Good morning, everybody. I'm excited to be joined by my colleagues, Dr. Lagogo, Dr. Maselli, and Dr. Tourez today for this exciting talk on updating biologics in airway disorders. Before we start the session, a couple of session notes. All these sessions can be evaluated by the mobile app. We will disclose any conflicts with these presentations. We want to make sure that you keep the aisles and the exits clear, and also silence all the cell phones and pages during the presentation. And you can claim the CME starting Wednesday, October 11th. And without any further delay, I'll introduce Dr. Diego Maselli, who is Professor and Chief of Pulmonary Critical Care at UT San Antonio. He'll be giving an update on the use of NTI-GE, NTL-5, and NTL-4 agents in asthma. Good morning, everyone. Thank you so much for joining us today. It's a pleasure to be here with everyone here in Hawaii. A lot of excitement about biologics. Thank you, Mohamed, today for putting up this session. The task I have is a challenging one, trying to, in 15 minutes, talk about some of the biologics. But I'm gonna focus on something more practical, and specifically talk about emerging data. As you know, there's a lot of articles out there. I'm gonna try to be selective and just point out some of the useful things. But also, I'm gonna talk about some of the upcoming things that are exciting in the world of biologics. So this is me. I'm Diego Maselli from UT San Antonio. Again, pleasure to be here with you. These are my disclosures. I'm a speaker, and I receive some funding from research as well, from various companies. And this is my objective, as I mentioned today, talk about biologics. So let's go ahead and get started. Omalizumab, a new medication. I'm just kidding. Since 2003, it's been around, right? So, and we know what it does and where it acts and how important it is. We also are very familiar with the eligibility of who is gonna be treated for this. This is specifically for allergic asthma. But can we use it beyond the specific range of IgE and weight, which is a restriction that we have a chart for? And yes, in fact, there's actually now nine studies that show that it can be effective just as patients within the range, and it can be used. In our experience in clinical practice, we've used it in ranges above 1,000, 15,000. I mean, very high levels, and it seems to be working. Is it safe in pregnancy? That's another characteristic that's important, a reminder of the expect registry, 250 women that receive at least one dose of omalizumab with no increased adverse events, at least in mom and babies. And so it's reassuring to have this data. Now, as you know, it's for allergic asthma, right? So often, these patients are either partially controlled or mostly controlled. So in these patients, can we use immunotherapy in combination? And this question often comes up as well. This is data from a recent meta-analysis of 11 trials, just incorporating some of the new data published last month, and it shows that, in fact, we can see improvements in rescue therapy. We can see it also in symptom scores. As you know, it's very useful for nasal allergic rhinitis, and in addition, it improves asthma control when we combine these things, and it actually, with no increased side effects. So it's an important tool that we still have. Immunotherapy continues to be something that we can use for our patients with allergic asthma. What about the real world? As you know, PROSPERO was published in 2019, showing that in real world, omalizumab works well. This is relatively new data, again, published a couple of years ago, one year ago, the Relief Study, and it highlights a couple of very important points. First of all, before omalizumab is started, you can see a lot of exacerbations in these patient population in the real world setting, and then after patients are started on this medication, then you can see that the exacerbations go down, and that's sustained through time, which is very important. It just highlights that we sometimes have delays in referral of therapies, and this just adds to our knowledge that we can use it in the real world as effective, and also in a safe way. This is the new trend. As you've seen this slide many times before, we're trying to always approach it at the end. We're trying to put out fires. We try to prevent airway remodeling, and this concept of people remodeling, really, we try to avoid that. And we know now that not everyone is the same, right? We know that sometimes the trajectories of lung function that can potentially lead to chronic airway diseases. So can we do earlier intervention? This is a very important, I think, hot topic to look for in the future. And actually, there's a study ongoing, the PARCC study, that's gonna be looking at this specifically. It's enrolling now. This is a randomized, double-blind placebo-controlled study that will take in patients that are younger, between two to three years of age, that had a history of wheezing and a diagnosis of asthma, and they're gonna be enrolled in this study where they're gonna get omelissoma for two years, and then they're gonna be followed for two years versus placebo. These are some of the inclusion criteria, very briefly, just to highlight what they're gonna do. And currently, the target is 250 children between the ages of two to three, and 14 sites are actually currently enrolling in the United States. We don't have data, obviously, now, but it's a study that I think is gonna change a little bit of our perspective and that question that can we do earlier interventions in some of our patients, which I think it's really important, instead of catching them where in the severe asthma clinic where they already have potentially some airway remodeling and people remodeling as well. Okay, that's IGE. Let's talk about IL-5 therapies. We obviously have three medications, very important for the prevention of activation of eosinophilic inflammation. We know that. What's current and what's the latest, right? So we have some real-world data that emerged recently. This is from ERS last month, and this is from the Reality A analysis. This is a two-year prospective study, multinational, that looked at patients before and after omelissoma. And here, you can see interesting analysis of the number of patients that have a lot of exacerbations, some of them had a little bit of exacerbations and some were in between, and what happened two years after the patient received therapy. Again, some patients have a ton of exacerbations, and this is something that you're gonna see as a trend in the real world. We still have a lot of delays in getting these patients into some of these medications. We, I think as a whole, have to do a better job of trying to catch them sooner. And we can see here that those patients that have 8.6 exacerbations in the previous year, on average, they were able to go down to around 1.7, and the same with others. So it's just highlights that's beneficial as well. This is another real-world study. This is a separate two study. This is a study that I participated on. Again, showing the same highlights. This was published, Jack in Practice, in July this year. And just to highlight that as you follow the patients through time, this has been relissoma, you can see a decrease in exacerbations with time that sustained, this is around 419 studies. We also have the chronicle studies with Nigeria as one of the authors of this manuscript specifically. Again, showing that patients, when they're on veneralizoma, they can, with time, can be significantly exacerbations decreased, and this is in the real-world setting, which is reassuring. As you know, the randomized controlled trials sometimes are very specific in selection of therapy. So it's nice to have real-world evidence that it works and it's supposed to be doing what they do. What about remission? Another extremely hot topic. As you know, last month we had a new statement, a consensus statement that was released. Again, Nigeria is one of the authors, and some of you in the audience, I think, are authors as well. Now more strict, right? More strict with some criteria with using less rescue medication, being on medium-dose ICS. But in the meantime, before we had some criteria, we wanted to look at no exacerbations, no oral corticosteroids, just on the daily basis, improvement in symptoms and improvement in lung function, and what can be achieved when we look at these four criteria. So this is the Redis study. This is a Spanish study of real-world, and it shows here that when you combine those four categories that I just mentioned, you can achieve remission in roughly one-third of the patients. This is data from Reality A. This was published at ATS in abstract form. And as you can see as well, when you use these four very important criteria, you can achieve around one-third of the patients can get into that remission. So it's an achievable goal. But still, I wish we were 100% in this, but this actually, in reality, was shown that it can be sustained through time. I'm gonna try to hurry up here a little bit. This is Orbit 2 study published last month, a similar kind of remission study looking at what can be achieved with venerealizumab. And in this case, the four categories around 43%, so around, again, one-third of the patients can be achieved. Now, a big question that always comes up in our practice is can we reduce our maintenance medications, right? Can we decrease those inhaled corticosteroids or LAMAs or others? Now we have some emergent data about this. This is data from ANDI in practice published earlier this year. And in this study, it's an open label, a study that was not open label, but it was randomized initially and then open label in two groups. And we were one of the sites, actually, for this study. And what they asked us is to try to, in different time frames, try to decrease the amount of maintenance medications that they had in a more organized way. And what was accomplished? Actually, you can see here, I'm gonna use my pointer, you can see patients on high-dose inhaled corticosteroids here. And after end of therapy, they have now more patients on medium-dose. And those that were on medium-dose, now some of them are on low-dose inhaled corticosteroids, which just highlights that these group of patients were able to decrease inhaled corticosteroids without losing control, so it can be achievable. I'm sure a lot of us here know that these patients, when they start on biologicals, they stop all the inhalers themselves. So we know that it's possible. Yes, you've seen it, right? But it's important to see it in a more organized way and so we can analyze and have more data to see. This is close to 400 patients, so it's a little bit easier to at least look at the trends here. Now, most recently, this is a Shamal study. This is a little bit more elegant because it looks specifically at reductions of high-dose inhaled corticosteroids. This was presented in Milan, ERS, last month. Again, trying to understand if we can decrease inhaled corticosteroids in a more organized fashion. They have a reduction period. These patients were on benrolizumab and reduced in a systematic way. And what did they found? They found actually that the majority of these patients can be reduced if you do in an organized way, in a protocolized way. If you see, like 92% of these patients were able to have some reduction. Now, with all this rescue therapy that can be achieved, now we see that a lot of these patients went down from high-dose to medium-dose and then some with low-dose inhaled corticosteroids. And actually, a lot of these patients were able to be on just rescue inhaled corticosteroids, which is, again, very interesting. So it seems like we can achieve this goal of trying to reduce maintenance medication without losing asthma control once you're on therapy. Bronchiectasis is a hot topic. I'm just gonna briefly mention, this is from the Dutch Registry, that it shows that patients that have comorbid bronchiectasis can actually have important reductions in conservations, even if they're on oral corticosteroid-dependent bronchiectasis. We get these patients all the time. They have the CAT scan. We see them. And then, should we treat them or not? And so this just highlights, in patients that have comorbid bronchiectasis, that it can be used. What's new with pregnancy in IL-5? Not a lot, but this was published last month in Jackie in Practice. Four cases that were exposed to benrolizumab without no new concerns with safety of mom and baby, only four cases. But this comes along quite frequently. Just last case, we had one patient with, here's one of my colleagues, Dr. Villalpando. We were discussing back and forth what to do with this patient. So it comes up. We need more data. We need more data for sure about this. Okay, that's IL-5. Sorry, but this is, we're on a crunch. Let's talk about now anti-IL-4, anti-IL-3. So this is the IL-13. This is dupilumab. What's the data on dupilumab, recent data? Here's some real-world data. This is from the, again, the Dutch Severe Asthma Registry. Just to highlight that, in fact, in the real-world setting, they can have reductions, significant reductions in exacerbations pre and post. There's other real-world data out there as well, but this kind of highlights the same feature and the same trend that it works well. What about remission? Again, this is from the QUEST study, then into the Open Label Traverse study. That shows, again, that when you look at patients that meet these four criteria that we mentioned before, around one-third of the patients can achieve that remission. I think with the new criteria that we're gonna be using, I don't know if we're gonna be able to achieve this one-third but perhaps it's something, again, just to try to aim really high. And finally, this is a very thought-provoking study. This is a study, again, published very recently in the Blue Journal, and they randomized a couple of patients on dupilumab versus placebo. They did a CAT scan and then waited four months and did another CAT scan in four months. And this, just to highlight that now there's a new trend of hot area in imaging in asthma, that suggests that there's things that we can see objectively when biologicals. And in this case, they were able to see that there was less mucus plugging, the airway wall thickening was decreased, and actually patients have improvements in ventilation. This is with MRI xenon technology, these fancy images that you see there. And it just highlights that we have other tools to measure efficacy in our patients with severe asthma. Particularly, we might need to have some phenotypes in the future of trying to understand a little bit better who can benefit from these therapies. Looking at the future, this is the ATLAS study. This is a study that's gonna be ongoing. Again, trying to understand if we can do earlier interventions to prevent the progression of the disease. This is gonna include almost 2,000 patients. Again, looking at lung function specifically, try to see if we can catch these patients earlier so that we can prevent the progression of the disease, potentially fixed airway obstruction, as you know, which is our goal really in our patients to try to prevent airway remodeling and prevent people remodeling with a lot of oral corticosteroids. So that's it. There's a lot of more information, obviously, but we have a little bit of time constraints. But I think we show some data that these medications in the real-world setting work well. Remission is an achievable goal, but again, in only around one-third of the patients, we are creating the criteria, but we should try to, again, aim as high as we can. There's emergent data that therapy can be reduced. We've seen it in our clinical practice, but we now have some insights of how we can potentially do it and that it can be done. And then finally, hopefully, we can do some earlier interventions. I think it's important to look out for these studies and see if we can change the lives of our patients at an earlier stage. Thank you very much. Thank you so much. I am not gonna introduce Dr. Logogo because otherwise we won't finish the session in time, but thank you so much, Dr. Logogo, for accepting the invitation. You're welcome. This is a feat when you try to cover all these things in one hour. So I got the privilege of talking about anti-TSLP and newer biologics. These are my disclosures here. I work at the University of Michigan where I direct our asthma program. So I'm really focused on TSLP today. I will touch on some of the newer therapies that are coming up. And we're really looking at the outcomes here, focused on inflammation, lung function, oral corticosteroids, mucus plugging, and of course, we would be remiss if we don't talk about remission in 2023. So many of us here realize that asthma is a disease driven by host-environment interactions. So the airways exposed to things in the environment which result in an immune response. And that immune response then causes the downstream symptoms that we see in the patient. And many of these symptoms expressed as treatable traits which was presented yesterday at a session about asthma and COPD. So when you're treating asthma, you really need to be thinking about what you're attempting to accomplish. So this is an airway disease, small or large airways. There are changes on the inside of the airway that are usually inflammatory in nature, can contribute to exacerbations, FEV1 decline, mucus scores, and may impact airway caliber. You also could have remodeling that leads to lung function decline which is what Dr. Maselli covered. And then you have your airway smooth muscle causing bronchoconstriction. And all these can occur very variably in each patient. So it's important to understand the pathophysiology of the disease and what our biomarkers are telling us. And I particularly like this paper because it really summarized how we should think about inflammation in asthma. And so the IL-5 cytokine is driving systemic inflammation and those are your eosinophils that are coming from your bone marrow. And that is what Dr. Pavard here called the BOM. That's the reservoir of eosinophils in the bone marrow that enter systemic circulation. However, for eosinophils to enter the target organ, you need eotaxin and that's driven by IL-13. And so the IL-4, IL-13 pathway is critical in chemotaxis of eosinophils into the tissue. And therefore, either depleting the eosinophils with one of the anti-IL-5 therapies or reducing them with TSLP and or impacting eosinophil, impacting chemotaxis is critical in improving outcomes. So there are actually differences in these diseases. The magnet-driven disease that's going to be IL-4, 13 likely TSLP-driven. This tends to be early onset and has a higher pheno to eosinophil signal. And interestingly, these patients do better on ICS and less well on oral corticosteroids. The patients with eosinophil-driven disease are going to have more late onset disease, perhaps less AOA hyper-responsiveness, some of the comorbid diseases such as eGPA, a lot more eosinophils, very sensitive to oral corticosteroids, which deplete the eosinophil reservoir and probably respond better to drugs that deplete eosinophils. And so eosinophils and pheno actually tell you different things about inflammation in patients with asthma, but they seem to have an additive effect when you're looking at bronchial hyper-responsiveness with patients that have high pheno and high eosinophils having the most bronchial hyper-responsiveness and the lowest PD20. Pheno is actually becoming quite a significant biomarker, and I think we really should start checking it on all our patients. This study here that was presented at ATS in 2022 really highlighted that if you take the study population in the green and you look at the red bars and you look at the intent to treat placebo versus pheno overall, you don't see a significant change. You see that the dupilumab patients do better and don't lose lung function over time, but if you look at the high pheno placebo patients, they are losing about 120 mLs in lung function in one year, and that's why the ATLAS study that was mentioned is quite critical, and another added point is that in Chamal, although 61% of the patients ended up on anti-inflammatory reliever therapy, those with high pheno actually had loss of lung function during that year that was completely disassociated from control or exacerbations. So we need to start thinking about pheno as a way of perhaps picking up people who are at risk of lung function decline. Now, pheno is quite variable, and you can see in this SARP data set that there are people who are low all the time, there are people who go up and down 26%, 36% are high all the time, and the high pheno group have more eosinophils, more exacerbations, and higher T2 markers, and interestingly, when you look at pheno level and you look at trimucinolone injection, you really don't see an impact, which highlights the fact that pheno is more of an airway than a systemic inflammatory marker. So the reason we are talking about this is that these biomarkers are quite important in predicting TSLP response. So TSLP is produced by the airway epithelium in response to specific and nonspecific allergens, and it has an impact on multiple different downstream pathways. You can see an impact on IL-4 and 13, thus a reduction in downstream IgE production. You can see an impact in IL-C2 cells, which impacts IL-5, so there is an eosinophil depletion component, and then you can see the non-T2 effects, which are modulated by IL-17 and Th17, and then lastly, we talked about this last year, but not today. TSLP actually has a role in mast cell biology, and it turns out that mast cells are very critical in airway remodeling through effects on fibroblasts and collagen. Many of you saw this a couple of years ago, which was basically the New England Journal publication showing the impact of tezapelimab in exacerbation reduction. You do see reductions in both non-T2 and T2 phenotypes, although the impact is much more significant in those with very high eos and high nitric oxide. So how about bronchodilator reversibility? So we look at this study is presented to look at the impact of tezapelimab on exacerbations and lung function. They divided these patients. Now remember, all of them had bronchio, they all had reversibility in order to get into the study, and you can see a significant reduction regardless of bronchio hyper-responsiveness. However, your lung function improvement is higher if you have high post-bronchodilator FEV1. How about an enhanced response? So this study actually looked at predictors of enhanced response to tezapelimab. It turns out that the predictors differ depending on the outcome. So if you're looking at exacerbations, then the prior exacerbations, pre-bronchodilator FEV1 and phenol predict an enhanced response. If you're looking at lung function, it's actually eosinophils, reversibility, and pre-bronchodilator FEV1. So what's the impact of tezapelimab on T2 markers? This is from the Cascade study. You can see blood eosinophils and phenol go down. Serum IL-5 goes down. IgE initially doesn't change, but goes down slowly over time. And then you have reductions in IL-13 and plasma eosinophil-derived neurotoxin. But what was quite interesting last year was that when you look at the summary data from the New England Journal publication of the Phase 3 study, it appears that the impact on T2 markers is about a 50% reduction, but it actually turns out that the reduction is based on your baseline biomarker. So the higher your biomarkers, the more significant the reduction. This is looking at eosinophils. You see a similar trend with phenol, and you see a similar trend with IgE, where the reduction depends on where you started, and so it shows significant target engagement. There is a lot of data slowly emerging on tezapelimab and oral corticosteroid reduction. I know many of you have heard of the SOURCE study, which likely had some design issues that led to a negative study. But this is the destination study where patients in SOURCE and Navigator went on to either continuing tezapelimab or being randomized to tezapelimab or placebo if you happen to be in the placebo arm. And you can see that tezapelimab does have an oral corticosteroid sparing effect in these populations. Dr. Maselli showed you a figure very similar to this. This here is looking at post-bronchodilator MRI, and what you can see is that there are not significant improvements in ventilation defects with bronchodilators. This tends to be more related to mucus plugging. The patients with higher mucus scores have more ventilation defects, and that does not change that much with a bronchodilator. And they also tend to have high phenyl and high IL-4. So this data was presented at ERS this year, tezapelimab's impact on mucus scores. And what you can see here is that the higher the mucus score, the higher the eosinophil count, the lower the lung function. So mucus scores actually correlate with clinically meaningful outcomes. Patients that were treated with tezapelimab had a significant reduction in mucus scores, which is highlighted in that representative image, and there were not many changes with placebo. In addition, it's important to tie this to a clinically meaningful outcome, and what you can see is that the change in mucus scores actually correlates very well with improvements in both FEV1 and FEF2575, which is a marker of small airways obstruction. You've seen the remission data that was presented. We just published this in CHEST a few weeks ago, and this just shows remission criteria across multiple biologics. So you can actually go and look at that. There are some differences in thresholds, but essentially you always end up about 30%. This is the tezapelimab data, and you can see that not only do more patients on tezapelimab than placebo achieve remission, but that remission, the patients meeting all four criteria, is stable over about a three-year period. Now the one thing to remember, and I think it's important to highlight, is some patients on placebo meat remission criteria, which highlights that good asthma care actually makes quite a difference. So now a very quick run-through of the newer targets. So one of the newer therapies that's being targeted in asthma is looking at OX40, OX40 ligand. OX40, OX40 ligand are very important in T-cell proliferation and migration and decreasing regulatory T-cells. And in asthma, that results in increased number of inflammatory CD4 T-cells, which causes T2 inflammation. There is some data in atopic dermatitis showing efficacy and ongoing trials to determine if targeting this OX40, OX40 ligand will be beneficial in asthma therapy. We also have the JAK inhibitors, and here you can see that JAK stat pathways are very critical in the downstream inflammatory factor of all cytokines. And so there are some targeted JAK inhibitors coming to phase two in an inhaled formulation, very exciting. We also have inhaled anti-TSLP antibody fragments that have been studied. Here's a study looking at allergic responses, and you can see that there's a reduction in sputum eosinophils and suppression of nitric oxide with inhaled TSLP, and those studies are ongoing. So in the future, we might have targeted inhaled therapies. Depimocimab, which is an ultra-long-acting anti-IL-5 antibody, currently in phase three, showed a 48% reduction in blood eosinophils from 24 hours post-dose, and an 82% reduction in eosinophils, and what's quite important is that the half-life is quite long, which allows Depimocimab to be dosed every six months. So in the future, we might have a therapy that our patients can get twice a year. There is also technology using nanobodies, so I actually had to learn a little bit about nanobodies, which actually come from camels, it's quite interesting. But the immune response there in terms of nanobodies is that they have these very simple antibody processes compared to the current conventional monoclonal antibodies, which are very hard to produce, very temperature-sensitive. Nanobodies are quite simple. You can attach multiple things to a nanobody. They are small, so they can penetrate tissue quite easily, and here there is currently an ongoing study with dual IL-13-TSLP nanobody technology, and the phase one results were presented at ATS, showing a significant reduction in pheno and improvements in lung function, and the phase two program is currently ongoing. Nanobodies are not temperature-sensitive, easier to reproduce, so perhaps that might be a future therapeutic intervention. Lastly, not a biologic, but gaining a lot of excitement, is dexprimipexel, which is a drug that was initially studied for ALS, as it were, and it turns out that dexprimipexel actually reduces eosinophils in a dose-response fashion. It is a pill that you can take, and so there are currently several ongoing phase three studies with dexprimipexel as a potential treatment for severe eosinophilic asthma. This is my team at the University of Michigan. We have both a research and a quality improvement team, and I would like to make a plug for clinical research. I showed so many different technologies. We need more clinical researchers to help us complete all these clinical trials and bring new therapies to patients, so thank you so much, and don't forget to evaluate this session in the afternoon. Okay, good morning, everybody, again. I'll be briefly giving an update on biologics since you already have about 12 minutes, so. Okay, so my name is Mohammad Idreesh. I'm at Baylor College of Medicine. I don't have any pertinent disclosures to my presentation today, so we'll be quickly going over some of the pathophysiological pathways for targeted biologics in COPD. I'll summarize some of the current evidence that we have and briefly review some of the ongoing studies. So going back to what we already discussed about eosinophilic airway inflammation, this is a slide from a paper by Ann Povart a couple of years ago, and he also eloquently mentioned two different pathways, ICS-sensitive and ICS-resistant pathways, kind of all, you know, this one is the early-onset disease, mostly allergic eosinophilic inflammation, whereas the later pathways, non-allergic and eosinophilic airway inflammation. What I want to highlight is the cytokines and the alarmis that are implicated in these pathways. You have already discussed them in detail, so I won't go into more detail in them, but those are some of the cytokines and alarmis that I will be discussing when I present you some of the biologic therapies in COPD. Similarly, neutrophilic inflammation is another treatable trait that has been recognized in patients with COPD. Patients who get exposure to cigarette smoking or irritants then stimulate the micro-microphages in epithelial cells to produce different chemoattractants and cytokines. These chemoattractants bring neutrophils to the airways that in cells release proteases and cause airway wall destruction and mucous hypersecretion. Some of the cytokines that are implicated in neutrophilic inflammations are TNF-alpha, interleukin-1, interleukin-6, and IL-17 pathways. So I'll start with my first biologic. This is mepolizumab. We got the data back in 2017 from metrics and material studies. Metrics and material studies were done together and were published at the same time in the New England Journal of Medicine in a single article. Metrics was a study that included 836 patients who were stratified based on eosinophil count, high stratum had blood eosinophils of more than 150 at enrollment or more than 300 in the last 12 months preceding the enrollment. Low stratum was the patients who did not have any of these criterias. These patients got 100 milligram mepolizumab versus placebo and they looked at the annual rate of moderate or severe exacerbation in the high stratum group, low stratum group, as well as in the overall group. In the high stratum group, there was about 18% reduction in moderate or severe exacerbations. However, there was also increase in time to first moderate or severe exacerbation. However, there was no differences in low stratum group as well as in the overall group. There was also no difference in other secondary outcomes that they studied, which included CAT score, SCRQ scores at week 52. METRIO included 674 patients with eosinophilic phenotype. Here they used two different dose of mepolizumab, 100 milligram and 300 milligram. If you remember, 300 milligram is the dose that we use in eGPA patients. So here also they looked at annualized rate of moderate or severe exacerbation. And in this particular study, there was no difference in this outcome. So kind of different than metrics where there was a difference in this outcome. There was also no difference in the low stratum group as well as in the overall group, and no difference in the other secondary outcomes of interest. There was a meta-analysis that was published of METRIO and metric study. And in that meta-analysis, they kind of saw a trend with improved mepolizumab outcomes with regards to exacerbation in patients who had elevated eosinophil counts. Metrics and METRIO was eventually not approved by FDA because of the same concern. One was that these results were not reproducible in both trials. Also, there was concern that a lot of patients in the study had prior diagnosis of asthma, and also the secondary outcomes were not met. And this is a very expensive drug, so nobody's gonna consider if you don't see consistent outcomes. Benrolizumab was studied in two trials that were done simultaneously. They are Galatea and Teranova. Galatea had 1,120 patient. They used three different doses, 10 milligram, 30 milligram, and 100 milligram. Here, also, the primary outcome was analyzed exacerbation rate in patients with eosinophil count. Here, they used a cutoff of 220. And this was, they didn't find any difference, so it was a negative study with regards to the primary outcome. Similarly, in Teranova, 1,545 patients. They used two different doses, 30 milligram and 100 milligram. Again, here, also, no difference in primary outcome. The post-hoc analysis that was published for Galatea and Teranova had some interesting trends, which is the basis for the subsequent Resolute trial that has been going on right now. It's a little busy slide, but I'll just bear with me. So here, in the blue bar, is the Benralizumab 30 milligram dose. The red bars represent the Benralizumab 100 milligram dose. So I'll start from this part. This is the area where they're looking at the previous exacerbations. And as you can see, the patient who had higher number of exacerbations did better when they got Benralizumab 100 milligram dose. Similar trends were seen for patients who had low post-bronchodilator FEV1, patients who had higher post-bronchodilator responsiveness, and patients who were already on triple therapy at the time of enrollment. So some of this information was used to design the Resolute trial, where now they are recruiting patients who have higher exacerbations and also had higher eosinophilic blood count at baseline at the screening time. And hopefully, we'll get those results in the next couple of years. Most recently, we got the data from Boreas trial. It included patients who were 40 to 80 years of age, and they had 10-pack year smoking history. However, they capped the current smoking at 30%. These patients had COPD for at least 12 months. Post-bronchodilator FEV1 was 30 to 70%, which is kind of in line with what we saw in patients in the mepolizumab studies and Benralizumab studies. These patients were on triple inhaler therapy. However, one thing that they did was that they also included the past history of asthma, which was not excluded in mepolizumab studies. Here, patients got 300 milligram of dupilimab dose and also got matching placebo. This was a 52-week trial followed by a 12-week safety period. Primary endpoint was an annual rate of moderate or severe exacerbation. Among the secondary endpoints, they also looked at the patients who had FENO of more than 20 for analyzed rate of exacerbation, as well as change in FEV1. As you heard earlier, FENO is considered an important biomarker in patients who are using anti-IL-4 and anti-IL-13 therapies. Here, we saw a reduction in analyzed rate of moderate or severe exacerbation. There was about 30% reduction in patients who received dupilimab. This reduction was even larger in patients who had FENO of more than 20, which was about 38%. Among the other study endpoints, which were met for FEV1, SGRQ scores, and respiratory symptoms scores, so all the secondary endpoints also met. Adverse events were similar between the two groups, and all these dupilimab is being studied in an ongoing NORTIS trial to confirm these findings. Some of the other drugs that have been studied in patients with biologic, first one I'm gonna present is stgolimab, which is an anti-ST2 monoclonal antibody. This is a drug that blocks the ST2 receptors, which is the binding site for IL-33. The phase two clinical trial, which was COPD-STOP, did not show any difference in exacerbation rates, but it did show improvement in eosinophil count, FEV1, and SGRQ scores, so now this is being studied in 2B and phase three trials, and hopefully we'll get these results in the next year or so. Tozorakimab is another anti-IL-33 monoclonal antibody, which mainly blocks the inflammation in the human cells, and also have some animal data of decreasing the inflammation in the airways. The phase two clinical study, Frontier IV, was done about a decade ago. We didn't have the results from those studies, but now it is being studied in phase three titania and oberson trials, and these patients have symptomatic COPD and had exacerbation in past 12 months, so we're hoping to get these results in 2025. Tazopelumab, which you already heard about, is also being studied in a phase two course in patients with COPD. We expect early results next year, so hopefully by the time we come back for next meeting, we'll have some of those data for you. Atypicamab is another anti-IL-3 antibodies, which is on the phase two trial, failed to show reduction in exacerbations, but the subgroup analysis showed reduction in exacerbation and improved lung function in patients who were former smokers, so now this finding is being studied in the ongoing ERIFI-1 and ERIFI-2 trials, and hopefully get this information in the near future. Among some of the neutrophilic inflammation markers, anti-IL-1, the drug among the anti-IL-1 were studied was canakinumab, which is an anti-IL-1 beta monoclonal. It was a negative study, didn't improve the COPD exacerbations, lung function, or health status. MedE8968 was another agent that was studied in a phase two trial for safety and efficacy, and again, didn't see any positive difference, so again, that was a negative study. CXCR receptor 2 is another area of interest in patients with COPD. The phase 2b trial looked at mild to moderate COPD at risk of exacerbation, with a drug named denerixin, and again, in this study, was also a negative study, there was no clear benefit for using denerixin therapy. Finally, anti-TNF agents in fliximab at NRSAB, and anti-IL-17 agency NTO6785 also are studied, and the data was less impressive than what we have for eosinophilic subtype of patients with COPD. So data is limited regarding role of biologics in non-eosinophilic COPD. The phase three studies for mepolizumab had their limitations, so there are subsequent studies going on to have a higher, more selective patient population, and hopefully we'll get these results in the next couple of years. Dupilumab was the first drug that was shown in phase three trial to reduce the COPD exacerbation by 30%. There are several trials underway, and hopefully we'll get some of the results in early 2024 and 2025. So, a lot of exciting news. Not as exciting as asthma biologics, like you heard earlier. You have talking about FEV1 and all that stuff. I don't have a lot of cool stuff to present, but again, there is a first ray of hope with this laborious trial that we have for COPD, and thank you for listening. Hi. Thanks again for joining us. You got to listen to all the exciting data about biologics for asthma, the upcoming data for biologics for COPD, and now I have the fun task about talking about navigating the healthcare system. My name is Meredith Turritz. I'm from Weill Cornell in New York City, and I have nothing to disclose. We'll just touch on the fact that obtaining biologics for patients is often very complex with lots of different stakeholders. All of that attributes to a lot of delay in time to getting doses in biologics, which we'd like to minimize, and that there are some disparities in access. So, in an ideal world, it would be great if you could just write your prescription, your patient would go down to the pharmacy, pick up their biologics, but it is not that easy to navigate. In fact, it's very complicated. There are issues on the provider side with time and resources. There's issues on the patient side with different insurance plans, different payers. There's issues in the systems, right? Different practices are set up different ways. Different practices have different infrastructures. Different practices have different access to hospital-related special pharmacies, or buy-in bill, or different ways to obtain their medications, and different practices have different payer mixes. And all of this is complicated because these drugs are extremely expensive. It's estimated that the average wholesale price for these medications is essentially the cost of a car per year, anywhere in the $30,000 to $40,000 range. That's not necessarily what the cost is for the insurance companies or for the pharmacies, but that's the cash price if a patient were to pay totally out of pocket. So how do we even begin to navigate? You know, you have a typical woman who comes with poorly controlled asthma who's adherent to her prescribed triple therapy. Despite this, in treatment of the modifiable risk factor, she's had several exacerbations, again, started on steroids, and you wanna start her on a biologic. How are you gonna get this for her? Is she gonna get it? Is she gonna have to pay out of pocket? How long is this gonna take? Again, there are so many different systems to navigate that it's impossible to give a one-size-fits-all response to this. You know, the provider decides to treat with a biologic and writes a prescription, and in SunSys systems, a dedicated staff person, whether that's a pharmacist, a nurse, a biologics coordinator, an MA, et cetera, initiates the prior auth process and sends that along to the specialty pharmacy. In other systems, the providers are attached to a health system specialty pharmacy, which is sometimes a bit easier because you put the electronic prescription in and the specialty pharmacy in the hospital initiates everything. They do the prior auth, they deal with the insurance companies, they do everything that they can to obtain the medications for the patient with less work on the staff time in the office. And in some systems, the physician practice buy the medications and bill after they give it to the patients. So again, this requires a whole dedicated staff who are dealing with prior auth, dealing with the insurance companies, and through all of this, you're determining whether these are pharmacy benefits, medical benefits, et cetera. Ultimately, people communicate with the insurance plan. The insurance plan takes their time, decides whether they're gonna approve these medications, and hooray, you get a thumbs up. Now, the healthcare systems are sending back the medications and depending on who you are, most of the patients now are taking their auto-injectors at home. Sometimes medications are going back to the hospital pharmacy, who's then sending it to the patient, or patients are getting them in infusion centers. But hopefully, we ultimately have a happy patient. Very often, though, the medications are getting denied, and whether that's because the documentation's not appropriate, et cetera. Very frequently, patients are denied, and then that starts this whole process all over again. So there are a lot of arrows here. There are a lot of different ways to do this, and all of this leads to a lot of confusion. Lots of different parts of this pathway and lots of different areas for error and delay. And a lot of this is because the stakeholders have different motivations, right? At the end of the day, the patient wants medications that are gonna help them feel better and make them less likely to exacerbate, get off steroids, and the physician wants to get these medications. They need to invest a lot of resources with prior auth, with communication with the insurance company, and specialty pharmacy, managing appeals, reauths, and beyond all the administrative time, they are also sometimes having to communicate with the delivery of the medications and timing with the patients, as well as managing the medications in their office practice as well as educating the patients and then monitoring them after the medications. From an insurance plan, payer plan, pharmacy benefits perspective, the goal is to limit access to expensive drugs that are unnecessary. And this is accomplished through different formulas depending on the plans, the possibility of requiring step therapy, prior auths, medications in higher cost sharing tiers. And then the pharmaceutical companies want patients to have access to the medications. They want their medications available. So their goal is to avoid these processing delays and they will help with assisting with prior authorizations, benefits investigations, financial assistance, and copay. So again, there are lots and lots of parts and the practices are different for different groups. So how can we improve the approvals process? One thing we definitely know that our big time delays in time from prescription to the first dose. This was a study a few years ago through the Penn State practice where they looked at 80 patients and the time from writing a prescription to obtaining the first dose for the patient was 44 days. And that was an insurance approval took an average of 21 and a half days and the special pharmacy to fill was another 22.8 days. And importantly, as the patients were waiting for their medications, there were consequences to this, right? 47% of patients exacerbated and required oral steroids during this time. People have investigated the reasons for these denials and delays and this was recently published this year. This group looked at biologics that were prescribed between 2018 and 2020 in two different systems, the Montefiore Medical System in the Bronx with 352 patients and Scripps Clinics in San Diego. And these are two very different practices. The Monte practice has a majority of African American and Latinx patients. The majority of their patients are on Medicaid. The Scripps had a majority of white patients and a majority of patients on commercial insurance. But similarly, the approval rates were actually quite similar, ultimately a 92.2 and 93.5 approval rate. Just to note, that was after being denied 38% of the time the first time and then having to go back and resubmit everything. So when they looked at the reasons that the biologics were denied, either no additional clinical information was provided, it wasn't part of the benefits, there was no indication in the notes that this was medically necessary, et cetera. And then when they looked at the median time from writing the prescription to administration, again, this was fairly similar with 34 days medium in both groups. But when they looked at the time to approval in the Monte system, it took a median of six days for approval versus the Scripps system of 22 days. So for Monte, it was faster to approve despite the fact that the majority of patients were in government-sponsored insurances. And for Scripps, it took a lot longer to approve, but it was able to get to the patient faster. And so when the authors sort of looked at the systems, some of the reasons they found associated with these delays were delay in approval, often on the private insurance and had to do with figuring out copayments and the finances, needing appeals because of inadequate information. And then the delay in administration, again, had to do with coordinating with specialty pharmacies, having these pharmacies get the medications to the patients, et cetera. And quite often, the patients were unavailable to return phone calls, and there were a lot of delays. And it's also very known that when there's a denial, often these prescriptions get abandoned. So the high 38% denial rate at the first time probably impacts the availability to get these later as well. So improving approvals and decreasing delay. I think most people would argue that you need dedicated staff who are very familiar with the prior auth process, who have a sense of what the different payer plans are and really are familiar with the guidelines that the insurance uses. And I think it's crucial to have even checklists if you need them with the clear progress notes, documenting this as moderate or severe asthma, documenting oral steroid use, et cetera, and all the information that you need to prove medical necessity. If denied, don't forget to try again. Don't abandon the prescriptions. And also helpful to establish relationships with specialty pharmacies. And again, I think this is why a lot of practices find it very useful to engage with their hospital specific specialty pharmacy because they will handle a lot of these issues and all the administration that goes behind it. There are so many different insurance plans. So how can we help to get our patient access? Well, even in commercial insurance, the copayment can be quite high. All of these programs have copayment cards that can lower the cost for patients. I think that this is contrary to what people think, but Medicaid, most drugs are actually covered with very little to no cost for the patients. They're not eligible for copayment cards. And then Medicare is the most difficult to generalize because of straight Medicare, Medicare B, Medicare D, what's the supplemental plan, et cetera. And for these patients, sometimes it's unknown what the out-of-pocket costs are gonna be depending on whether this is a medical benefit or a pharmacy benefit. But often, after deductibles and catastrophic coverage, patients are being asked to pay anywhere from $3,000 to $4,000 per year, which is prohibitive for many people. And there are multiple different patient assistance programs and foundation programs as well. So how does the different insurance affect access? So this group looked at commercial claims data of people who are prescribed biologics between 2003 and 2018. And what they found during this time is that biologic utilization was overall very low for the number of documented severe asthmatics and that the people most likely to receive biologics were those commercially insured, higher income, and access to specialists. And I think that's important to note. A lot of these insurance companies require that these biologics come from specialists and a lot of patients who are on government insurance or who are disadvantaged don't have access to specialists. Another study recently looked at disparities in the use of biologics for publicly insured severe asthmatics and again, looked at use of biologics between 2003 and 2019 with a big database. And they found that privately insured patients were three times as likely to have biologic treatment-related visits and that there were 16 per 1,000 asthma-related treatment visits for biologics and publicly insured versus 28 per 1,000 in privately insured. And that among the publicly insured, white patients were 60% of the visits but accounted for 80% of the biologic treatments. And again, the majority of prescriptions were from specialists. So I think it is very important to be cognizant of how disparities are affecting access to our patients and be mindful of the fact that publicly insured patients have access to these medications and this should not prohibit people from prescribing these drugs. So again, biologics expensive. The process is complicated. It's impossible to generalize because all the health systems and practices are different. But to really be aware that the delay in care, whether it's the prior off end to get approval or even the specialty pharmacy to patient end are areas that practices can focus on to try to decrease the delay. And that, again, there are evidence of disparities in access to these biologics. Thank you.

biologic medications

airway disorders

prior authorization process

specialty pharmacies

medication cost

disparities in access

dedicated staff

out-of-pocket costs

streamline process