Good morning, everyone. I'm glad to see all of you here this morning. Thank you, Diego, for chairing and inviting me for this session. It's a very important topic that we commonly encounter, how many years of biologics is needed for our patients, and what are the studies out there shows. As you know, in the last 10 years, we have six biologic agents that we've been using for our asthma patients. I have no disclosures for this talk, but I'll be using the ARS, so please use the ARS questions when it comes. So we'll be reviewing the long-term efficacy and safety of biologics in patients with severe asthma. So let's start off with the first question. So this is a patient who comes to our clinic, 40-year-old woman with history of severe persistent allergic asthma, has been on triple therapy, ICS Labalama, and also been on Omalazumab for 10 years. And she's inquiring about long-term safety and use of Omalazumab, how long do I need to use, and is there a safety out there? So which of the following statements is best for Omalazumab? Is it the real-life data showing no effectiveness of Omalazumab after 2 years, there's no sustained reduction in asthma exacerbation after 2 years, after adjusting for confounding factors, there was no increased risk of cardiovascular events in patients who were treated with Omalazumab, the need for oral corticosteroids is increased with Omalazumab-treated patients. So which of these is the right answer, would you say to your patient? So you have 15 seconds to answer. OK, 86% of you got it right. That is the right answer. So we know the omalizumab is one of the oldest biologic or the first biologic that we've used for severe persistent allergic asthma. And this is the data from Dr. Hanania, who is my mentor, who published this recent review article on 42 publications on omalizumab long-term effectiveness or safetiness. And what is shown here is he had 30 of those studies with two to five years experience and 12 studies with more than five years experience. What is shown here is that you can see the omalizumab reduces asthma exacerbations. And it's kind of persistent up to nine years. The purple color is nine years. So it does reduce exacerbations even on continued use. And also, the asthma control test or the control of the asthma is much better. And it is persistent up to five years that we can see here from the studies that have been used here. What is also shown is there are some serious adverse events for use of omalizumab. But it also, when compared to this other non-omalizumab treated group, it's not statistically different. Although it shows an increased risk of cardiovascular events, it's not shown to be high risk. So it is a safe drug to use, omalizumab, for our patients. And it is not coming up with much adverse effects. And the effectiveness is still there. So that's why that was the right answer. So the next question, the 55-year-old man with history of severe eosinophilic allergic asthma feels much better after starting my polizumab six months ago, which is the usual case when we've seen our patients who have been struggling for many years not getting improved. So he's wondering if he could stop the monthly injections after one year, which is, again, a common question that we always encounter. So which of the following statement is true regarding the long-term effect of mepolizumab in severe persistent eosinophilic asthma? The annual exacerbations remain low in patients with receiving mepolizumab. The reduction of oral corticosteroids is maintained at four years. Of mepolizumab, asthma exacerbation increases significantly. The eosinophils remain suppressed at four years. All of the above statement is true. My questions get easier as we go by. So we know the test-taking strategy, all of the above, is always true. Yes. Majority of you got it right. E is the right answer, not D. So you are all right. So mepolizumab is another drug that we use, anti-alpha drug, which is shown in four randomized placebo-controlled trial, the DREAM, MENSA, SIRIUS, and MUSCA, that has shown reduced in exacerbation. In addition, it is also shown to improve quality of life, asthma control, and lung function. In the SIRIUS trial, it has shown that the patients who are receiving mepolizumab had significant reduction in oral corticosteroid use than the placebo group. So what is shown here on the left-hand side is the MENSA group. And these are open extension label studies in COSMO. That's one year after the MENSA trial was enrolled. And you can see there's decreased exacerbations. Actually, this is the blue one. So you can see the, sorry, this is the blue one. That's a placebo. You can see there's decreased exacerbations with use of continued use of mepolizumab after one year of the MENSA. And also, we can see there's persistent decrease in oral corticosteroid use continued for the next one year in the COSMOS trial that's shown beneficial of mepolizumab. So it does reduce exacerbations. It does reduce oral corticosteroid use if patients are already on. And then came our COLUMBA study, which is another long-term safety and durability of mepolizumab response in patients with severe eosinophilic asthma. It's an open-label, single-arm, multi-center extension study where patients were receiving mepolizumab once a month for up to four and a half years. And there were about 347 patients. And these patients were coming from the DREAM trial. Of treatment, mepolizumab, you can see there's increased significant exacerbation risk when patients don't take mepolizumab. And then when they were extended onto this COLUMBA open-label study, you can see there's persistent decrease in exacerbations, which was maintained up to four and a half years, three years shown here. So there's overall 56% reduction in exacerbations rates if patients continue to use mepolizumab, which is the same thing shown here, that pre-treatment, there's a high risk of exacerbations per year. With the DREAM trial, showed some difference in exacerbations, decreased exacerbations. And that kind of persisted up to three to four and a half years with the treatment of mepolizumab, with no significant adverse events, although more than 10% had adverse events, mainly respiratory tract infections. There were less rates of pneumonia. And then there's also headache and bronchitis. But overall, there was no new safety concerns in the long-term use of these mepolizumab in at least 1,200 patients years. So it's definitely safer and continues to decrease your exacerbations and oral corticosteroid use. And there's also real-world data that shows that mepolizumab, when given, even after one year, has significant reduction in exacerbations rate by almost 70%. Again, another real-world data showing that there is decreased exacerbation risk with continued use of mepolizumab. And what happens if you stop biologics? Here, the study showed that if you stop biologics at year one, there is increased risk of exacerbations with patients who are not on mepolizumab. And also, there's poor asthma control if you stop the mepolizumab. So there's clearly data showing that if you stop the biologics, you will have increased risk of exacerbations. There was not much study on reslizumab. There's an IV medication that we give once a month, but there's one open-label study that showed that we had 1,000 patients. We did show that there's persistent good lung function for up to two years in either both reslizumab-naive or experienced patients. There is persistent improvement in lung functions. Both FEV1, FEC, and even peak expiratory flow rates were better with no significant adverse events. So last question for my session. So with rapid liberation of eosinophils with benralizumab, the extension studies have shown increased risk of serious infections. Is it true or false? Do you expect to see increased risk of infections when we use benralizumab? See, the questions are getting easier and easier. I hope. Excellent. It is true. I mean, it is false, that we don't see increased risk of infections. So that false is the right answer. So we know that Benralizumab has been used in the last five years. These are the three major trials that were done, phase three trials, open label, I mean, sorry, randomized controlled trials that showed great benefit of Benralizumab in reducing exacerbations. So that continued into the BORA trial, which was a one-year extension of those three trials, which again showed decreased exacerbations. And then we have this Mel-T-Me, which is the longer four and a half years continuation of these Benralizumab. So what it showed was the Benralizumab, when we continued after the predecessor studies, there was shown persistent reduced exacerbation rates, which maintained up to four years. So you can see that all these patients, it was an open label, no placebo, so it was continued Benralizumab studies. Even the placebo groups were given the Benralizumab, and there was persistent reduction in asthma exacerbation rates, and that persisted up to the four-year mark. And there was significant number of zero exacerbations per year. That's what we want in our patients. So it did show a good, you know, decreasing risk of exacerbations. Again, the real-world data again shows there is significant reduction in exacerbation rates by 73%, although only 14% were non-responders in this group. And there was also another study from the Zephyrs II, which had 429 patients, showed significant reduction, almost similar, 72.8% reduction in exacerbation rates after one year after initiation of mepolizumab. So there's great data out there for Benralizumab that shows there is persistent reduction in asthma exacerbation rates with no significant adverse events. And then coming to Dupilumab, which is again dual alpha receptor blockers for four and 13. Here we have the Liberty Asthma Quest and the Liberty Asthma Venture, the two randomized controlled trials that showed reduced exacerbation rates and improved lung function as well as quality of life, and also reduced the oral cortical steroid use. So there are one study that shows the continuation of these open-label extension study, that's our TRAVERSE trial, which continued for up to two years. Here you can see that there's significant decrease in exacerbation rates as the continued use of Dupilumab. And also especially in type II inflammation type, which is where these biologics works great, there is persistent improvement in your lung function, and that's kind of maintained up to two years. So the take-home message, biologics have revolutionized the treatment of severe reosinophilic asthma, it keeps our patients away from the hospitals. So all these medications have shown efficacy for more than five years, mainly your omalizumab, mepolizumab, Benralizumab. There's data out there for Dupilumab for two years. And we also see that in real-world studies, these biologics are very safe and effective and helps our patients. Thank you so much. Excellent question. You know, it's always a thing that we have in our practice. And I did know that this question is going to come. What is the safety of biologics in asthma, I mean, pregnant patients? So the only trial or only drug that have shown efficacy is Zolair or Imalizumab that has been shown efficacious or no congenital defects in pregnant moms who are using this. But definitely, there is no, I mean, you can continue using Imalizumab or even start. But the data for the newer biologics are not very sure. Like you said, there's no randomized controlled trials. Dr. Diego, do you have anything about the new drugs? I know Imalizumab is very safe, but the other drugs, I'm not sure. Yes, I don't know if I'm on the. Yeah, you can use. No, I don't have a lot of comments to add. I think you said it correctly. I mean, the expect registry has up to 250 patients that had at least one dose of Imalizumab and no increased rates of more side effects or fetal problems and malformations. And Imapolizumab has also an ongoing registry as well, but they have less than 20 patients so far. But they're looking at this. But this is a very good question, Victor. What biologics do you recommend if the patient's not allergic and has eosinophilic levels less than 300? I think that's another question. What drug do you use? What biologic do you use for non-type 2 asthma? I think the data on tezolipumab is coming up on that. That's the only drug I think that we use right now for non-eosinophilic. Good question. Thank you. Okay, thank you so much. We have our next speaker, Dr. Linda Rogers. She comes from the Incan School of Medicine in Mount Sinai and National Jewish. She's a good friend of mine. And she's gonna talk about some case discussions on the use of tezolipumab for non-type 2 asthma. And she's gonna talk about the use of tezolipumab for non-type 2 asthma. Some case discussions on the blockade of the Alarmans, which is the new paradigm for severe asthma. Thank you. Thank you, Diego. It's nice to be here with a lot of old friends. I won't tell Carl Icahn you mispronounced his name. Anyway, it's nice to see you all again. And so I was tasked to talk to you about the Alarmans, which we'll do in a case, hopefully a case-based manner. I really always, I have, for those of you who know me, I have a large practice of severe asthma with a lot of work in biologicals in New York. And I like to kind of bring my really difficult cases here to share with you all because I learn so much from them as I'm desperately trying to figure out what to do with them. And so I'll show you one of those. These are my conflicts. I am a clinical investigator. I have research funding and I'm an advisory board member for Sanofi. I do advisory boards for a number of other companies. And I will be talking about non-FDA approved treatments and I'm supposed to tell you that. So I just did. So this is DW. He's a 35 year old male with steroid dependent, allergic and eosinophilic asthma. And he has been oral corticosteroid dependent for the past 10 years since age 25, which obviously is concerning to all of us. And it's been variable over the course of that time. He's done, had periods of time where he's been as low as five milligrams, but he had moved here from out of state and established care with me and then initially was doing okay. And then kind of really just got worse. And we got to a point where we were unable to taper him below 20 milligrams. A little bit about him, he's a lifelong non-smoker and he had five intubations in the five years that I know him. And this was in the context of treatment with high dose inhaled corticosteroids, long acting beta agonists and chronic oral corticosteroids with excellent adherence technique and no things like smoking or vaping that I think would influence that. He has multiple flares a year despite his 20 milligrams of prednisone and he has had a 60 pound weight gain despite bariatric surgery. He has atopic dermatitis, which is mild to moderate, mostly involving the scalp and allergic rhinitis. And over the course of the years I know him, I kind of put him on everything. He had been on omalizumab before I had met him and had not really done much for him. We cycled through the anti-IL-5 drugs. And at this point in time, when I'm seeing him, he was on dupilumab, which was really great for his atopic dermatitis and probably had some impact on his asthma, but was really not controlling it. On the right here, you can see he has pretty significant persistent airflow limitation. Let me see if I can get a pointer going here. With an FEV1 of 60% predicted. That's on all these therapies. So this is on oral steroids, ICS, and LABA. His pheno here is 14 parts per billion. Pretty allergic, IgE 1025 with lots of sensitivities. And his bloody acinophil count has been really variable. I've seen him as high as 2300. But more recently, he's got counts in the zero to 400 range and that probably goes up and down a little bit depending on how much oral steroids that he's on. And he's got a pretty shockingly normal chest CT. And so are there any other therapies that can help this patient? He clearly needs help. And so let's talk about the alarmins. And so the alarmins are a set of cytokines, including IL-25, IL-33, and TSLP, thymic stromal lymphopoietin, that are produced by the airway epithelium in response to a number of stimuli, both allergic and non-allergic. And so these are produced in response to our classic allergic exposures, but also to infections and other things. And they are really central to the immune response. They're involved in the innate immune response and the adaptive immune response, typically involved in allergies. I knew that I would do that if I used the pointer there. And basically they are upstream of this type two alert, the type two response, which is characterized by production of interleukin-4, 5, and 13. And you can see sort of some of our biologicals in this slide and sort of where they interact. Omalizumab, as you know, blocks IgE. Anti-IL-5s and dupilumab block IL-4, 13, and 5. And you can see here that there are now drugs in development to really block the alarmins. And that includes tezapelumab, which I'm gonna tell you about first and is now FDA approved. And several others. Etocumab, I'm not gonna talk a lot about that, really kind of failed in phase two development. And I will talk about etepic, I can't pronounce it, etepicumab. So let's have a question. Which of the following cytokines are reduced during treatment with antithymic stromal lymphopoietin, TSLP, with tezapelumab? A, IL-6, B, IL-8, C, TNF-alpha, and D, IL-5. You can see I did not throw you the softball of asking about TSLP because that would've been too obvious. So let's see what you guys. So, mixed answers. So a lot of you, 46% did IL-5, which is the correct answer. But you guys also kind of dived into some of those non-type 2 cytokines, which may not be completely wrong. But let's show some of the data. And so what's the mechanism of action of tezapilimab? So TSLP, tezapilimab blocks thymic stromal lymphopotent, TSLP, which is, as I already said, an alarmin. I won't sort of revisit the top of this slide, because we just talked about this. But TSLP is really central to airway inflammatory response, both type 2 and probably type 2 low inflammatory responses. It's involved in allergic inflammation, switching of naive T cells to make them into TH2 cells that produce the type 2 cytokines that most of us are familiar with at this point. That's involved in eosinophilic inflammation. But you could also see here that there's a segment of eosinophilic inflammation that's non-allergic that comes from innate lymphoid cells. And also, TSLP may be involved in neutrophilic inflammation there, in terms of class switching to TH17-producing T cells. So it may have a variety of responses, not just on the type 2 inflammatory pathway. And so the last couple of years, we've had a couple of clinical trials. I'm going to show you. This has been presented at these meetings before. So I'm going to walk through it fairly quickly. These are the phase 2b studies for tezapelimab. This was proof of concept. And this is a little bit of a busy slide showing the outcomes of this study. And I'm going to try to simplify it for you. You can see these colors, blue, green, and orange. These are different doses and intervals of tezapelimab. But the currently approved dose is 210 milligrams every four weeks. So you can disregard all the different things. But just look at these colors as sort of a group compared to placebo. And the y-axis here is annualized rate of exacerbation. So you can see here high degree of efficacy with significant reduction in exacerbations in these patients, regardless of the dose or the interval. But there was also interesting biomarker data in these clinical trials. So this drug reduced a broad range of biomarkers. It reduced exhaled nitric oxide, sputum eosinophilia, and blood eosinophilia. And this was designated as a breakthrough therapy in 2018 by the FDA due to the fact that type 2 biomarkers were not required for response of the drug. So if you look at the x-axis here, breaking down the clinical response by eosinophils, pheno, or something that the company called type 2 status, which was a kind of a combination of eosinophil cutoffs and IgE cutoffs. And you did not have to have an elevated type 2 biomarker for this drug to respond, which is what led to the breakthrough designation and led to the phase 3 trials, which were Navigator and Source, which I'll show you now. And so Navigator, which we participated in, was published in New England Journal last year around spring. So this was a typical biological phase 3 clinical trials. Patients not controlled on moderate to high dose ICS and a second controller who were having two or more exacerbations a year. 500 randomized to tezapilimab, 500 or so to placebo. Overall results, again, reduction in exacerbations, reproducing the phase 2 results. And again, the biomarker data really replicated what you saw in the phase 2 program, where the drug clearly responds more in people who have type 2 biomarkers. And as you can see here, the higher you go, here going from greater than 150 to 300 to 450 cells per microliter in eosinophils, there's a dose response here. And similarly with pheno, higher pheno, there's a dose response. But you could see here below 150 and below pheno of 25, you still have a clinical effect there. ATP had nothing to do with response to this drug. So if you had positive allergens or not, you were equally responsive to this drug. And biomarkers are measured in all the phase 2 and phase 3 programs. And again, these were two publications that were ancillary studies to the phase 2 studies showing reduction of eosinophils, pheno, IgE, and IL-5, which was the answer to the question. It doesn't look like they did not show data on the others. So I'm presuming that those weren't lowered in blood. But I think they mostly measured type 2 cytokines there. So this year also saw the publication of Cascade, which was really a mechanistic study looking at the effect of tezapilimab. And so this was a study of about 100 patients who were randomized to drug or placebo and then underwent serial bronchoscopy before or after treatment. So really dedicated patients. And they were looking really to understand the mechanism of action of this drug. And so they measured airway, eosinophils, neutrophils, T cells, and mast cell proteins, tryptase, and chymase. And you can see here that really actually the only effect they were able to detect with these bronchoscopic biopsies was the reduction of eosinophils that was already hinted at in the results of the peripheral blood. There was also an experimental, sort of an exploratory endpoint looking at bronchial hyperactivity, which I think is interesting and that probably there's going to need to be follow-up on. You can see here that patients treated with drug had a reduced bronchial hyperactivity. You can see here the graph goes up. But this is a higher PD20, meaning they were at less bronchial hyperactivity. And the data shown in a different way, which is sort of the log full difference in change in the PD20 to mannitol. So the drug seems to reduce bronchial hyperactivity. And that becomes relevant to the patient that I showed you. And I'll show you that here shortly. But what about tezapilimab as an oral corticosteroid sparing drug? That's less clear. So this was SOURCE, which was the paired phase three study with NAVIGATOR. The exploratory endpoint was categorized percent reduction in daily oral corticosteroid dose. And when you look at the results here, if you ignore the placebo column, it looks actually pretty good. You can see here 54% of the patients had 90% to 100% reduction in their oral corticosteroid group. And the majority of patients seemed to have their oral corticosteroids reduced. But look at the placebo group. There was a huge placebo effect in this study. And so there was no difference here. So the study did not meet its primary endpoint due to this large placebo effect. But if you start to delve into biomarkers, you can see here that in patients that had higher biomarkers using a cutoff of eosinophils greater than 150, there may have been evidence of increased likelihood that they were able to reduce their oral corticosteroids. But that was not part of the original design of the study. So this was considered technically a negative study. What other drugs are coming down the pike? Many of the anti-alarmings coming are targeting the IL-33 pathway. And this is a super busy slide. And I'm going to just do a fast overview. So IL-33, like TSLP, is an alarmin. It binds something called the ST2 receptor, which you can see here in green. And this is obviously, it's involved in a lot of things. And this is a complicated slide. But just to make it very simple, it's involved, it binds to basophil receptors and is involved in preformed mediator release from basophils. It binds to mast cells and promotes the adhesion of mast cells. It is involved in innate lymphoid cells here that produce IL-5 and IL-13. It promotes the expansion, pardon me, expansion and functional differentiation of different T cells. So also involved in eosinophils, macrophages. So you can see it has the potential to affect many pathways involved in asthma. And so this study, Astagolimab, which is not an anti-IL-33 cytokine directly, it actually blocks the ST2 receptor, was published in the past year. And this was sort of a phase two dose response study of this drug. And you can see the design a little bit here. And they stratified patients. They controlled the enrollment such that patients were stratified so that there were at least 30 eosinophil high patients in each subgroup and enough lower, less than 300 cell eosinophils in the other group. And so they were balanced in terms of eosinophil high and eosinophil low, but really favoring this eosinophil low group. And you can see here the results. There was definitely a reduction in exacerbation with any of the doses and any of the intervals, as you can see here. Side effect profile looked pretty decent in this phase two study. And so this, we'll see what happens with the development of anti-ST2 treatments. And then there is the drug I can't pronounce, Itapicumab. That's really hard, TPK, Itapicumab. And so this is a monoclonal antibody to interleukin 33. This was also published over the last year. And this was studied in an interesting way. And so this is made by the same folks who make dupilumab. And they studied it both as a drug in and of itself and then combined with dupilumab in this clinical trial, which went out for 32 weeks with about a 12-week treatment period here. And this was modeled after how the dupilumab was developed, where they kind of tried to taper off patients' baseline inhaled therapy, dropping their inhaled steroids after they were randomized to drug and removing their LABAs. And you can see here that there was clearly effect compared to placebo in terms of loss of asthma control, which was the primary endpoint of the study. It's not clear that combining it with dupilumab really added much, but there was proof of concept of some clinical efficacy here. And you can see here that, interestingly, this drug reduced eosinophils. So blue and red here are the two groups. Green, if I remember correctly, is just dupilumab alone. And the blue and red are itapakimab alone, and it combined with dupilumab. And you can see that it reduced eosinophils, where eosinophils went up on dupilumab. And oddly enough, you can see here IL-33 went up on the treatment groups. And that's because it's detected in the blood longer, because it's bound. It's not necessarily active drug. But pheno goes down with this, and also IgE goes down with this, similar to dupilumab. So how would you treat the patient that I showed you? And I'm going to give you four choices here. And I see some smiles by some of my clinical trial co-investigators in the office. So your choice one is to treat the patient with both omalizumab and anti-IL-5. Two is change him to tezapilimab. Three, enroll him into the PRECISE clinical trial. And this is available at multiple sites across the country and is studying five novel treatments for severe asthma, where patients, including patients who are not completely controlled on biologicals, can be entered. And so you can look this up on the PRECISE website and see if there's a center near you. And that's an option. Or enroll him in an IL-33 clinical trial. And I'll give you time to all answer. I didn't give you all of the above. This is actually really, there's not a, well, I would say there's one answer that I probably wouldn't do. But there's not a real right and wrong here. So most of you are going to give him the FDA-approved drug. And that's available and clinically available. And that's a great answer, obviously. And I really appreciate the 30% of you who are going to refer him to PRECISE. Because that, I think, will be really great. Because these are drugs that are not being necessarily developed by industry. And we are trying to come up with additional options for our patients with severe asthma. And I'll tell you what I did with this patient. So at this point in time, we hadn't opened for PRECISE yet at our site. So I had changed him to tezapilimab. And this is what happened to him, interestingly. So he's been on it for about six months. His oral corticosteroid dose is down to 7.5 milligrams. And his lung functions maintain really nicely. His activity tolerance was great. And what was really fascinating to me was that this was somebody who always had a really high rate of beta agonist use. And that has really dropped tremendously. And so I'm thinking that of the impact on bronchial hyperactivity we saw in the studies, although I don't really know what particularly about this patient led him to respond to this drug. He's singing again. And he really couldn't sing before because he was a pretty sick guy. And he's not needing albuterol daily. So he had a good clinical response. So now he's still on 7.5 milligrams of prednisone. So now I'm going to put him into our clinical trial also to see if we can get him down that last mile. So I will stop here. And I will leave it to Diego to tell us whether we have time for questions or not, or whether we want to hold them. Thank you. This one from the source, the oral steroid sparing study? Yeah. Does this study suggest that melatonin works better for mood or anorexia? It's not necessarily that it works better. This was specifically an oral corticosteroid sparing study. So just going back, let me show you the two, both NAVIGATOR, which was the phase 3 study. So in NAVIGATOR, these were more typical patients, not oral steroid sparing patients, but patients who were on high-intensity inhaled therapy and had two or more exacerbations per year. You can sort of see in that patient population, the drug was effective for everybody, but there was a greater reduction the higher your type 2 biomarker went, irrespective of whether that was eosinophils or pheno. If you look at the oral steroid sparing study, the oral steroid sparing study as a group, with everybody grouped, irrespective of biomarkers, was technically negative for its primary endpoint. But you see a hint that it might be oral steroid sparing for the subgroup, although the study was not designed to answer it by separate biomarkers. Does that make more sense? Okay. Other questions? Great. Thank you for putting the plug in. I couldn't resist, yes. Yeah, you know, I have to say, I don't, and I'm questioning this in my own practice. Let me ask, let's put this question out there here. I don't routinely monitor eosinophil counts during treatment with dupilumab and whether we should, you know, is kind of a question. So I don't necessarily use that. You know, if you look at, it's not the same question, but if you look at IL-5 as an example, you know, everybody's eosinophil count goes down if you treat them with anti-IL-5. They don't necessarily have a clinical response, and so you will have patients where you'll give them an anti-IL-5, you'll eradicate their eosinophils, and they are not controlled. And so I think that that is important in terms of what pathways are driving their disease. And similarly with my patients, it was hard with him because he's also oral corticosteroid dependent, but if you think about it, he had eosinophil counts as high as 400 while on some amount of oral corticosteroids, and I think that is telling you that he has relative steroid resistance, number one. I think it also tells you that eosinophils and type 2 biology are not completely driving his disease, and whether, you know, you're just by blocking IL-4 and IL-13, you know, back, would I have given this patient maybe anti-IL-5 and dupilumab? Maybe. You know, it's harder to get that for pragmatic reasons, obviously, in terms of approvals. Any other questions? Great. Thank you so much. Great. Thank you so much. Thank you so much for those fantastic talks. So, our next talk will be focusing on asthma-associated comorbidities. Again, this is me. How are you guys? These are my disclosures. I speak for a number of companies and also consult, and I have received some research funding from various sources. And I also start with a case. This is a case from my clinic I saw, like, I think five weeks ago. So, this is Ms. LM. She's a 52-year-old with a history of allergic rhinitis. She got some nasal polyps, hypertension, and severe asthma. She's on triple therapy, as you can see there, and also intranasal fluticasone and some Montelukast. The asthma history, very important. Two exacerbations that required steroids in the past 12 months, although her last exacerbation was four months ago. She's been relatively controlled, but still using some albuterol here and there two to three times a week. It's not too bad, actually, for her. And no nighttime awakenings. Biomarkers. This is the biomarkers that were done a couple of months before that date. So, actually, like, four or five months before. So, no recent biomarkers, but this is what we see. So, we see clear signatures of type 2 inflammation there with a high IgE, relatively high IgE, positive allergy testing, some blood eosinophils at 202, and a pheno that's relatively elevated at 28 parts per billion. Spirometry, so mild obstruction, but she does have a positive bronchodilator response. What was interesting is, when I was looking at the physical exam, I saw this. And this highlights that we should definitely look at patients' nose all the time. My dad was an allergist, and he would always take a look at a patient's nose, and he's like, are you taking a look at patients' noses? And I said, sometimes. And I'll be the first to admit that I don't often look at them. But when a patient tells us that they're congested or have a history of nasal polyps, we should take a look in there. And, as you know, nasal polyps, you need to diagnose them with fiber optics and a CAT scan of the sinuses. But it's interesting that sometimes with just looking with the otoscope, you can actually see some of these ones. And when you ask her, she says, well, she had actually a sinus surgery before, but the problem now is she has no sense of smell, and unfortunately, she has daily congestion. So what do we do for her? So here we can do a couple of things. We can add some Astiline, some Budesonite irrigations, nasal saline washes. Try to refer for ENT for a second surgery, so reconsideration of surgery. Refer for allergy for immunotherapy. I mean, she had definitely some positive allergy testing and relatively high IgE. Maybe we should do a biological for her asthma. She had two exacerbations in the past 12 months. She meets some criteria. Still not fully controlled. Or we should ask, actually, for a meeting with ENT and allergy. What would you choose? Relatively easy question. Very good. Very interesting. So yes, I think so for 45% actually half and half chose four or five. I think either is fine. I think obviously we're providers that we want to treat, but I think in this case having a multidisciplinary discussion with allergy and ENT is potentially a good option for our patient. As I'll explain to you my strategy when it comes to comorbid conditions, how do we approach this. So this is really my objective is to just review the indications for asthma, biologicals in other conditions and as a tool for us to decide what therapies we're going to use for our patients. And as you know there's a lot of interest in comorbid conditions because it affects our patients, increased health care utilization. Typically patients that have more a lot of comorbidities typically will do worse, but what is interesting is that some of these comorbid conditions actually may share some pathophysiological mechanisms and some of the same pathways are activated. So here's our list of biologicals that we have and the targets and the treatable traits that we use, but as you know these medications have been approved for other disease states out there and you can see that there are several. This is actually FDA approved therapies and there's a lot of other diseases that are under investigations. COPD, ABPA, non-CF bronchiectasis is a big one nowadays and I show only the ones that are approved but there's a long list as I mentioned before of many of things that are under investigation. I'll focus today on nasal polyps just because we have a lot of information and because it's often associated with patients with asthma. In fact 3% of the whole population has a nasal polyp. Some of them are small, some of them are big, but it's pretty frequent that we encounter this in the general population. In our patients with asthma around like 50 to 60% of patients with asthma may have nasal polyps and patients that have nasal polyps often have asthma up to 80%. We were talking about the pathophysiology of some of these nasal polyps and some of them when we look at biopsies a large majority of them have intense eosinophilic infiltration. So you know it gives us some idea that these medications may be helpful for patients with nasal polyps. So we're briefly going to take a look at some of these studies. This is the polyp 1 and polyp 2 studies, very cleverly named. And this is a study of two studies of omelizumab. Very important. These patients had high IgE levels and have allergic sensation so they had some, they were chosen by that characteristics and they received the usual care versus omelizumab or placebo for 24 weeks. Very interestingly more than half of them had coexisting asthma and these patients actually did better with regards to improvements in nasal polyps scores, in the nasal polyps congestion and size of them and also in the health care or health associated quality of care, the SNOT questionnaires. So it was effective and this is one of the reasons why omelizumab is now approved for nasal polyps. What about other biologicals? We have the sinus 24 and sinus 52, another cleverly clearly named study. So this included more than 700 patients that had nasal polyps and they treated these patients with 300 milligrams of dupilumab versus placebo for 24 in one study in the sinus 24 and 52 weeks in the sinus 52. Again a lot of patients had coexisting asthma. Around 60% of these patients had asthma and it was what it was shown is that when you looked at over time these patients had a less occurrence of events related to surgeries or oral steroids. So kind of like an exacerbation. So definitely an improvement in these in these patients compared to placebo. What was interesting is that it also helped with the polyps scores and nasal congestion and obstruction and this study I thought it was very interesting because in the sinus 24 after the patients received 24 weeks they actually were stopped and they still continue to see the patients and as you can see when you're off treatment unfortunately the congestion kind of comes back and this is very analogous to the comet study that Darani showed us earlier. When you stop biologicals unfortunately disease comes comes back. She showed us the metpolizumab study and this is just a highlight that again I'm gonna go back just to see show you that they unfortunately symptoms come back after you stop biologicals. And then finally this is a synapse study. This is a study of metpolizumab included around 400 patients, 100 milligrams every four weeks for recurrent refractory nasal polyposis. These patients had a previous surgery and again a very huge proportion of these patients had coexisting asthma and they improved the nasal size of a nasal obstruction but also prevented surgeries compared to placebo. Now I'm gonna go back to this study just to highlight that in these studies it's all comers so it's not pre-selected for high eosinophils or hypheno or anything it's just all comers and the same with the synapse study metpolizumab they did not select it for high eosinophils again it's all comers and the reason they did that again is because the majority of polyps nasal polyps have a intense eosinophilic infiltration so it kind of selects automatically just by having polyps. Now what are the other indications and in the interest of time I'm not going to cover all of them. These are less frequently encountered in our patients with asthma but when we are selecting therapies we may consider some of these ones. So you see that for skin there's multiple now biologicals that we can use for conditions chronic corticaria melissomab, dupilumab has now two indications in the in the dermatological space with atomic dermatitis and just three weeks ago prurigo nodularis was added to the list. EGPA which often obviously coexists with asthma and hyper eosinophilic syndrome we can use metpolizumab. For GI now we have for eosinophilic esophagitis we have dupilumab and then we mentioned the nasopolyps for these three medications. Now as you can see and I put it in different colors and different schemas now we've kind of seen different specialties. Recently I pulled my database of patients on dupilumab for example in my clinic and I noticed that there was a lot of names I didn't recognize and it's because some GI doctors are using it and some dermatologists are using it and we're using it separately. We don't talk amongst ourselves so I think it's very important that if we're going to start using some of these medications that we kind of talk amongst us particularly with ENT for example allergy which we always have collaborated because sometimes in our patients we can select what's the best therapy for them. So in the patient that I showed you with I spoke with the ENT physician he was leaning actually towards doing surgery on this patient again and I said listen the patient has asthma the patient is not very well controlled is doing better I think we have an option for her let's why don't we try this for a little bit and see and if the medication doesn't work maybe we can proceed for surgery and a bit of shared decision-making with the ENT doctor and me the three of us kind of came up with a plan of trying at least four or five months and see how she does. And I think that is my last slide. Thank you so much for your attention. I'll take any questions if someone has one. No questions? Very good. Okay now I'd like to introduce our last speaker Sandy Corona. She's from Rochester New York and it's a pleasure to have her here today with us. Thanks. Hi everyone. So you know I it's not an easy task what I'm going to talk about today that selection of biologics and it is a fairly evidence-free zone because there have been no head-to-head comparative studies of biologics so I'm going to share with you what I use and I'll be happy to hear I should love to hear how you select these biologics because as you know most of these are in the type 2 space so that's me. My disclosures are I have some research grant funding for a clinical study with American Lung Association and royalties for a textbook on asthma that I had co-edited. So we'll describe I want to just review the predictors of response to asthma biologics and then discuss how comorbidities, biomarkers, patient preferences they can guide biologic selection. So let's start with this patient. I think this is you this will feel very familiar to all of you. I think we all see these patients come in. Carol is a 45 year old non-smoker. She has 20 plus years of or 20 year history of asthma, nighttime symptoms, missed work due to daily symptoms. She's on high intensity asthma therapy. She's on high dose inhaled steroids, long-acting beta agonist, leukotriene modifier, as needed albuterol and despite this she has had three exacerbations requiring treatment with oral corticosteroids in the last year including two ED visits and on spirometry she did have mild airflow limitation with a positive bronchodilator response and you know after optimizing her comorbidities and ensuring adherence you know all the good things that we all should do and do as much as we can we phenotyped her or and you to try to endotype her get some biomarkers and these are her biomarkers or exhaled nitric oxide levels elevated at 65 parts per billion. This is just by high dose inhaled steroids. Her eosinophil count is is quite high 2,000 cells per microliter. She has elevated IGE and she has allergen testing positive for cats, dogs and dust mites. So I guess the question here is now is is it biologic the appropriate next step for our patient and if it is then you know what is the what is the right biologic for her? Should we choose a biologic that would be given at home or in an office setting? How would we monitor response? When to stop? How long to treat? When to switch? What about combination therapies? So it's really you know it is it's too many choices and we don't have clear guidance. So let's start about what we know about Carol's phenotype. We know she has adult-onset asthma. She is appears to be exacerbation prone so that is great because all the all the biologics have used exacerbation reduction as the primary outcome. She has bronchodilator response so she appears to have asthma objectively documented on PFTs and she also has elevated type 2 biomarkers. So are there any additional data that can guide our selection of a biologic for Carol? And I just wanted to share this with you because again we have six biologics currently FDA approved promising data on a couple others that Dr. Rogers presented but five out of the six biologics except for tesopilumab has indication for type 2 high asthma and there is a significant overlap in type 2 biomarkers. So this data is from the International Severe Asthma Registry and they found that at least 59 almost 60% of patients with asthma had significant overlap of type 2 biomarkers. So they were both eosinophilic and allergic and could be pheno or acetyl nitric oxide level positive. How many people here are using acetyl nitric oxide level measurement? Okay that's great because that I think is such a great point of care biomarker that can really help us guide with the selection. So what else can we use from our patient's history? What additional information will guide us in biologic selection? I think there are clues from the biomarkers that can help you know whether somebody has higher pheno versus more IgE levels or more allergen driven or if they had more eosinophilia. So if we could figure out what the dominant biomarker is I think it could help guide selection. What about comorbidities? Dr. Masali-Diego just did a great you know we've listed all the comorbidities so if you we had somebody who had asthma and atopic dermatitis perhaps dupilumab or somebody had urticaria perhaps omelizumab would be better for them. What about patients who are on maintenance oral corticosteroids? Not all of these biologics have shown efficacy in a randomized controlled trial in corticosteroid dependent asthma. There's only three of them. So I think that again you know if somebody is on maintenance oral corticosteroid perhaps one of the three that have been studied for efficacy should be should be evaluated. What about exacerbation triggers? You know omelizumab would be good for allergen driven and then the study by Bill Bussey showed that it also attenuates the viral induced seasonal exacerbation that September epidemic so I think that is something to consider. What about patients who have had history of anaphylaxis? There are two biologics omelizumab and reslizumab that have an anaphylaxis label so perhaps those might be avoided in these patients. Are patients able to self-inject? Is there a preference? Are there issues with adherence? You know are those patients who we feel they always are no-show in clinic, they are not filling their medicines and you have to you know contact them frequently or they forget taking their medicines. If there's any issues with non-adherence are these the patients we actually want to bring them into clinic and give them the medications almost directly observed therapy so to speak. Are there plans for allergen immunotherapy? Omelizumab may have an advantage in that space especially if the goal is to get somebody desensitized or get to maintenance quickly. Are there plans for pregnancy? That was a great question that came up earlier. You know omelizumab really has the most robust pregnancy data and the guidance is that if somebody if your patient is on omelizumab already and get pregnant you know you can safely continue that but we don't have as much safety data to support use of the other biologics. And I just want to share with you I'm not going to go through this but this is just at a glance the biologics which makes our job even more difficult. You know there's been no head-to-head comparisons and the inclusion criteria for randomized control trials for all of these biologics is very different. So there's quite heterogeneity in patient selection so you really can't even compare outcome data from one study to the other. But if you just look at all the outcomes the asthma exacerbation ratio, rate reduction, the lung function, quality of life, asthma control, you'll see that at least the decrease in asthma exacerbation is very similar across the board. It's about 50% decrease in exacerbations, some improvement in lung function, some improvement in quality of life, some improvement in asthma control. And then the three studies mepolizumab and relizumab and dupilumab have been effective when systematically studied in patients on corticosteroid-dependent asthma and result in about 50% reduction in maintenance corticosteroid dose. Very quickly I'll just walk through a few studies in terms of predictors of response to these biologics. So this was the extra study on omelizumab and the this Nick Hanania was the first author and this showed that in patients who had high pheno, high exhaled nitric oxide level, elevated eosinophils, and high periostin level. Periostin is an L13 biomarker that is not available clinically for use but was being developed as part of drug development for an anti-L13 antibody that did not make it to approval. And this shows that presence of eosinophilia, high pheno, was associated with a greater reduction in asthma exacerbations with omelizumab and interestingly the IgE level did not predict response. Similarly for IL-5, this graph is from the mepolizumab study but I think this is very similar to what's been seen with benrylizumab as well, that the baseline frequency of exacerbations for our patients and their eosinophil count is what dictates or what predicted response to pretty much all the IL-5 biologics. And you can see these are the placebos at different levels of exacerbation for three or two previous exacerbations. The drugs here and you can see the separation is more when you have more baseline exacerbations and it occurs at a lower eosinophil count. The presence of nasal polyps was associated with improved response. Patients who had late-onset asthma had a greater response to IL-5 therapies. So I think this is something we can consider when selecting but again otherwise there's significant overlap. Interestingly for the IL-5 therapies, the exhaled nitric oxide did not predict response. So eosinophils predicted response but not exhaled nitric oxide level. And then this data is from the dupilumab subgroup analysis that showed that patients who had, so if you had high exhaled nitric oxide levels greater than 25 parts per billion or eosinophils greater than 150 cells per microliter, these are the two doses of dupilumab compared to placebo. A significant response here. Also a significant response if you had low phenol but high eos. Significant response if you had high phenols but low eos. But if you really had truly non-type 2 asthma, so low phenol and low eos, there did not appear to be a significant benefit from dupilumab. And tezepilumab, the new kid on the block, you know, that's the one that we really, it has indication for severe asthma regardless of type 2 status. Also appears to have a dose response effect in terms of the type 2 biomarkers with, you know, higher phenol, higher eosinophil count and higher exhaled nitric oxide levels appeared to, the drug seems to be more effective in that and Linda reviewed that. So I just also want to share with you this graph, this guidance from the GINA severe asthma guide. You know, 2019 is when they first, this is a really nice difficult to treat and severe asthma guide that the GINA strategy, GINA guidelines has published since 2019. It's updated every year and they have provided some guidance on how to select patients who have severe asthma that is uncontrolled and I've listed that here. So, you know, IgE of course and somebody who's exacerbating meets the dosing criteria based on weight and IgE level and has allergen driven asthma. IL-5 if they have exacerbations or blood eosinophils that meet criteria. Dupilumab if they have exacerbations. High blood eosinophils in this 150 to 1500 range and exhaled nitric oxide level greater than 25 parts per billion or if they're taking oral corticosteroids regardless of their eosinophil count and then tezepilumab only if they've had exacerbations. There are no other eligibility criteria but they've also provided predictors of response which I've already reviewed. They're all right here. So nasal polyps for IL-5 but we know for dupilumab 2 nasal polyps is a approved indication. But as you can see high pheno, high blood eos. High blood eos, high pheno, high blood eos. So it's really a lot of overlap. So I don't know that I have answers for you after this talk. I don't know, you know, that we have, like I said, it's really a shared decision-making with our patients. So things that I consider when I'm selecting a biologic in my patient, I try to look for clues from the biomarkers, you know. If they have eosinophil predominant, especially if they have very high pheno, a very high eosinophil count and Gina now recommends checking both stronger loides if their blood eosinophil count is more than 300. Check for strong loides infection. If it's more than 1500, make sure you're looking at ANCA and ruling out eGPA. But if it's a very high eos, you know, go with an IL-5 first. But if they have high pheno, IL-5 may not be your best choice, you know. Consider dupilumab, tezepilumab, or melizumab. And then, of course, if they have non type 2 asthma, you can go with tezepilumab. Comorbidities that Diego nicely covered are listed here, you know, urticaria, or melizumab. Corticosteroid dependent, I usually go with one. If I'm not able to document eosinophilia, then dupilumab would be the first choice, only because, you know, I think they may have eosinophilia that's masked by corticosteroids used, but we're not able to document. And sometimes the insurance carrier will not cover it, you know, all except rezulizumab. And currently, tezepilumab is also approved for in-office administration, but, or at least to be administered by a health care provider. And then, you know, if their plans for pregnancy could consider melizumab, I must say that I think the, and this is the separate one hour lecture already, but pregnancy and severe asthma is what makes us lose sleep in patients who have had, I've had patients where I've had to start melizumab in pregnancy because they just were not safely controlled. I've had patients where I've left them on low-dose oral corticosteroids during pregnancy. So I think it's really about shared decision-making, trying to get some of the primary data, and have that discussion with the patient. And then what do you do once you start the patient? So there's also guidance from Gina on how long to trial, to assess for response. About four months is adequate, and if they have good response, you continue. If they don't, you switch to a different biologic, and if they, if you're not sure, just extend the trial by six to twelve months. And at the end, I just want to leave you with our Rochester experience, and just silver lining in all of this is that, one, of course we have such great therapies available, and two, we actually don't do a bad job of selecting. Whatever criteria we're using for our patients, I think we're doing a good job of selecting these biologics. Farouk Abbas is one of our former fellows. He's actually with us in the room. This is his study. He's currently faculty at VCU. We looked at our data for about 112 patients, and we found that we actually were able to, you know, our patients really responded really nicely to biologic therapy with outcomes that was very similar to other real-life, real-world data, very similar to other randomized controlled trials. And we also looked, we had about 26 percent, so about one in four of our patients did not respond to our first choice of biologic, and when we switched them to a second biologic, they had an incremental benefit from switching, regardless of the biologic that they were switched to. So I think this is just proof of what we're learning, that it's important to use multiple, you know, data points to select your initial biologic, assess for response, and then switch to a different biologic if they don't respond. I just left this here. This is a, if you haven't seen it, this is a great review from Guy Purcell in NEJM that was published in 2022, and they actually have this decision guide as a table, as a graph here, that I was reading through this, and I, you know, this is very much what I think makes, it makes sense, and I found myself sort of nodding my head going through their selection mechanism, so certainly something that I often use when I'm trying to select a biologic. So I'll stop here. Thank you for your attention.

biologics

asthma patients

biomarkers

comorbidities

preferences

response to previous therapies

eosinophils

exhaled nitric oxide

IgE levels

personalized approach