steroid medications, they probably got more prednisone, or they got more inhaled corticosteroids. Actually, there was no significant difference between either inhaled or systemic steroids in these 2 groups. And so that really just showed us that targeting Eosinophils can have really dramatic improvements in outcomes related to asthma. So we started studying Eosinophils more. So what do we know about them? We talked about interleukin. 5. Interleukin 5 is like fuel for an eosinophil.

Right? It causes them to differentiate the bone marrow, it helps them to migrate into tissues. Once they get to the tissues, it causes them to become activated and produce their inflammatory proteins, and it causes respiratory bursts which leads to further inflammation. So how can we target this? There’s 3 different biologic medications that target this pathway, 2 of them Reslizumab and Mepolizumab target interleukin 5, and just prevent it from binding to the Il 5 receptor. And when that happens, the Eosinophil can’t get the signal to become activated and to proliferate and produce more. And so eosinophil levels kind of gradually decline relatively quickly. The other way to target this pathway is through the interleukin-five receptor. And so that’s what Benrolizumab does. Benrolizumab is a monoclonal antibody that binds to the Ilr 5 receptor attached to the Eosinophil and it kind of flags the Eosinophil and says to the immune system, Hey, this isn’t supposed to be here, and the immune system comes in with a natural killer cell and performs antibody. Dependent cell, mediated cytotoxicity. So it comes in and actually kills the Eosinophil. So you get rapid depletion of Eosinophils. Usually within just one or 2 days. So what happens when we start using biologics to target Eosinophils for asthma?

Well, consistent feature of this is that they reduce exacerbation rates, and so on. The right. Here you can see this is a study looking at Mepolizumab versus standard of care versus inhaler medications alone, and you can see that reducing eosinophil levels through binding to il. 5 reduces exacerbations by about half. Interestingly, whether the patient has atopic disease or not, or has allergic disease, I should say, has no impact on whether they respond to Mepolizumab or not. But the most impressive responses are seen with people with more Eosinophils around. So this is one where a high Eosinophil count peripherally would be a good biomarker to predict a good response to Mepolizumab or an Il 5 targeted agent

On the left, we see another way of looking at similar data. We see the patients on the far left in the mepolizumab group were likely to have dear exacerbations and the placebo group was likely to have zero exacerbations. Let’s talk about interleukin four and interleukin 14. These are heavily involved in allergic and atopic disease. The primary source is Th2 cells. But you can get it from other cell types. Using the airways as an example. It increases goblet cell production and activity to increase mucus production. It can cause naïve T cells that have not decided what type of terminal T cell they will be to become Th2 cells. It kind of boosts the response. It increases adhesion molecules in the vascular endothelium to draw in more vascular cells and causes the cells to start producing IGE or allergic antibody compared to other types of antibody at increases mast cell activity by increasing receptors on mast cells and with airway smooth muscles it causes increased airway hyperresponsiveness, all the things we think of as contributors to asthma they are involved in. Why do we talk about these two interleukins together? They produce a lot of the same at downstream effects. They have overlapping effects as well. There are two types of interleukin 13 receptors. There is a type one receptor and a type two receptor. The type one receptor is comprised of an interleukin four alpha chain and the other part is a generic gamma chain. Type two receptors are comprised of an interleukin four alpha chain also that also has an interleukin 13 receptor offline chain. That means interleukin project can combine to activate cells through either type one or type two receptors but only interleukin 13 can — interleukin 13 can only bind to type two receptors. The initial reproach is that blocking the pathway, there are a lot of different ones. Blocking interleukin four or interleukin 13 through consuming it with antibody they tried using an interleukin four sector antagonist or a soluble aisle four receptor to consume interleukin four. And a lot of the studies initially had mixed results as far as efficacy and asthma as far as the overlapping effects of these two cytokines that makes targeting either one of them individually less effective. In comes this interleukin four receptor blocker, D upilumab. it prevents activation of the type two receptor as well. When they started studying this in the context of asthma, I will draw your attention down to the left lower part to down there. It was a study from Dr. Sally Wenzel in 20 13. 

They took moderate to severe asthmatics and they were on inhaled steroids plus another, mostly long acting beta agonist. They entered them into the study and four weeks in they withdrew their long acting beta agonist medications and they were following asterisk — exacerbation rates and then the placebo group started having exacerbations and two weeks later they tapered off corticosteroids and not surprisingly the placebo group started to have higher rates of exacerbations that continued until the end of the study. But look what happened with the appeal you map Dupilumab Dupilumab — group — with the Dupilumab group. Nitrous oxide levels in the placebo group did not really change with removal of the lava, which is not surprising. When you took away the glue court avoid, E and O levels go up. You know levels in the Dupilumab went down and stayed low through the rest of the study. Similarly, neurotoxin did not change much. And total IGE levels, you would not expect them to change with alterations and inhaler therapy and it did not. But you can see after treatment with Dupilumab IGE levels went down and continued to trend down throughout the study. I mentioned exhaled nitric oxide a couple occasions throughout this talk and it is a useful biomarker for type two disease. Nitric oxide is something everybody’s respiratory epithelium produces but in the presence of type two information the number goes up. They produce more. It correlates with sputum eosinophil ia. I use this frequently I am a clinic. The American thoracic Society has said these levels predict the likelihood of responsiveness to inhaled steroids more consistently than other things we used to measure asthma like spirometry, bronchodilator response, peak flow variation or a — AHR to NASA coding. We note the levels are elevated together. We will use your sinful — eosinophil agents and see the levels go down but that is what we expected when we started studying monoclonal antibodies that target eosinophils. 

This is a study with mepolizumab . When they follow blood eosinophil count the eosinophil levels drop when you start mepolizumab and stay low throughout the study. Look at the exhaled nitric oxide levels. They don’t really change much. Despite reduction in eosinophil levels. What does that mean? It means E and O — ENO is not a surrogate marker of eosinophilia . Productions aren’t just reducing eosinophils but more broadly reducing type two inflammation. All right. Let’s talk about thymic stromal ly mphopoeietin and endothelial derived cytokines, an upstream mediator that can affect several downstream mediators. On the allergic side, it can contribute to allergic disease through the secretion of interleukin four and 13 and IL-5. It contributes to allergic inflammation and eosinophilic information. Any patients that don’t have eosinophilic or allergic disease , it contributes by having receptors on mast cells that can cause activation of them in that way, on smooth muscle cells, and on fibroblasts. It is not that it might contribute to remodeling we see in asthmatics over time. 

Initially, when they were studying Teze — Te zepeulmab with the gray the placebo they noticed an improvement of exacerbation rates regardless of whether they had low or high eosinophil counts, low or high ENO or TH2 status based on a larger. That’s how they presented this medication initially. That biomarkers really don’t matter. You can just prescribe it for anyone. Within the same study, we did see the biomarkers. Looking at ENO we know that you too –t2 biomarkers do decline. Studies are showing that while this is helpful in tea too high and tea too low asthma patients that have moret2 inflammation are more likely to benefit from teze pleumab. This is the total population appear. 

Down here we can see patients with greater than 300 blood eosinophil spirit with allergic sensitization and they included whether they would qualify for treatment with Omalizumab as well. Though the total population benefits patients with t2 disease showed more pronounced benefits. You can see it on the right. The blue is the placebo group looking at annualized exacerbation rates. In the placebo group, and the Tezepelumab group you can see that. This is the total population. There was a significant reduction in exacerbations. When you look at patients with less than 300 eosinophils, they were still likely to have exacerbation reduction. But it was not nearly as pronounced as the exacerbation reduction in patients with blood eosinophil levels. It shows T2 high patients are more likely to benefit from Tezepelumab. That’s a lot on asthma. He will shift gears to talking about eczema for a little bit. There are several different tissue biomarkers that aren’t ready for clinical practice yet but are being studied currently. 

Some potential predictors of responses to medications. If presidents have — patients have CCL 2, a tissue marker they are more likely to respond to different therapies. See X CO2 is expressed on cells and patients have that are more likely to respond to Dupilumab. Interleukin two can create a likely hood of response to fe zkinumab. And these patients are more likely to respond. Let’s talk about the Biologics available for eczema currently. There are two Biologics, tra lokinumab and lebrikizumab. Interleukin 13 can cause down regulation of flag ran and perpetuate or exacerbate disease. We have already talked about the mechanism of Dupilumab blocking both interleukin four and interleukin 13. Some information on how well it works for eczema. This graph specifically looks at results related to a study with Dupilumab, on something called the easy score. The eczema severity — eczema area and severity index. You look at different body parts and the extent and severity of the disease and one of the outcomes you can look for in the clinical trials is what percentage of patients improved their score by 50%, by 75%, or by 90%? That is what we are looking at. You can see the placebo group did not do as well. But both of the Dupilumab groups at around 80% improvement. 50 in their easy 50 and their easy 75, almost 70% of patients were able to achieve that. Almost at a little — a little over 40% and at the end of the study close to 50% were able to have 90% clearance of their skin. Another outcome measure to look at when we are talking about eczema is symptoms of itch. There are different ways to measure this. For the most part they give the patient a zero to 10 scale, like a pain scale and say pick a number, how itchy are you? This is the percentage reduction in the treatment group with Dupilumab compared to a princely bow — compared to a placebo. Any of you prescribed Dupilumab for eczema, it can be a life-changing medication for people. This shows the progression of improvement in three patients over the course of several weeks. After treatment with Dupilumab. Nemol izumab targets interleukin 31 also released by Th2 cells the primary mediator of itch so it binds to perilla for all — peripheral nonce and causes symptoms of itch. Nemolizumab used for atopic dermatitis. The VAS score is the visual analog scale similar to the pain scale, a marker of symptoms of itch. Let’s plug back panel B. This is — let’s look at panel B. 15 days into treatment you can see patients symptoms of itch improved dramatically. 16 weeks out you can see the trend continues. The easy score we talked about on the last slides. We have seen improvements in the Nemolizumab group as well and the ISI score is the insomnia severity index. Patients with severe eczema often have problems with sleep. There is an insomnia index on a scale of zero-28. At less than seven is considered normal. 

Patients with a score of less than seven were much more likely to be in the Nemolizumab group compared to the placebo group. Moving on to urticaria. Omalizumab is the only biologic approved for urticaria reducing IGE decreasing the survivability and proliferation of mast cells and increasing the stimulus threshold needed for the granulation of mast cells improving the outcome of patients with chronic, Spun Terry is urticaria that fail H1 antihistamines. As far as biomarkers are concerned, low IGE, low a ascent and low basil fill — low eosinophil. As well — far as how well Omalizumab works in urticaria, yellow is the approved FDA treatment goes for Omalizumab looking at symptoms of itch. These are different doses. You can see the patients got three doses at the 0, 4, and eight. You can see they have a pretty dramatic improvement in symptoms. Then they start losing that benefit once dosing was discontinued and you can see a similar pattern with the number of hives. Omalizumab is approved for treatment of food allergy. Of Christ, you require a positive skin test or IGE test. It increases the reaction threshold but it is not a cure for a food allergy. It is being studied as an adjunct to oral immunotherapy to increase tolerability and dosing more rapidly and maintain higher doses. A study by Dr. Robert Wood. The primary endpoint was whether or not patients were able to tolerate peanuts. To enter the study they had to react to less than 100 milligrams of peanut and fathered other outcomes related to other foods. They had to have a reaction to less than 300 milligrams of one of these other foods, cashew, and milk with hazelnut. They started on Omalizumab as a placebo and if they came back and to tolerate at least 600 milligrams of peanut that was the primary endpoint and secondary endpoints were tolerating 1000 milligrams of one of these other foods you can see in the treatment group they were more likely to be able to tolerate data than in the placebo group. A good protector from developing allergic reactions. Chronic rhino sinusitis with nasal polyp assist. Omalizumab Dupilumab and mepolizumab all produce symptoms compared to placebo. There was an indirect comparison study that we are looking at on the left looking at outcomes related to nasal polyps, quality of life, sense of smell, corticosteroid use. Need for surgery. 

Then, score size based on polyp size. You can see Dupilumab, the green means it works really well. Dupilumab worked really well in all categories. The next best in this was Omalizumab followed by mepolizumab. Right now we don’t have any biomarkers available but nitric oxide is being studied. How do you decide? We have gone through several disease processes. How do we know what to choose? Part of it is using biomarkers like we talked about, going over which patients are more likely to respond but for me I think about comorbid disease. If I can use one biologic medication to treat two or three disease aspects I will choose that one. You can talk to your patients about disease exacerbating factors. If my patient says I don’t have problems with asthma except during allergy season and then Omalizumab might be a better choice. Dosing frequency is important for some patients. Some are dosed weekly, biweekly, once a month, or every two months and some are coming out that are even less frequent. Some patients take comfort that these medicines have been around a long time and we know about long-term safety and efficacy. Patient preference and of course more often then wait like insurances help dictate the medications which is based on coverage. What is coming down the line? DEpemokimab will be an every six months or does medication that will be looked at for asthma and nasal polyps. Fezkinumab is being studied for atopic dermatitis. It is an interleukin 32 cytokine. That is why it is being used there. Nemolizumab we talked about for atopic dermatitis but is being studied for other peer Riddick –pruritic conditions. Etokimab is being studied for atopic dermatitis. Rademikibart is similar to Dupilumab being studied for atopic dermatitis. Eblasakimab, interleukin receptor also. We briefly talked about ox40 involved in atopic dermatitis and there are three medications being studied to target that pathway. 

Then Barzovolimab a tyrosine kinase inhibitor. If you want more information the American College of asthma and allergy has a toolkit with a Biologics cheat seat — cheat sheet of Biologics at a glance. This is an example that tells you what the medication is, how it works, how it is indicated for different dosing strategies and side effects and things like that that you can look at. It is a great source of information if you are looking for specific features of these biologic medications. In summary, biologic medications haven’t really revolutionized the management of allergic diseases. Some of the disease states, we have biomarkers that can help us select certain biologic medications more likely to be beneficial for patients. Really understanding the underlying pathology and the interactions between cells and interleukins and at different cytokines helps us understand which medications are more likely to be beneficial for our patients. We are really having targeted therapy at that point. Or, personalized therapy. That is all I have for you today. I’m happy to answer questions. I appreciate your time. I will turn it over to Ruthie for the question and answer session.

Ruthie: We have lots of questions and we will answer as many as we can. The first question that came in was regarding biomarkers for chronic sinusitis. The question is kind of tailored towards, is that because there is not enough research yet on chronic sinusitis?

Jared Darveaux, MD: I think that is part of it and I think part of it is they have not found biomarkers that have consistently been shown to predict outcomes related to the biological medications we are using currently. The Biologics available, all three of them work in very different ways. This can make it difficult for one particular biomarker to be a predictor of response to all three different Biologics.

Ruthie: Awesome. Next question. Considering the risk for hyper eosinophil ear with Dupilumab, do you have a cut off or what would not initiate Dupilumab for asthma or just monitor if the baseline is very high? Works great question. You —

Jared Darveaux, MD: Great question. You know, when they were doing the initial trials for Dupilumab , you have to take into account they excluded patients with high eosinophil counts in their initial asthma studies. They did notice patients that started Dupilumab, several of them had transient increases in eosinophil levels and those usually normalized throughout the study. And in some patients were found to have things like hyper eosinophilic syndrome. The latter situations, my suspicion is this patients had those diseases, probably underlying. Starting Dupilumab simply unmasks that. That said, I don’t have a hard cutoff. But I will tell you the mark they used in the clinical trials was 1500 euros Senate bills. When patients have baseline levels above that I think about using an eosinophil target agent rather than Dupilumab. It can be tricky because the ego center fill targeted — eosinophil Biologics week showed earlier were not as effective treating nasal part of disease and in that case Dupilumab, if I can treat more than one disease at once and patients have both asthma and nasal polyps I will try to treat both of them with one medication. If you have a suspicion for an underlining youth center fill — eosinophil separate from the disease you are treating it would not be wrong if you are going to start Dupilumab to check eosinophil count after or only check them if you feel like they aren’t responding or developing other features of the disease process.

Ruthie: Awesome. Thank you for that. We have another question related toFENO. Can you talk more about the use of FENO in your clinic? Do you obtain levels on every patient or only as an aid in treatment decisions and do you evaluate levels during exacerbations?

Jared Darveaux, MD: Yes, in certain situations, to all of those things. When I see patients for initial evaluation I usually check the baseline FENO level to see how much ongoing inflammation there is regardless of what kind of treatment they are on. Sometimes patients are on medium or low levels of inhaled steroids. They might respond to a higher level. We know that ENL levels rise quickly after somebody stopped at their inhaled corticosteroid. It is also a good tool to use to monitor adherence. If I have a patient come in with an ENO over 150 and I start them on an inhaled steroid and they come back three months later and it is still 150 sometimes I call the pharmacy and I say, are they filling that? If they are not filling their medication you are having a different discussion with that patients, not about lack of efficacy, but adherence to medication. I don’t generally check ENO levels during exacerbation because either I expected to be high where it won’t alter my management decisions that much. As far as monitoring throughout, if patients are gradually having worsening spirometry over the course of months or years, sometimes I will throw in an EN O level to check if there is another inflammatory process or if we have worsening disease despite having been stable previously. I don’t check it on every patient, every visit, but I’m not shy about checking it either. Dupilumab —

Ruthie: Time for one more question regarding safety during pregnancy. For atopic dermatitis and pet allergies are any Biologics safe during pregnancy? Works this a quick —

Jared Darveaux, MD: This occurs frequently. We have this conversation frequently with patients. There are no studies that use pregnant women in their clinical trials. We know that these biologic medications are antibodies and window antibodies are transferred across — and we know antibodies are transferred across a placenta and the baby is exposed to them. It predominately happens during the third trimester. Of the medications available, there is a website called mothertobaby.org that follows patients that have either started biologic medications during pregnancy or continued on biologic medications after becoming pregnant. That, at least, gives us retrospective data on the safety and efficacy of those medications. So far, of the medications available for atopic disease, there are not any known detrimental effects to the baby. Over the medications available, both Omalizumab and Dupilumab are available for treatment all the way down to six months of age. I understand a six month old is not the same as an unborn child. But we do have good safety and efficacy data in that population and I’d make sure I have the conversation with patient saying, no, we don’t have specific data during pregnancy but we have good data that is safe for a six months old and above.

Ruthie: Thank you so much. Lots of great questions. Thank you, again, for this presentation. I hope that everybody had a great time. And was able to walk away with some answers to their questions. Zoom will email you in a few days with a link to the recording, and evaluation, and supplemental resources. I would like to share upcoming webinars we have we hope you will attend and enjoy. On April 24, next week, at 4:00 p.m. Eastern, we invite you to join us for our series five on chronic urticaria in the Hispanic and Latino community titled “more than hives.” where Della Martinez will share her story and a journey living with chronic you to carry out. Learn how living with chronic urticaria has taught her resilience and determination. We hope you are able to attend and connect during this meaningful conversation on May 13 at 4:00 p.m. Eastern, join us for another engaging and informing webinar on eosinophilic esophagitis, managing and understanding the condition presented by Dr. Joe Lieberman. We will present a comprehensive overview of eosinophilic esophagitis. Join us as we dive into the latest advances in understanding , diagnosing, and managing it. Thank you again for all of us at the allergy and asthma network where we strive daily to be your trusted research — resource for people with allergy, asthma, and related conditions. Thank you everyone, and thank you again, Dr. Darve