Good evening everybody. Thank you for joining us this evening. I'm excited to have this session, a moderated session, on biologics in airway disorders. I'm joined by Dr. Hanania, Dr. Lagogo, Dr. Maselli, and Dr. Chouette. And we're going to be discussing a few topics in biologics and asthma. I'm just going to go a little bit over the format of the session. So my name is Mohammad Idrish. I'm in Baylor College of Medicine. I don't have any disclosure pertinent to this part of the talk that we have today. So these are our four topics that we'll be discussing. I'm not going to go into details because our speaker is going to discuss them. We're going to give an opportunity to learn about the biologics and their use in asthma. We'll also discuss their use outside asthma, what evidence we have in COPD and asthma-COPD overlap. We'll be dividing this session into four topics. We'll try to spend less time on the presentation part, and we want to spend a lot more time in the discussion part that we have with you all. So there are several ways for you to share your questions with us. We have a Twitter hashtag that we are following for this session, which is AskTheExperts2022. So if you want to ask the questions on Twitter, you can put that question over there. And you know, time permitting we will try to ask that question to our experts during the session. You can come to the mic right here. You don't have to submit your question. I think we all have Twitters now. And we will have this question by open-ended short response format in the audience response system. So once we are done with all the presentation, we'll open a question for all of you. And you can just log into the poll, and you can type your free text, and we will be able to read all those questions from using the ARS system. So there are a few ways for you to ask questions, whatever way you feel comfortable to ask questions. And without any further delay, I would like to introduce my first speaker, Dr. Diego Maselli, who will be presenting use of INTL4 receptor subunit as well as NTiG. Thank you, Mohamed, for putting this together. I appreciate it. Thank you so much for joining today. And we're going to try to do a quick presentation so we can actually dive into the questions, which is the objective of the session. And I thought I would pose some questions already so that we can start kind of thinking about other questions with regards to melisma and dupilumab, which is the topic I was assigned. This is me. I'm an associate professor of medicine, and I work at the University of Texas in San Antonio. And this is my disclosure. I work as a speaker and a consultant for the companies that make biologicals, pretty much, and I received some funding for research before. So these are our learning objectives. We mentioned already what we're going to be discussing. We're going to actually focus a little bit on the frequently asked questions as well. So this is the type 2 inflammation. You guys will be extremely familiar with this. I don't think I have to explain this. Today we're going to be talking about really omelizumab and dupilumab as they inhibit both IgE and IL-4 and IL-13. And let's dive into when do we use omelizumab in our current practice. And I thought we would review quickly the eligibility. As you know, these patients have to have positive allergy testing and IgE levels between 30 to 700 in adults. But in children, as you know, it's been opened up to a higher level, so around 1300. And you have to adapt that to the weight and the IgE level. And this has been approved now for ages 6 and older. And this is an example of the table that you have to use. Now, a common question that has been posed is can we use it beyond this dose range? And this is a non-FDA, obviously, indication in this case. And in fact, we've done some studies on this and show that, in fact, in adults it's been efficient or effective in ranges beyond 700. And most recently it has been also shown in pediatrics in a study done by Atkinson recently published that patients do respond well even beyond 1300. So at times we may be considering these medications when they're beyond range. Again, this is a non-FDA approved specific use. But I want to make sure I mention that because it's a frequently asked question. As you know, it's been useful in other conditions. So it's been approved now for different things. As you know, it's been approved for nasopolyps. It was initially approved also for chronic corticaria. And it's interesting, there's some evidence of ABPA, again, a non-FDA approved medication. But as you know, patients with ABPA have high IgE levels. So often it's useful to find out. Is it safe in pregnancy? A very common question about this. Jennifer Namasee has, over the past several years, has expanded her registry, expect registry, and now includes 250 women that have received at least one dose of amilizumab. And this is the largest registry of pregnancy in biologicals. So I think it's a useful characteristics when we're selecting medications that this is actually a characteristic that we can discuss with patients that may want to be expecting soon. This is the predictors of good response. We have here Dr. Hanania that described these predictors actually. And based on his study, the extra study, the guidelines actually decided to put this as some of the criteria. Now in real life, how does that really translate? Actually the PROSPERA study showed that you can have different patterns of biomarkers and you can still have good response 12 months after therapy. So these criteria are useful, but in general the patients still respond to other characteristics depending on age and depending on different biomarkers. Other things to consider, as you know, it requires initial in-office administration, but we can actually switch. As you know, with the pandemic, we had to do some switches and that has been achieved. So the question is, when is it safe to do at home in administration? And when do we switch? So there's some data that looked at the episodes. As you know, anaphylaxis has occurred. It happens really infrequently and that's why we use EpiPens. But the majority, the vast majority of anaphylaxis episodes occur in the first two or three doses. So if the patient has responded relatively well without any problems after the fourth or fifth dose, I think it's a good option to switch them if the patients want to or for other reasons. But there's some safety at least to support this and that's what, at least in my practice, that's what I'm doing. If the patient's interested in switching, it's really after three months of therapy with no events. They still will have the EpiPen at home, obviously, and they can administer the shots at home in these pre-filled syringes. What about dupilumab? So when do we do dupilumab? These are the eligibility criteria. As you know, this is for the eosinophilic phenotype or the patients that require oral steroids on a day-to-day basis, six years or older, and ability to administer at home. The question always comes up, when do we use 200 or 300? For the patients that have moderate to severe asthma with the eosinophilic phenotype, we can use either or. I tend to gravitate to the 300 milligram dose. I have used the 200 milligram dose when there's been side effects and actually the 200 milligram dose has a little bit of a better safety profile with regards to injection side reactions. So that's one of the reasons. Obviously, if you have a patient between 12 or 18, you can use a lower dose as well. In the pediatric doses, it's completely different, but I won't spend too much time on that. As you know, it's also been approved for a number of other conditions, including atopic dermatitis, nasal polyps, esophagitis, and most recently, prurigo nodularis, which is another skin condition. There's some evidence again of AVPA, and there's ongoing studies on COPD, as you know. So this has not been approved yet. So we have some of the indications there. So that might be useful when we're selecting therapies. Any other side effects to look for in patients with atopic dermatitis, uveitis has occurred, so it's something to keep in the back of your mind. Predictors of good response, this is from Mario Castro's study, the QUEST study. That showed that patients that have high eosinophils and even higher eosinophils tended to do better with regards to other groups, the same with pheno. So that's something that we can use as a predictor of good response, and that's what the guidelines also suggest. What about long-term efficacy and safety? As you know, this is always a topic of discussion with the new extension studies that all the biologicals have available now. We now know from the TRAVERSE study that patients that have been exposed for more than two years actually had sustained improvements in exacerbations with no new safety signals. So it appears to be at least for three years that it's safe and remains efficacious through time. There's also evidence that lung function remains high through time as well. And other things to consider, as I mentioned, the lung function, it requires an in-home administration, so that's something that you have to make sure the patients are able to tolerate, and we talked about the safety information based on the QUEST study. So that's it, very simple and very short, as you requested, Mohamed. Perfect timing. We're going to try to save a lot of time for you guys to think about all the questions that you have so that we can have an engaging conversation. So I'm going to now introduce Dr. Hanania, who will be discussing an update in anti-IL file therapy. Thank you, Mohamed, for putting this together, and I look forward to the discussion. Okay, I'm not going to present for Dr. Maselli again. I don't think you want to hear me talking about what he said. Okay, so I'm going to also be brief, and obviously anti-IL files have been here for a while, so I'm not going to bore you with the classic studies, but I will do my best to summarize what's new out there, long-term safety, long-term effectiveness, and then what's coming. These are my disclosures. I, too, serve as consultant and advisor to multiple companies, and my institution receives research grant support to support my clinical trials in asthma COPD. I'm going to be clear. I'm going to provide a quick update on biologic targeting IL-5 and focus on some of the new data emerging and maybe focus on predictor of response and try to summarize at the end the choice for anti-IL-5s. We all know how why interleukin-5 is a very important cytokine in pampering, recruiting, maturing, and making ASF very happy, and obviously targeting IL-5 can be either through the receptor, like benrelizumab, or targeting the actual circulating IL-5, like mepolizumab and reslizumab. Hypothetically, benrelizumab can also increase cell death, so the eosinophilic effect of benrelizumab is much higher. However, the translation of this to the clinical differences between the two is unknown. So we also need to keep in mind that IL-5 is important in eosinophilic inflammation in multiple system and not just the lung, and so this is an airway disease discussion, although I'm not going to dwell in details, but these are some of the systems where eosinophilic inflammation plays a role, and some of the agents targeting anti-IL-5 indeed have been approved for some of these diseases, including eGPA, hyper eosinophilic syndrome, and of course the eosinophilic asthma. The others are being looked at, like eosinophilic COPD. So when you look at what we have right now, the three anti-IL-5s available, and you see the approval in regarding the cutoff is age and route of administration and frequency. All three are approved for eosinophilic asthma, so you have to have a patient with severe disease and eosinophilia to qualify for administration of any one of these. Mepolizumab is approved for children six years in age and above, given every four weeks. Reslizumab is an IV infusion, weight-based, and it's given every four weeks. And then Benrelizumab is given every four weeks for three months, and then every eight weeks subsequently. And Benra and Mepol have been also studied in COPD, but not yet approved for that indication. Mepol is approved for eGPA, nasopolyposis, as well as hyper eosinophilic syndrome. So when you look at the pivotal studies, and again, this table is not really meant to put these in perspective and compare one with the other, but the effect of these drugs are highly targeting eosinophilic inflammation. It's shown in patients on already high-dose inhaled steroid and another controller, and the reduction of exacerbation is around 50% on average between these two studies, between all these three drugs. So reduction of exacerbation is one of the very important outcomes with these drugs. And very similar, although this paper comes from the Benra-Mepo study, but very similar data from Benrelizumab, that the higher the blood eosinophil at baseline, the better effect in reducing exacerbation. The more severe the patient's asthma is, the higher the number of exacerbation, the better effect with these agents. So these two aspects are very important. High blood eosinophils, severity of the disease, predict response. And in all these clinical trials, people have looked at other outcomes. The FEV1 changes vary from study to study. Improvement in PROs also varies from one study to the other. But in general, there is a trend of improvement in PROs. Oral steroid sparing has been shown in very nice studies with Benrelizumab and Mepolizumab, and you can see the percent reduction in oral steroid need. And of course, they all reduce exacerbation. This study, this slide just summarizes the Sirius and Zonda study, both of which looked at oral steroid sparing in eosinophilic asthma in a patient dependent on oral steroid in Mepolizumab and Benrelizumab. Now more important is, how do they play long term? And I think there's been, since these have been approved now, we have long-term studies. The Columbus study is the longer study from Mepolizumab, where they extended the follow-up of these patients in open-labeled fashion, showing that reduction in exacerbation is actually maintained over time, up to 156 weeks. And this is the same Columbus study, where they looked at actually improvement in lung function, sustained ability to improve ACQ, which is the asthma symptom questionnaire, as well as decrease in blood eosinophils. And of course, safety was a big important issue. And in the Columbus study, they looked at adverse effects, and these are where the common adverse effects that were found in this long-term follow-up of these patients. Overall, no new safety concerns that were identified with these long-term studies. Now, MEPO also has been studied now in real-world studies. Real-world studies give us lots of reassurance, because they include patients with comorbidities. And in real world, it is more generalizable to our patient population. And these two real-world studies suggest that there is a sustained reduction in exacerbation with Mepolizumab in this population. What about Benrealizumab? There's also been now an open-label extension, up to four years. These are data from the Meltemi study, where they looked at patients who were enrolled in the main studies, and then the BORA, and then follow-up. Again, suggesting that the reduction in exacerbation continues in patients. Initially they were randomized to placebo, but those patients got open-labeled Benrealizumab. And you see that extension studies, the numbers go down, obviously. Some patients drop out. But the effect on effectiveness on reduction in exacerbation persists. Same thing with Benrealizumab. Real-world studies were done. In fact, there was a poster early on here in the conference looking in more depth at the Zephyr 2 study, which is a large study looking at Benrealizumab in the real world, suggesting, again, reduction in exacerbation, and of course, a sustained safety profile. One of the interesting studies that I thought I should mention is the Ponenti study. This was a very nicely done study to look at oral steroid sparing in eosinophilic asthma. The unique thing about this study is that they did go through a very important algorithm of oral steroid reduction algorithm to avoid adrenal insufficiency in these patients. The bottom line, these oral steroid dependent eosinophilic asthma, 62% of patients were able to eliminate oral steroid use or reduce oral steroid, and also in addition to having lower exacerbation. So the question with anti-IL-5s then is, when do we use them with this plethora of biologics that we have? Obviously, this algorithm seems to be very complicated, but I highlighted in purple where anti-IL-5s may play a major role. Certainly, patients have to have blood eosinophilia more than 150 at least, and that's where the options end exacerbation. Or if they're oral steroid dependent, if they have eosinophilia, then anti-IL-5s may be a good option as well. And obviously, in patients with very high blood eosinophils, after ruling out other causes, anti-IL-5 may be the only option, especially if blood eosinophils are above 1,500 cells. If the blood eosinophil is between 150 to 1,500, there are other options depending on the topic manifestation of the patient, but certainly anti-IL-5s may play a role in this group as well. We'll talk more, I think, in the discussion as to how do you choose, but these are the patients who I think the profile fits in for an anti-IL-5 therapy. So the question is, how long do I treat? In general, this is a question that comes in with every biologic. Right now, the suggestion is to treat for four to six months, and if they have some efficacy endpoints, which may be symptom improvement, reduction oral steroid or improvement in lung function, exacerbation takes time to follow. These are patients, if it's borderline improvement, continue for another up to 12 months. I think there is quite a bit of data to show that some of the predictors of response to anti-IL-5, including higher blood eosinophils, higher number of exacerbation, adult-onset asthma, non-allergic eosinophilic asthma with nasal polyposes, this phenotype tends to be more responsive to an anti-IL-5 agent. Obviously, what if it doesn't? They don't respond, and this is true for all these biologic. These come from recent guidelines. I participated in with the EACI, the European Allergy and Immunology Group, where we said that we look at three things. One is medication-related factors, disease-related factors, and patient-related factors, and I think we'll have opportunity to discuss this in the panel. I won't spend too much time on this, but it's important to not to rush in changing or switching before you go in and check these issues and determine what is the cause the patient is not responding, but also you have to be very patient and not just switch after one injection or two injections. So in summary, what I tried to convey is that anti-IL-5s are here to stay. There are options now. These agents are very effective in eosinophilic diseases of the airways, now with asthma but maybe in the future with other diseases. Certainly, blood eosinophil level, asthma severity, nasal polyposes, and adult-onset disease predict response. There are now several reassuring long-term effectiveness real-world studies and also continuation of the large clinical trials that have confirmed the safety and effectiveness of these agents. There are also several ongoing studies to determine their efficacy in other eosinophilic diseases, including COPD patients who have eosinophilia. And the exciting part is that there are now early studies looking at long-acting anti-IL-5 agents. One of them is Depimociminab, and it's actually, we're one of the sites testing this. There are two large trials ongoing to look at it, and this is a drug that's given every six months for eosinophilic asthma. So we're not there yet to give a vaccine-like type of thing, but at least we are looking at long-acting agents that target eosinophils, and hopefully we'll see some results in the next few years. Thank you very much. Thank you, Dr. Hanania. That was very informative. It is my pleasure to now introduce Dr. Nejiro Lagogo, who will be presenting data on neurobiologic agents. Thank you so much. I'm from the University of Michigan in Ann Arbor. These are my disclosures. I do participate in clinical trials as well as consultation. So today we really wanted to talk about use of biologics in asthma-COPD-asthma-COPD overlap. I'm hoping Diego and Nick will comment on the latter two conditions, particularly the overlap patient, although there was some discussion about whether it is an entity or not. Nick is very firm that it is an entity. So I got the lucky job of looking at TSLP and anti-IL-33. So it makes sense to group these two because they are both alarmins, and the purpose of this slide here is to give two or three specific messages. So the first message is that inflammation occurs across a spectrum. So although we like to think about people as allergic or eosinophilic, you can see here that the vast majority of patients kind of mix there in the middle, and there is considerable overlap between these two pathways. We do have some neutrophilic patients, and we have patients who have primarily structural disease that is mast cell driven in some cases, and that is modulated by TSLP. So TSLP is produced by the airway epithelium in specific or nonspecific allergen or non-allergen mediated triggers. And what you can see is when the airway produces TSLP, there are multiple downstream pathways that are impacted, and this presents in the phenotypes that we see clinically. So the other thing about inflammation is that it actually, although it's portrayed as a static issue on the previous slide, inflammation is rather dynamic, and the type of inflammation you have may vary depending on the exposure. And so we need to really keep that in mind, that patients may have different types of inflammatory pathways that are upregulated depending on the trigger. Now, tezapelumab has a unique mechanism of action, and you can see that tezapelumab, which binds TSLP, would likely have a role in allergic inflammation, which is modulated by dendritic cell antigen presentation and type two differentiation. It would have a role in eosinophilic inflammation, primarily because of IL-C2 cells driving IL-5 production and eosinophil maturation. And then lastly, neutrophilic inflammation, where the dendritic cell actually plays a role, but the cells differentiate to TH17 cells, which cause neutrophil-modulated inflammation. Now, these types of inflammatory pathways can lead to a lot of symptoms, and therefore, we would expect tezapelumab to reduce asthma exacerbations, improve symptoms, and lung function in the three phenotypes here. Now, I put this figure in here just to highlight the role of mast cells. I think as a pulmonologist, I don't think of mast cells very often, and I think of them as being primarily an allergy cell, but it turns out that mast cells play a key role in increased airway smooth muscle mass and deposition of extracellular matrix. And it turns out that mast cells actually have TSLP receptors on the surface, so there may be some impact on mast cell-mediated inflammation outside of the allergy pathway, and perhaps some possible effects on remodeling. So what did the phase two study show us? The phase two studies with anti-TSLP therapy are demonstrated here from 2017, and you can see a significant reduction in exacerbations regardless of the eosinophil count, regardless of the phenol level, and regardless of type two high or low status. Now, the medium dose of tezapelimab is what was approved by the FDA at the end of 2021, and is currently in use clinically. A couple of unique things to know about anti-TSLP therapy is that tezapelimab is actually the only biologic that reduces nitric oxide, eosinophils, and IgE. By approximately 50%, the other biologics affect some of the biomarkers, but not all of them equally. Now, tezapelimab is effective in reducing exacerbations. This is the New England Journal publication in 2021, and it certainly is more effective in type two high disease, and you see that in asthma in general. All my colleagues here have shown you data about the fact that the patient that's more eosinophilic has a better response. Dupilumab data that Diego presented looks the same, very high, better response in higher nitric oxide groups. But what's unique here is that our T2 low patients are also having an improvement in exacerbations, and therefore, we feel that tezapelimab may have a role in non-T2 asthma for patients who didn't really have options in the past. Tezapelimab improves lung function, and this is some data here. I didn't show the ACQ and AQLQ data, but there are improvements in patient-reported outcomes as well. Now, this is the Cascade study, and the purpose for showing this study, as I had mentioned earlier, mast cells have TSLP receptors, and there was some interest in seeing if mast cells would be reduced in submucosa, and actually, we didn't see an impact there, but what you do see is a very nice reduction in submucosal eosinophils. And more importantly, and clinically relevant, is that you see tezapelimab reduces ALA hyper-responsiveness in response to mannitol. When you compare these two alarmins, IL-33's also an alarmin, and TSLP modulates multiple effects. Here, we are showing you the TH2 effects. IL-13 is predominantly produced by the epithelium in response to cellular damage and also exposure to infections, and IL-13 causes activation of basophils, mast cells, and innate lymphoid cells, causing airway inflammation. So IL-33 is produced by the epithelium, much like TSLP. It binds to two types of receptors. These are soluble ST2 receptor, which is a decoy receptor, and then the membrane-bound ST2 receptor that causes downstream inflammatory gene transcription and immune response in inflammatory cytokine and chemokine production. So what do the anti-IL-33 drugs tell us? This is estagolamab, and this study here shows a reduction in eosinophils and phenyl. And it reduces the time to first exacerbation and also increases the FEV1, although modestly. But there does seem to be a drug effect in terms of the standard outcomes that we expect to see being improved in asthma. Now, when you look at exacerbations and you divide the patients on the basis of eosinophils, we have the overall population, eos less than 300, eos greater than 300, divided on the basis of less than 150, greater than 150. They certainly signal that the more eosinophilic you are, the better the reduction in exacerbations, but people with low eosinophils also got a reduction in exacerbations. This is itopecumab, and here we are looking at this phase 2B study that was published in 2021. A couple of interesting things about this particular study. So one is that when you looked at dupilumab by itself, you got the most significant reduction in incidence of loss of asthma control as background therapy was withdrawn. Itopecumab had an impact, although not as significant as dupilumab, but I think what was most interesting for people like me who sometimes think, well, maybe two biologics are necessary in a patient, is actually the combination of itopecumab and dupilumab did worse than either drug alone. Now, I don't know how to explain that, and many of us get a lot of questions about dual biologics. I think the jury is still out. There are certainly no clinical trials apart from this one where dual biologics were given, but I can tell you that itopecumab development is focused now on COPD and not progressing in terms of asthma. So estigolumab is another anti-IL-33 drug, and this study was done in COPD. And so overall, there was really no significant impact on exacerbations in patients with COPD. And unfortunately, we see this repeated over and over again. I'm curious to see what my colleagues think, but it's been very disappointing to experience this over and over again with multiple different molecules in COPD. Now, we are hoping that will change. There were two exceptions to this. So one, if you really did some subgroup analyses to try to identify potential markers of response, it turns out not only did they have subgroups of response, but they had different responses within the subgroups. So the ex-smokers had an exacerbation reduction, and those with elevated eosinophils had an FEV1 improvement. So it was kind of interesting, this dichotomy of response in the different subgroups. And maybe that's the issue. Maybe COPD patients, much like when we started with mepolizumab many years ago, maybe what we are calling COPD is a very heterogeneous condition, and therefore our studies are not working because we're not really studying the same patient population. So in conclusion, tezepilimab has a unique mechanism of action that reduces exacerbations in both type II, non-type II asthma. IL-33 targeted therapies did result in reductions in exacerbations in asthma, approximately 30% reduction, although I believe that most of the IL-33 development programs for asthma are not moving forward, and the focus has shifted to COPD. It really didn't result in any additive benefits when combined with dupilimab. I'm happy to talk about dual biologics if that's a question that comes up. And then IL-33 targeted therapies have differential effects. So I think this goes back to the treatment paradigm that requires us to really look at patients as individuals versus grouping them in particular groupings. And the jury is still out on the impact of IL-33 targeted therapies in obstructive lung disease. And although I didn't show the data here, we did share a poster at ATS this year from the Chronicle study, which is a large registry. And in fact, asthma-COPD overlap patients have a very good response to biologics, about a 50% reduction in exacerbations in that group. And so, you know, I really do think those people are unique. I'm curious to see what Dr. Hanania has to say. So thank you so much. I look forward to all the wonderful questions. Thank you very much, Dr. McGurgu. I'm going to introduce my next speaker, Dr. Tourez. She's going to be discussing a very important topic, which we all face in our daily lives when we prescribe biologics, is how to navigate insurance and some of the other issues that come with it. Hi, everyone. Thank you for joining this session. My colleagues got to talk about optimistic things that make people happy, and I get the honor of speaking about something that doesn't put a smile on anyone's face. All right. I'm Merida Tourez. I'm at Weill Cornell in New York City, and I have no disclosures. Okay. So, again, you guys just heard about all the different biologics, all of the fantastic data, the mechanisms of action, the fact that these drugs really do reduce exacerbations, improve symptoms, get people off oral steroids, and it would be fantastic if getting our patients these drugs was easy to navigate, but it is not. It's quite complicated, and it's a big mess. There's so many different players and stakeholders in this system. All the systems are different. There's so many insurance plans. Insurance plans are different in all different locations. It requires, really, a lot of provider resources, navigating through PAs, through denials, et cetera, and then, ultimately, for the patient, what they get really depends on their insurance plan, their deductible, the formularies, et cetera. So there's no one-size-fits-all for any of this. You guys know that these drugs are extremely expensive. I heard a speaker say yesterday that this is equivalent to buying a car every year. So how do we begin to navigate this? We're all familiar with a patient like this, a 46-year-old who has poorly controlled asthma adherent to their prescribed medications, including an ICS and LABA, and despite this and treatment of modifiable risk factors, she's had several exacerbations over the last year, and again, it started on oral steroids. She has evidence of elevated T2 biomarkers, and you decide to start her on a biologic. So the drugs are expensive, and therefore, the system is very complex, and again, I think there are a lot of people, a lot of different players in this system, so there are the providers, the physicians, who really are motivated to get the patients feeling better. This takes a lot of resources on the provider side of things. Most people have a dedicated person in their office, whether that's a nurse practitioner, a nurse, a clinical pharmacist, et cetera, who's dealing with prior authorizations, communication with insurance company and the specialty pharmacies, managing appeals, dealing with reauthorizations, and all of this takes time and essentially is costing the practice and the hospital money. Then you have the healthcare insurance companies who have a different set of motivations, and they're more motivated to limit access to these very expensive drugs, and they do these through a variety of mechanisms like creating formularies, requiring step therapy, so you're forced to potentially fail one drug before you can go on to a different class of medications. Again, the need for prior authorizations and very detailed histories and recommendations and medical records, and they pass some of this on, obviously, to the patients in higher cost-sharing tiers. And finally, you have the pharmaceutical companies who are very motivated to sell these drugs to people, and their motivation is to actually avoid these processing delays, so they are working closely with providers to help with prior authorization, to help with benefit investigations, and to provide co-pay assistance and financial assistance to patients. There's so many different insurance plans. Again, you can't generalize any of this. Again, for commercial patients, it's fairly easy to get access to these drugs. Again, depending on your plan, the formulary, the step therapy, you might end up with something different. Depending on your deductibles, the co-pay may be different, but all of these drug companies offer co-pay cards that really can get the price of the medications down from anywhere to zero to $100 per dose. Usually they cap it at $10,000 to $15,000 a year, but it gets the pay down. They also offer denied savings programs, so if your patient is denied through the insurance company and then they fail the appeal, the companies will give you drugs for free for a year. They have fast start and bridge programs to get your patients on medications before the PAs go through. If you have patients on Medicaid, again, different in every state, most therapies are covered at little to no cost for the patients. As this is a government program, they're not eligible for co-payment cards. Medicare is a complex mess, so depending on whether you have B or a D in supplementary plans, it really can be a different price for everyone. Those patients are not eligible for co-payment cards, but they may be eligible for patient assistance programs, and ultimately the uninsured can occasionally be okay for a patient assistance program or have access to medications through foundation grants. And again, drug costs can be prohibited even with insurance, so if you have a patient who has Medicare D and they're going on their pharmacy benefits, you can see that they first have to pay out their deductible, then get through the coverage gap and the catastrophic coverage, and even though the amount that they're paying per month goes down, you can see that annually they're paying anywhere from 3,000 to 4,000 plus out of pocket, which really is prohibited for people to get drugs. The workflow to acquire and dispense these medications varies, and I'm certainly not here to tell you how to set up a practice. Dr. Maselli gave a fantastic talk during the network session this afternoon about the business of biologics. But again, this really varies depending on who's in your practice, what your practice is, whether you're associated with a hospital system, a healthcare system, et cetera. But some people and some hospitals do buy and bill where they buy the drug directly from the manufacturer. They give the medication as a medical benefit to the patients, and then when the patients come to the office or to the infusion center to get the drug, the providers bill back out to the insurance company the administration fee as well as a bill that is more than the price of the drug. So they can buy drugs for a lower cost and then charge the insurance company a higher amount of money that typically is used to go back into the practice and create resources to get through these processes. The insurance companies, though, want patients to be taking medications at home and to be getting their medications through pharmacy benefits, and so many insurance companies will deny buy and bill and direct patients to specialty pharmacies that are often aligned with the insurance companies. So then you're putting in a PA to the specialty pharmacy. You're waiting to get the prior authorization back, and depending on who the patient is, you may be sending drugs directly to the patient's home where they're self-administering, or to the practice and having the patient come in and get the medications in the office. And a lot of hospital systems are moving to healthcare system-related specialty pharmacies where these healthcare system specialty pharmacies are trying to gather up all the patients who are on biologics, get some power to buy drugs at a less cost and be able to control the flow of product and make sure that they're being stored correctly, et cetera, and then can get these medications either to patients' homes or to the associated doctor's practices more quickly than the typical specialty pharmacy. So I mentioned that managing these biologics requires a lot of provider resources. I mentioned, again, the amount of time that it takes to do the PAs, the communicating with the insurance companies, the specialty pharmacies, the RE-AUTs, et cetera. Then the practices have to coordinate the drug delivery to their practices sometime at the same time that they're coordinating the patient's visits. They're managing the inventory and tracking these medications. And they're also spending time monitoring the patients after the drugs are given. So I can't tell you how to fix this system, but I'm letting you know that it is very complex. And this complexity obviously affects access to medications. There is a small study that showed that there are quite a lot of delays in time from prescription to the first dose. So this was a study of an office that took care of asthma patients, had 80 patients, and the average time to get a drug into a patient's body from the time that the prescription was written was 44 days. And that was broken down into 21 and a half days needing for insurance approval and the specialty pharmacy taking 22.8 days to fill the medication. And these delays have consequences because in this small study, 47% of patients had exacerbations and required steroids in the amount of time that patients were waiting for therapy. Who is more likely to receive biologics? I don't think the answer here is gonna surprise anyone. Inselman et al. looked at commercial claims data from 2003 to 2018. So it was commercial insurance as well as Medicare Advantage claims. And that overall, the biologic utilization was low, so much lower than would be expected for the percent of severe asthmatics that are out there. And again, not surprisingly, the people who are more likely to receive biologics were those who were commercially insured, have a higher income, and have access to specialists. And obviously, these things tend to all go together. Akinroy et al. also showed that disparities in the use of biologics for publicly insured asthmatics exist. They looked at data using biologics to treat asthma from 2003 to 2019 from another claims base. And what they saw is that over time, you know, there was initially anti-IL, anti-IgE therapy, and then all the rest of the drugs. And so you could see that the visits for biologics increased over time. But you can also see that the purple diamond is the private and the green triangle is public, that there was quite a gap in the visits. So a lot more visits for biologics for patients who had private insurance. Three times as many visits compared with publicly insured biologic treatment visits, or 28 per 1,000 asthma-related visits for privately insured versus 16 per 1,000 for publicly insured. And among the publicly insured, white patients accounted for 60% of the asthma visits, but a disproportionate amount of the biologic treatment at 80%. And again, requiring prescriptions from specialists. So again, the patients who are probably most likely to need these drugs were the burden of the disease's highest, and those who are publicly insured are having access to these medications much less frequently. So again, I think that we all know that these drugs are expensive. The system to get the medications is complex. Everyone has a different motivation and a different infrastructure. But to be aware that delays in care can lead to clinical worsening, and there still exists evidence of disparities in access to biologics, suggesting what we all know is that there needs to be some sort of reform in the system to make these drugs accessible for all. Thank you.

biologics

airway disorders

asthma

eligibility criteria

effectiveness

safety

eosinophil levels

research