This webinar was recorded on August 25, 2022

Dr. James Tracy will walk us through an overview of biologic medications with a focus on how they connect with Type 2 inflammation.


  • Dr. James Tracy

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

Speaker 2    00:04

Today we’ll be discussing biologic medications and their connection to type 2 inflammation. The webinar series you’re listening to is sponsored by the American College of Allergy, Asthma and Immunology, and we work together to share the latest information on advances in allergy and asthma with you. This is Sally Schoessler, director of education for Allergy & Asthma Network. Today’s webinar helps  Allergy & Asthma Network live out our mission. And the needless death and suffering due to asthma, allergies, and related conditions through outreach, education, advocacy, and research. We are so pleased to welcome today’s speaker, Doctor James Tracy. Doctor Tracy is a senior partner for Allergy, Asthma and Immunology Associates, PC in Omaha, nebraska. If we can move to the next slide, he is a frequent speaker as well as author and reviewer of numerous scientific publications. He’s a graduate of the University of Maryland, where he completed his undergraduate studies with his medical education at the University of New England College of Osteopathic Medicine. The doctoral efforts included a pediatric residency at David Grant, United States Air Force Medical Center and Allergy and Immunology Fellowship at Wilford Hall, USAF Medical Center in San Antonio, Texas. He is clinical professor of Pediatrics at the University of Nebraska School of Medicine and Assistant Professor of Medicine at Creighton University School of Medicine. He currently serves on the American College of Allergy, Asthma and Immunology Board of Regions as treasurer. Thank you so much for being with us today, Doctor Tracy, and for walking us through this important topic.

Speaker 1    01:48

Well, good afternoon everybody. That was a wonderful introduction Sally and I truly appreciate the opportunity to share some of my experiences with this group. I’d also like to thank Tonya Winders, who’s the President and CEO of the network and of course the College of Allergy, Asthma and Immunology for their sponsorship. This has been a really, an interesting talk for me as you’ll notice that I added a little bit to the title and digital. Initially it was biologic basics, the Type 2 connection, but for me this has really been a little bit of a walk, what I call a walk down memory lane. So the more I got into this, I couldn’t help but think that there’s a lot of things that sort of have transpired over my career and really was sort of deja vu all over again. For those of you that might remember that phrase and that general that’s Yogi Berra. This, as you can tell, or will know, I finished my fellowship in 1993 And what we’re going to talk about really is it is an evolution of a concept that started really about in that period of time. What we’re going to do here is I’m going to give you a little bit of background and a little bit of history about the TH two TH one sort of why it’s called that how it but sort of got to where it is little bit about the of the immunology that goes along with it and then I’m going to use that to kind of sift through the various elements that have evolved over time that would distinguish what we often refer to as the phenotype or the endotype. So the phenotype is sort of what we see or measure, the endotype is really looking at mechanisms. So kind of slipping back, a published paper on cell sorting, back when flow cytometry was really relatively novel. Back in 1993 the AIDS epidemic was just going crazy. And at Wilford Hall we were right in the thick of trying to understand the immunobiology of the diseases as it as it presented itself. For those of you that remember back in the early nineties AIDS was pretty much a death sentence. So a lot of what we did was trying to understand that. Now on the immunology side, we decided that we were going to kind of take a look at what we call T cell activation. And so flow cytometry was relatively new, it was quite expensive, but we wanted to see if we could get a little bit better understanding of the mechanisms the T cells kind of engendered it’s a bit of a joke in my family that as we were doing this stuff over the years at the dinner table, we, I would also often talk about these things, T cells and B cells and all that stuff. And one day at dinner we started talking. My son said Dad, we’re not going to have another T cell lecture, are we? And so of course they said of course we’re going to have another T cell lecture. So this is another T cell lecture. So if you look at this one carefully, basically we were looking at activations with the immunotherapy. And it kind of is interesting because if you look at this. So this is in the abstracts for the Academy back in 1993 if you can see mine was a number 5-9-9 for those of you that are in the audience, if you take a look at the other abstract, that’s 5-5-9-7 Grass pollen immunotherapy and a three-year follow-up. This is by a guy, it was by Walker Berry Kane and Steve Durham were actually published this now although it has really nothing to do with our topic at hand. It’s it is noteworthy that this is the one of the primary studies that helped define the basic tenants with allergy immunotherapy of a three to five year window for treatment and I thought it was kind of kind of. School that I got to have equal billing with these great people. And I’m going to circle back a little bit to Barry Kane, Steve Durham because that is relevant to our topic. But let’s just take a quick look over at the at sort of , the kind of an overview now this happens to be about chronic rhino connect with nasal polyposis. Now this is a graphic by Tanya Laidlaw. It was in the animals a year or two ago and I just think it’s incredibly instructional. Now this is about nasal polyps, but it’s quite similar for the other major disease states that we deal with which of course are atopic dermatitis allergic. To the public asthma obviously polyps is eosinophilic gastroenteritis and those types of things but. So really these are the targets for new Biologics for this. Now again, this is nasal polyps, but it holds true for the other Type 2 inflammatory processes. So we’ve got DMP 2. You’ve got aisle 4R in aisle 13. You’ve got IgE. We’ve got aisle 5. We have TSLP and all of these. Endo types which are mechanisms will lead us into sort of what I refer to as therapeutic opportunities downstream. So it’s important to understand in probably 2. Now obviously not the only two, but these are both gentlemen from the UK. Mary Kay has recently passed away, but Steve Durham is still with us. And I’ve sort of gotten, when I started doing my work with cell T cell activation, it was really the work by Durham that kind of got me thinking about this because he was publishing at the time phenotypes looking at CD four cells that had a different sort of what we would then call the phenotype. So it’s a Type 1 phenotype or a Type 2 phenotype and the type one and we’ll get to that in a moment. And then the Type 2 which is basically defined by a cytokine profile that we’re going to talk about in a few minutes. So the very beginning of these things really goes back to mice. And as you can see here, they’re looking at two different types of helper cells with mice. And basically what they were doing is they were defining this, the specific lymphocyte, not so much on how it looked under the microscope, but sort of the secreted proteins and lymphokines that were being generated by it. And these later became you know, type one and of course Type 2. And what those are and we’ll talk a little bit about those specifics in a minute, but this is really the beginning and it would happen obviously in mice first, but it gradually evolved. And so in the second paper, the activation of T cells increased the T TH two type and again work through the cytokine expression using MRNA. And as we better define these two types of the, at that time mostly, lymphocytes, activated lymphocytes, I should say we now know that other cells also secrete these cytokine profiles, but back in those days we’re really thinking mostly in terms of lymphocytes. And we really began to figure out where they really sort of fit and that these really were two different types of cells. And although they may look the same under the microscope, what they were generating and how they were interacting with them with the inflammatory process was quite novel and quite specific. And as you can see, this is really again going right back into the early 90’s was in 1994. So, let’s talk a little bit about the human T cell subset. So this is kind of a busy slide and my pointer doesn’t really work but if you take a look at this; so you see on the left and with the green cell and naive CD four T cell and the dendritic cell is really an antigen presenting cell. And so as it kind of goes through its two top elements you’ll look at the red or pink on the top and you can see it says TH one cell. And as you look at that, you can sort of see how it interacts in back regulates with gamma interferon and ultimately produces gamma interferon IL two IL 10 TNF beta and the diseases that it’s affected are really it goes after intercellular organisms and it’s an it’s a proinflammatory mediators and it’s what we refer to as type 1 inflammation. Coming down to the next level, same again activated. Now you CD4 T cell is evolved through the interaction with aisle 4, aisle 25 to become a TH two cell. Combination of transcriptional events within the cell through the GAP 3 protein ultimately activates STAT 6 GAT 3 and it spits out that cytokine profile you’re seeing in the box immediately to the right of the blue lymphocyte. So it’s aisle 4, aisle 5, aisle 9, aisle 10, aisle 13 and aisle 25 And these are relevant within the context of allergic diseases, parasitic infections and again. The various disease states that we’re going to talk about as this webinar kind of evolves and again the disease states really are asthma, atopic dermatitis, nasal polyposis and again multiple types of asthma. I’m not going to walk you through the rest of these are fairly self-explanatory but not particularly relevant to this talk today. But I will say that their role in other disease states are in disease spaces. It’s really critically important. So here we are once again with this kind of zipping through it. These are the targets. Got a little off here, so I apologize. But we’ll be back to this slide again here now they get that fixed. So these are really the main targets. As you can see from the top, this is where the various instigators of inflammation occurred. Fungi and nonspecific irritants such as pollution or smoke infections from such things as staff, aureus, bacteria, virus and obviously allergen. As you can see the mix between viruses and allergens is often bridged by mass cells. That becomes relevant downstream, so. The biggies we’re going to talk about are going to be the anti aisle for our aisle thirteens. Anti IGE Anti aisle fives. And the anti TSLP’s So what are the major properties of this CD4 subset well the big players from a from an inflammatory role is really number one is under the TH one is gamma interferon and as you can see there’s four aisle 4-5-6 and 13 and as we as you looked to the graphic to the right on the top bar you have the effector cells again TH one two TH seventeen and so. On and if you look along the horizontal emanating across the very top, so we have the defining cytokines, the principal target cell that major immune reactions host defense and of course its role in disease. So starting at the top gamma interferon, its principal targets are macrophages and its major immunologic reaction is macrophage activation. And it’s from a host defense standpoint, it goes after intercellular populations and it’s big with chronic inflammation. And of course, autoimmunity. Th two is the aisle four five and thirteen standpoint. This actually is the target cell is the eosinophil. So it’s acted with eosinophil and mass cell activation, alternative macrophage activation, it’s host defenses really filaments or parasites and it’s role in diseases allergy and for neutrophils which is the next aisle 1722 neutrophil activation and recruitment extracellular the host defenses for extracellular. Bacteria and fungi, and again its role in diseases. Again autoimmunity and inflammation. So tease, let’s talk a little bit about T cell development. We won’t get into a lot of this here because mainly because of time. But as we hear, you can see from the top, again we have the epithelium and how it’s induced through the activation of the naive T cell through the antigen presenting cell, the dendritic cell which cascades it into a sort of a self. Self modulating process through aisle 4 and through the aisle 4 effect from mast cells and then through the combination of other amplifications you can see where the were through stat 6 and GAT 3. It ultimately brings about the full development of the TH two type cell TH. One is very similar. It’s in again it’s induced by aisle 12, it’s transcription factors T beta. It produces gamma interferon and TNF alpha. Again very much pro-inflammatory cytokines and the and as in most of these mechanisms there’s a considerable amplification, in this case it’s from interfering gamma interferon. So aisle four five six thirteen and gamma interferon so that they’re the various factors. The sources are at this point mostly T cells but there are other for each of those elements and the critical function. So aisle 4 is critical for the school IG switching to IgE again decreases pro-inflammatory cytokines, it suppresses delayed type hypersensitivity. It’s targeted cells and targeted agents are anti aisle four with the alpha component as well as aisle 13 and it’s most active agent right now is dupilumab. It’s diseases, this is sort of the disease state that or scope that we talk about. So it initially became prevalent with atopic dermatitis, later asthma and then further down with chronic sinusitis with nasal polyposis. Now there’s a question mark on E and it’s now been approved for that also. Aisle 5 again its sources T cells increases eosinophil production. There really three agents out there reslizumab, mepolizumab, and benralizumab again affected with eosinophilic asthma, eosinophilic granulomatosis with polyangiitis and again chronic sinusitis with nasal polyposis. The two the MEP has been approved. The Ben is currently under as I understand it’s still outweighing approval, aisle 6. Lots of cells produce it. It’s relevant with B and T cell proliferation and acute phase reactions. It’s big diseases, that we use to treat as rheumatoid arthritis and JRA. You can see the drugs that for the targeted agents, not a real big player in the allergy space. But obviously RA and JRA are really important diseases that can profoundly affect quality of life. Aisle 13, again very similar to aisle 4, anti aisle 4 are alpha and 13 and again dupilumab is the player. Here again atopic dermatitis, asthma, EOE and chronic sinusitis with nasal polyposis. The last one which is a little different and obviously it’s a TH one process is gamma interferon. The big difference here again a product of T cells but it affects adhesion molecules. Major histocompatibility components and expression and activates T cells and NK cells and macrophage. There are really no targeted agents against this or specific, but it is approved for the use with chronic granulomas, chronic granulomatous disease and malignant osteopetrosis. So let’s kind of move into the little bit about what we’re here for this, which is to say the biologics umm. So as you look through this, it’s important to kind of understand that some of these things have been around a long time and some have been around not so not so long. And the granddaddy of these, this whole biologic within the constructs of the of the allergy and asthma space is really omalizumab it came on board in July 2003 and that time was approved for asthmatics at greater than 12 years of age, and that is one of the things I started at the beginning is that this is this whole pathological mechanism of endo types and biologics really has been the undercurrent of my entire professional career as an allergist. And I can still remember when Omalizumab came on board. And as you can see, it was 11 years before there was any changes and that was really omalizumab indication for chronic idiopathic urticaria. Now, what we often refer to as chronic spontaneous urticaria in 2015 Mepolizumab was approved in November. Of for asthmatics greater than 12. Res came in a little bit later in June of 2016 That was an interesting one because I was actually on the FDA Advisory Board for this particular drug. I couldn’t make the map for various reasons, but it was really interesting as you looked at some of the primary endpoints and data points that they were using at the FDA and level. It’s, and at the time Teva had taken over this drug and was working really hard. It’s still in use today. It’s, it is Ivy and we’ll talk a little bit about that in a minute. But as you can see it’s really in 2014 that things start picking up and not just in terms of the types of biologics, but also in their various ages and indications. So in July of 2016 Omalizumab got approved with ERA asthmatics greater than six. That was a huge deal in our space. The big player came in one of the big players. Payment in March of 2017 that’s when dupilumab was approved for as for eczema in individuals greater than 18 years of what years of age. That was just a huge evolution therapeutically because up to this point we were kind of managing atopic dermatitis with them with topical, with topical medications, with quite frankly only modest benefit much of the time. So dupilumab was a. It was a huge breakthrough. Ben came for asthma and in March Mepolizumab came in November of 17. Mepolizumab got its new indication for GPA dupilumab got approved in October of 2018 for asthma.That was a big deal. And then in early 2019 they dropped the age for eczema down to 12. And as you can see a lot of the evolution here is really indications as we move from adults to kids. But again MEP is at 6 and in 2019, Dul it gets their indication for chronic sinusitis with nasal polyposis. And then it basically follows through all the way through various other opportunities and most recently met got approved for chronic nasal sinusitis with polyposis and dupilumab got approved for asthma for greater than six and a bit now it’s clear for atopic dermatitis down to six months of age. So everything is changing fast and I just find this to be a really, an interesting profile and time. So it’s been really the other thing as we’ve developed these new agents is sort of. The various manufacturers have gone to great lengths to kind of promote their products and I think it’s been really interesting and how they’ve done that and because these are truly very novel agents and their level of effectiveness is just, it’s just life changing whether you’re have atopic dermatitis, you’ve got allergic asthma, you got chronic sinusitis with nasal polyposis and again most recently with eosinophilic esophagitis. So let’s kind of talk a little bit about the what I call the granddaddy that’s omalizumab as far this is the molecule to the left, it’s pharmacology is that it inhibits the binding of the of the IG E to the high affinity IG receptor on the surface of mass cells and basophils. There’s a substantial reduction in surface bound IGE on the high affinity I GE receptor bearings bringing this cell limits to a degree that in the release ability of mediators. Of the various allergic responses, it’s indicated for moderate to severe asthma, chronic idiopathic hereditary and relatively recently to uncontrolled nasal polyposis. And as you can see here, this is its area that it really goes after, affecting mostly basophils and mast cells and again very effective. It does have lab requirements or at least suggestions and it should be an IGE mediated with the IG or greater than 30 and as part of their package insert you need to demonstrate. An allergic phenotype with a positive blood or skin test to a perennial allergen. In the case of chronic idiopathic vertical area, you need six weeks of uncontrolled hives with high dose antihistamines with nasal polyps. There’s really no lab requirements for prescribing, and most insurance carriers require an inadequate response to nasal intranasal stick corticosteroids. Right now it’s indications and from an age standpoint greater than six for asthma, 12 or more for chronic idiopathic archeria and greater than 18 for nasal polyposis. Which brings us to dupilumab. Again, I really have a fascinating disease and the graphic to your right is just how it is the individuals who go on this medication, it is just absolutely amazing. I’ve had some patients that have told me that they could feel a drop in itching within hours after their first injection. And as we know with atopic dermatitis, it’s not so much the rash that itches, it’s the itch that rashes. It’s really the mechanics of scratching that generates the rash. So if you interrupt the itching cycle through whatever means. You can have a very immediate effect on the outcome from a symptomatic standpoint. So it’s pharmacology as it’s really a monoclonal antibody that targets the aisle 4 receptor alpha subunit and blocks the inner cell signaling of aisle 4, aisle 13. It’s indications moderate to moderate to severe uncontrolled atopic dermatitis, moderate to severe uncontrolled eosinophilic or oral corticosteroid dependent asthma. And then again, more relatively recently is uncontrolled chronic rhinosinusitis with nasal polyposis. And this is where it kind of sits. Remember this cascade kind of falls down at the top. You got TSLP and on the mass cells and then the adaptive TH two response and then the innate 2 TH two response and the aisle four thirteen is at that point. Again, the lab suggestions atopic dermatitis. Really no lab suggestions before prescribing. However, there are almost always clinical, depending on the carrier, about relative percentages of body surface area with asthma. No specific range for each cinephilic, but there is evidence that efficacy exists with the acidophilic. The better efficacy exists for easing uphill accounts greater than 150 again as with omalizumab. There’s really no lab requirements for chronic renal sinusitis with nasal polyposis. Ages down to six months for atopic dermatitis, which is just absolutely amazing. 12 or higher for asthma. 18 or more for chronic sinusitis with nasal polyposis. Kind of slipping down the cascade here to aisle 5 and if you remember it’s sort of parallels at that similar level with the aisle 4. But in the case of the anti aisle fives, we’re really looking at three different drugs which are three different monoclonals which although these have certainly have similar effects of how they’re dosed is different and some of their endpoints are a little bit different. And again, as I mentioned before,, it sort of sits right next to aisle 4 in the innate type 2 inflammation position. So Mepolizumab obviously an injection, it’s humanized monoclonal antibody that binds to aisle 5, inhibiting the bioactivity of the L5 by blocking its binding to the alpha chain of the aisle 5 receptor complex, which is of course expressed on the surface of eosinophils. It’s indications though it certainly is add-on therapy for patients with severe asthma, but again you have to have it any eosinophilic phenotype. It’s been approved for eosinophilic granulomatosis with polyangiitis for GPA, again only for adults and also for Hypereosinophilic syndrome. For those greater than six months without an identifiable non hematologic secondary cause. Gannon Jackson Lab requirements lease suggestions consider herpes zoster vaccination of medically appropriate before you start what you need. Eo’s greater than 150 within the last six weeks or 300 within the last within the past 12 months umm. Age requirements greater than six for asthma, greater than 18 for GPA, greater than 12 for HHS. And Resilumab. Again, very similar. It’s pharmacology. It binds to the aisle 5, inhibiting the bioactivity of aisle 5 by blocking binding to the alpha chain of the aisle 5 receptor complex on the acidophiles. Again, its indication is for severe asthma with the eosinophilic. That’s actually phenotype, not phenotype. It’s lab suggestions are EO’s greater than 400 age greater than 18 and it’s dosed interestingly which is now worthy here is that it’s dose based on weight which is unusual because most of the other ones are single dose opportunities based more on age than actual weight. It isn’t. It is an IVinfusion versus a sub Q or IM process. Benralizumab, again similar, binds the alpha subunit of the aisle 5 receptor on the acidophiles, blocking the action of aisle 5 and inducing apoptosis and essential oils through the interaction with NK cells by antibody dependent cell mediated cytotoxicity. Again, its indication is for severe asthma with the eosinophilic phenotype. So although there are some similarities between, there are some differences. There’s no doubt that Ben basically is a knockout for a for SNF feels. It really does take the eosinophil count from really wherever it was to effectively 0. Lab suggestion, no specific range for acidophil counts, but evidence of epic efficacy. Superior efficacy exists for ease and ability counts greater than 100 and 550 It’s for those individuals 12 and older and again, it’s those 30 milligrams every four weeks and then ultimately can be spaced out to every eight weeks. Tessa Tessa here got a lot of their marketing. The again, it’s a human monoclonal antibody that blacks thymic stromal lymphopoietin TSLP and thus inhibits TSLP signaling to the TSLP receptor complex. It’s indication is really add-on maintenance for severe uncontrolled asthma with really no specific phenotype or biomarker limitations. As it’s noted within the insert that it’s not indicated for the relief of acute bronchospasm or status asthmaticus even though it’s pretty high in the on the chain. And it kind of lives up here again, if you, I always kind of think of this as kind of downstream. So with TSLP or anti TSLP lives at the top of the cascade. I’m not sure that analogy is completely true, but that this is sort of how I mentally visualize it. Again, it’s pharmacology. It’s a it’s a human monoclonal antibody that binds thymic stromal lymphopoietin and thus inhibiting TSLP signaling through TSLP receptor complex and getting its add-on for severe uncontrolled asthma. And again it lives up here. Lab suggestions really none. Ages are 12 and older. The dose for asthma is 210 milligrams administered subcutaneously every four weeks. This does have to be administered in a clinician’s office, but you can see what, how what TSLP really affects. See all CD four cells with T cell differentiation, basophils, dendritic cells, mass cells and natural killer type and again we talked about those pro-inflammatory. Viruses or inflammatory cytokines or proteases or bacterial products. And here we this is really a nice graphic this was published in June of this year. It’s in the Journal of Allergy and Clinical Immunology and practice. I’ll circle back to that in a few minutes, but really this gives you kind of a nice little overview. Now, much of the previous cartoons were really centered around nasal polyps. This is definitely about asthma, but as you can see it gives you kind of a nice picture of sort of the biomarkers. They’re involved, so it’s bloody acidophil. Count that at whatever level they are, so it becomes a little far left. If you have bloody use of greater than 300 and a phenol greater than or equal to and greater than or equal to 25 the anti aisle 4 receptor antagonist dupilumab or one of the anti aisle 5 would be indicated. Anti TSLP would be indicated for that. If you got peripheral equals greater than a thousand and a phenol greater than 25 the anti aisle fives would work if you have acidophil counts. Less than 300 But a phenol greater than 25 the anti aisle 4 receptor antagonist or TSP would be indicated. So this would be, I should have mentioned here, the one of the challenges that we face clinically is that a lot of these individuals that we see with severe asthma have been on generous doses of oral corticosteroids, which in inherently suppresses the peripheral acidophil count making sometimes the diagnosis a little bit challenging for the clinician, but again keep moving to the right. So we’ve got you eosinophils greater than 300 With the phenol glass than 25 so whether it’s even in this case, the anti Al fives are very much indicated as first line therapy CEO’s less than. Less than 300 but a phenol, the Pheno that’s also less than 25 anti TSLP would be the way to go. And as you can when you look at sort of the second line, you would consider the TSLP or the anti aisle 4 receptor antagonist in the same place where the blood elves are exceptionally high really regardless of where the phenos live. So as we’re as we kind of approach the end of our talk and open things up for questions, there’s just a few things I sort of wanted to sort of, kind of touch on. The 1st is really this picture, this is the cover. Of the Journal of Allergy and Immunology, Clinical Immunology and Practice. This is really a marvelous journal volume it’s theme really is chronic rhinosinusitis. But as you’ve seen from my talk there’s an awful lot of overlap between the various allergic disease states as it relates to the biologics and the various utility amongst the biologics and there’s definite overlap but this volume really does a nice job at working through many of the of the clinical pieces indications and then a couple of the controversies that really are often looked at. You know the one of the there’s a couple things that you always have to ask the question is so one of the differences with the manufacturer. Easy sort of AstraZeneca light uses the fact that basically we’re knocking out the US Anopheles to zero. And one of the questions is, you know, that I bought, I’ve often raised myself he said does that have a downstream effect that we don’t know about? I mean I always tell folks, I said we got to put those zeros in there for a reason and if you bring it down to 0, does that going to have an adverse effect? Well, it’s interesting. So that was kind of addressed in this journal article. In one of the journal articles by. But yeah. I’m blocking Crystal Lieberman and Jerry glide and really looked at in a in a in a constructive way it is there relevance here and it and it’s although the disease is the disease states may vary may not be it may might be. Ok I’ll just refer you to that specific article the other really is really, how long do you treat these people is this something that’s for the rest of their life? Is it something that’s going to have to be, you know, looked at. I mean is there an endpoint. We know that a lot of these diseases depending on the age are lifelong. Does that mean they need to be on a biologic? This is definitely an unanswered question that only time will tell the other thing is really cost effectiveness. So again, there’s several works that have been in place both in the European literature and it’s addressed here from an economic standpoint and we really don’t have time to go into it. But there’s an article here on the biological comparison to the biological effects and with the various biologics compared with endocyte endoscopic sinus surgery, but looking at it not from a disease management standpoint. And disease burden standpoint, but mostly looking at it from an economic standpoint where we look at the cost of these therapies which is considerable in proportion to you know what are, what are the various opportunities. And there’s an article by Rick yeah in this, in this, in this journal volume that kind of looks at that in a very productive and important way. So these are really sort of important elements and so you know kind of just a couple of quick thoughts. I am just completely amazed at over the course of my career and how our understanding the biological, the biology of inflammation has LED us to understand sort of the mechanistic elements of the of the various disease states which of course has lend lend itself to understanding therapeutic what I refer to as therapeutic opportunities and there’s no doubt that there are. They’ll be more you know and really I touched on just you know a few of them. There are many other biologics there are currently in development and I think that and there’s they may and they’re not just again TH two types but as we move through our practice careers you know this is definitely the future the immunology and how it affects life at the cellular level is really is a been in critically important and will continue to be critically important. I just find it really it for myself interesting if this really started at the beginning of my career and as I as I come to the towards the end over the next few years you know you have to ask yourself you kind of what’s next. And my personal feeling is that is going to be some of the technology that we’ve seen with the recent COVID epidemic in the MRNA vaccinations the whole the whole biology of gene modification through the CRISPR techniques that have been implemented and which we’ve actually operationalized at many levels is really kind of I think the next step in the future. And I think it’s just intriguing that the longer we’re here the more well the more we learn as it has indeed as indeed it should. So with that Sally, I think it’s time to open it up for questions if you you’d like.

Speaker 2    43:19

Oh, thank you so much, Doctor Tracy. Totally appreciate all your thoughts on this. We do have some questions. Our first one is do biologic medications lose their effectiveness over time? Can you switch biologic medications?

Speaker 1    43:37

That’s kind of a debated topic that the answer to the second question is easy. But first of all, they don’t work with everybody and so there’s definitely room to move things around if your clinical response isn’t what you thought it would be. An excellent example was when Omalizumab came on board, we realized that and I could say in my practice, I mean I had hundreds and hundreds of patients on this stuff, but it clearly worked better for some people. What it did for other people and for individuals where it works good, they kept going on it. But as new biologics evolved, particularly the aisle 4 and aisle 5 products, we switched them and for whatever reason their phenotype was more responsive once you work through the endotype. So in their case going after the eosinophil instead of the anti IG may be the way to go. It’s also nowhere. The similar observation kind of came with nasal polyposis. Those of us that have been doing this for a while, we realized that although we were treating them for with for asthma umm. We’re treating them for asthma. We noticed that in some of these patients their polyps got better and that’s kind of led us ultimately to a deeper understanding of this disease product. So the short answer is my personal feeling. They don’t necessarily lose effectiveness, but they may not be necessarily effective with everybody all of the time and moving them around probably has a place.

Speaker 2    45:13

Thank you. Our next question comes from a patient, she says. I started receiving omalizumab every four weeks back in April when I was diagnosed with eosinophilic asthma. I’ve been a lifelong asthmatic. I’m in my late fifties. Do you know how long it will take to take effect? I still have to use my rescue inhaler about once weekly, especially before going to bed, and I still take my controller medication daily. The main symptom I have had for the last two years is a chronic cough, no COVID-19 Infection ever. Thank you for answering my question.

Speaker 1    45:47

Well, before I move somebody to a different biologic, I usually wait at least four to six months. I didn’t pick up exactly how long it had been since she started. Can you repeat that part, Sally?

Speaker 2    46:00

She said she was diagnosed in April. She was given the Med in April.

Speaker 1    46:07

So if she started in May. You know, I’d give it. This is what I usually do now. There are differences of opinion here, but I usually wait six months before I make a switch and then what I would do is then I would probably see if she fits into one of the other phenotypes.

Speaker 2    46:25

Ok. Our next question is what do you recommend that we tell patients when they ask how long they will be on the biologic?

Speaker 1    46:34

If I could answer that one. I could win the Nobel Prize? The short answer is I don’t know. We don’t know. And for a lot of these agents, that would just. Again looking at the TSLP model we don’t know exactly if you if you disrupt the TSLP at the highest level of the inflammatory cascade is that going to have a longevity effect? We don’t know. Mostly what I tell folks right now is it’s we really it, it’s indeterminate but it is possible it could be for the rest of your life. But at this point we just don’t know. What we do know is that we have patients. On Omalizumab since 2000 and three. I’m sorry. Is it three? I guess 13 and they and they’re still on them. But we also know that some people for whatever reason have come off of them and they’re and they seem to be doing reasonably well. So we really don’t know the answer. I usually tell folks it’s we don’t know yet, but it’s possible it could be for life. Could be for life.

Speaker 2    47:39

Ok. Our next question is what’s a biosimilar? I’ve heard of those. And how do I know if I’m getting a biologic medication or a biosimilar?

Speaker 1    47:49

Yeah so basically a biosimilar is a generic form and so they and in our disease state here, there really are no biosimilars yet. The first one that’ll come out would probably be omalizumab. There are biosimilars, similars in other disease spaces which you know to be honest like the TNF alphas, there’s several that are out there and the answer to your question is you just have to ask and unfortunately a lot of those choices are driven by carriers and insurance. And the other just again in Full disclosure I’m so you have to be with them, I think it’s 10 to 15 % for generic drugs. I don’t know what the FDA parameters are for biosimilars off the top of my head. But I’m guessing there’s something similar.

Speaker 2    48:40

Ok. Our next patient question is I started OMALIZUMAB in clinical trials. It is a life changer. When will the black box label be removed? I need more freedom to live my life outside of the doctor’s office.

Speaker 1    48:54

That’s a great question. Sure answer is I don’t know. It’ll ever be completely lifted. What I can tell you though in the post hoc analysis that they’ve done. So the reason the black box is, well, there’s a couple issues. One is tumors and I’m not sure why that is. And the other one is anaphylaxis. So the anaphylaxis 1. You know I’m not sure exactly where Genentech and the virus are with that and you know it’s really hard to get a black box removed. I personally would; I tell patients is through reassurance that the if you’re looking at the anaphylaxis piece and again I’m, it’s been a long time since I looked at the package insert for omalizumab. It’s been out so long I just really don’t worry about anaphylaxis anymore and if somebody asks it because you know, we have A at the questioner here is obviously very sophisticated and so you know when you when you read this stuff, black box warnings are there out of an abundance of caution and the dynamics that drive it are quite variable and some of them are science based and some are a little more. Emotionally based in this case for anaphylaxis. I mean we give tens of thousands of doses of this stuff and I don’t know that I’ve ever seen a real anaphylaxis and I definitely heard about them and I know my partners have, but I myself have it with regard to tumors. And perhaps that was the other element the so in the in the original studies they didn’t exclude solid tumors in and so that got put as a as an AE in the post hoc analysis when they reexamine the stuff where they excluded those individuals and there does not appear to be any risk of malignancy associated with oralism app and if it’s if it’s been as big of a disease changer then I’m just keep doing it.

Speaker 2    50:48

Ok. Our next question is what about biologics and treatment with patients that have COPD with asthma overlap?

Speaker 1    50:57

Umm. You know. You have to meet the various criteria for this. So if you know if their asthma has been long standing but it’s eosinophilic really driven and you and you meet the various parameters in terms of either Pheno or Amphenol and I and totally acidophiles. I would think that would still be an effective therapy. Some of the newer agents like Tessie you know that we don’t know yet it’s relatively new and I’m not sure they’ve gone for that indication. It’s a little different disease state and you may not get quite the level of effectiveness as you would if you had a pure asthma state just because of the nature of the disease. But I would think that it should be helpful at least in a certain percentage of patients.

Speaker 2    51:51

Ok. We have two more questions. Our next one is how can Pheno testing better steer treatment selection?

Speaker 1    52:01

You know. So the whole idea of Pheno is it is it’s. Its utility and ease and accessibility for. Recognizing an eosinophilic driven airway process. The reality is that you can have an eosinophilic driven easy process and still have a normal piano. I think it’s. There is great difference of opinion on how much weight that decision becomes into it. It’s definitely easy. It’s definitely relatively inexpensive to do, although it’s often not reimbursed, again because of the it’s variable variability in it and it and its utility. I’m speaking only for myself i kind of stopped using Pheno unless I really I was I use it more as a gauge for compliance quite frankly than the than a therapeutic driver it just because I find it so variable and erratic some of my most severe and I know he is synoptically driven asthma and have phenos of like five or two or less and so I just don’t know. You know, if it’s low, it just doesn’t make that much. It doesn’t change my perspective. I the other markers are much, in my opinion anyway, are much more reliable.

Speaker 2    53:28

Ok. Thank you. Our last question is, do you think there will be more biologics available that can be safely administered at home?

Speaker 1    53:38

Yeah I don’t I don’t know when I mean there’s several out there right now that are under development and so yeah this is this is definitely a growing industry and an evolving therapeutic you know window here I don’t know when on the top of my head we’re still kind of dealing with a lot of stuff from COVID and from a pulmonary standpoint and there’s but the but I think that I don’t have. They doubt that this is going to continue as we move through our practice lifetimes. And but yeah, I I’m sure there will be. So and again I’m just kind of circling back to that question in the journal article title page that I just, that I have up on the screen right now. We actually, they actually talk about that and all the various things are sort of in the pipeline and the disease states that they might be applicable to. So yeah I think that there will be I as far as home use that’s going to be that’s often a regulatory type of thing. So the short answer is I’m sure they are. I don’t know when that will happen and even if they are approved when they get approved for home use is going to be different. Some things are, can get through pretty quick. Some things, you know, not so quick and so yeah.

Speaker 1    55:08

Well, thank you so much, Doctor. Tracy, you’ve not only talked about what there is to look at now, but we even made you get out your crystal ball a little bit and take a little look at the future. But we really appreciate your time and energy and expertise today. And lastly, I’d like to thank our listeners for joining us today. At this time, please download the certificate attendance from your control panel. If you have any difficulties, please email us using the link in your emails. If we could go to the next slide, please join us for our next advances and allergy and asthma webinar as we discuss current and future treatments for food allergy. This webinar will be on September 27th  at 4PM Eastern Time. You can register for this webinar on our scroll to the bottom of our home page to webinars. You can also view our recorded webinars on this page for on our website. And if you can go one more slide for me, please visit our website for quality guidelines, resources on allergy and asthma. Also access important medical information on allergies and asthma from our partners, the American College of Allergy, Asthma and Immunology and Allergy and Thank you again for joining us today. Please stay online for two to three minutes to complete the evaluation survey. This is Sally Schoessler for the staff at  Allergy & Asthma Network. Thank you for looking at Biologic. Medications with us today as well, and we look forward to having you join us next time on advances in allergy and asthma.

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