Welcome to Biologic Therapy for Patients with Severe Asthma, Impeding the Inflammatory Cascade, presented by the Global Education Group in collaboration with the Asthma and Allergy Foundation of America at Immunology Live. My name is Dr. Jonathan Koren. I'm an Associate Clinical Professor of Medicine and Pediatrics in the Divisions of Allergy and Immunology at David Geffen School of Medicine at UCLA here in Los Angeles. Today's session is part of a patient-physician tethered initiative. On Monday, August 15, 2022, we held an education session for patients affected by severe asthma, either newly diagnosed or currently being treated, and their caregivers.
During that session, we polled the patient participants to gauge their experience managing their severe asthma. We'll be discussing results from those polls in several points of today's presentation. This session is also interactive, allowing us to take your questions in real time throughout this presentation. We encourage you to enter questions at any time in the box below. Now I'd like to introduce my co-presenter, Dr. Michael Wexler, Director of the Cohen Family Amistad Institute at National Jewish Health, and Sanaz Eftikari, Vice President Corporate Affairs and Research at the Asthma and Allergy Foundation of America.
Thank you, Michael and Sanaz, for joining me today. Let's get started. Here you can see our disclosures.
And what I'd like to do now is show us our learning objectives for today and go through them one by one. First, identify how epithelial alarmans impact both type 2 and non-type 2 downstream inflammation and asthma. Then differentiate the mechanisms of action of available biologics for severe asthma. Next, summarize efficacy. and safety data related to alarm and blockade with biologic therapy aimed against thymic stromal lymphopoietin or TSLP.
And then finally, identify which patients might benefit from treatment that actually targets TSLP. So let's begin by really addressing some of the unmet needs that we find in our patients who have severe asthma. I think it's appropriate to start with the most widely accepted definition. of severe asthma and severe uncontrolled asthma. Severe asthma being asthma that requires GINA level 4 or 5 medications to be controlled or which remains uncontrolled despite that treatment.
The GINA 4 or 5 level medications that are mentioned in the document include high-dose inhaled corticosteroids plus LABA and or leukotriene modifiers or theophylline for the prior year and or systemic glucocorticoids for at least 50% of the last year. If we now hone that down to about 5% of patients who have uncontrolled severe asthma, this would be defined as patients who, despite that therapy, may continue to have exacerbations, defined as two or more requiring oral steroids in the prior year, serious exacerbations requiring escalation of care, and or persistent airflow limitation of FEV1 at less than 80% of predicted. all in the background of patients who have a daily burden of disease that's not well controlled. So what I'd like to do now is gauge your own level of experience with this and your own actual experiences with your patients based on your current practice. What percentage of your patients do you believe are unsatisfied with their level of asthma control?
There are six possible answers I'd like you to consider. A, 0%, B, 1% to 25%, C, 26 to 50%, D, 51 to 75%, E, 76 to 100%, or F, I do not see patients with asthma. Now, while you're thinking about that, I'd like you to keep in mind that a large amount of research has delved into this topic and really had a variety of different findings depending on the type of practice, whether you're in a primary care practice or a pulmonary practice or an allergy practice. While we're waiting for the answer, I'd like to turn this over to Sanaz for a moment, who's going to give us some of the data from a recent program that was done at patients and caregivers. Sanaz?
Thanks, Dr. Koren. As you mentioned, we hosted a patient program last week where we asked patients to report how would they rate their level of asthma control. And in that live program, we came out with about 50% of the patients and caregivers who are participating reported that their asthma control had room for improvement.
improvement. So this is really, I think, a key importance for moving forward with this program. And with that, I'm going to pass it back over to Dr. Koren for the results to our poll here. So what we see is really a split between answers B, C, and F.
So really, I think a wide variety of experiences with our perceptions of how our patients are doing with respect to their asthma control. And I think a lot of this does have to do with the type of practice we have. So what I want to do now is sort of take a step back from our clinical experiences and really look at some of the issues relating to the immunobiology of this disease. And what we're going to be looking at is a very nice pictorial, which was published in the New England Journal of Medicine a few years back, that looks at some of the important molecules that are involved with.
the immunoregulatory side of asthma, and the inflammatory side of asthma. And we can see that this slide is really split into three different sections. On the left, we can see that there's a Th2 cell, which really guides all the processes that take place with an allergic asthma.
That's really the orchestrating cell under the influence of TSLP, which comes out of the epithelium and allows these cells to respond to allergen in a very specific way. We end up then with IgE, and we end up with IL-4 and IL-13, both of which are instrumental in guiding a lot of the inflammatory processes. In patients that don't have allergy and don't have Th2 cells that are wired to respond to allergen, these are the patients really that have more of an eosinophilic phenotype, which we're going to talk about momentarily. This is really guided by what we call the innate lymphoid cell type 2, right in the middle of the slide in blue.
And with respect to that slide, it releases the same type 2 cytokines that we see from the Th2 cell. IL-4, 5, and 13. And this cell really helps guide, under the influence, again, of both TSLP and IL-33, many of the downstream processes. And then finally, on the far right, a group of patients, which is much more difficult to characterize, a much more heterogeneous group, patients that we refer to as low type 2 asthma, where we speculate that Th17 cells, Th1 cells, and ultimately neutrophils may play a role in many of these patients.
there's also a very, very important role for mast cells in this group. So we kind of broke down asthma into three pathobiologic pathways, which now takes us to, I think, a very important concept is, when we examine a patient in the office and do a variety of tests, what do they appear to be? What group do they really fall into? And this introduces the idea of phenotypes and endotypes, a phenotype being an observable property of an organism.
that's produced by the interactions of both their own gene along with the influence of the external environment, which gives rise to a number of clinical and physiologic characteristics. This should be differentiated from the concept of endotype, which is really the underlying biology, which gives rise to a phenotype. So it's a specific phenomenon that would explain many of these characteristics we see based upon chemical messengers like cytokines and other molecular mediators, cells that are present.
like eosinophils, and then finally other mediators that may be relevant. So what we can see is some of the common asthma endotypes. And we've split this up very, I think, conveniently into those we would consider to be type 2, previously called Th2, and those that are type 2 low.
What we have amongst the type 2 patients are allergic asthmatics, where IgE plays a very important role on the basis of IL-4 and IL-5. IL-13, along with the presence of eosinophils in about 80% of these patients due to the presence of IL-5. There's more of a pure eosinophilic phenotype where allergy is really not involved, based again upon IL-5, but IL-13 playing a very important role of getting those eosinophils into lung tissue.
And then finally, an endotype we would consider to be sort of a hypertype 2, or a magnification of the eosinophilic phenotype would be asthma exacerbated. respiratory disease, or excuse me, aspirin exacerbated respiratory disease, also known now as NSAID exacerbated respiratory disease, which again, many of the same cytokines that are involved. And we're going to go through these in a little bit more detail, looking at really specific patient scenarios. And then finally, type 2 low, poorly characterized, maybe neutrophilic, but in many cases, there really is no inciting cell that we can identify, no effector cell. And very often we refer to this group as a posse cranial acidic.
So if we explore some of these, starting with allergic asthma, in children, this probably constitute 90% of the patients, in adults, between 50% and 60%. Very strong family history of atopy in these patients. Typically comes on in childhood or at the very latest in adolescence up to about age 20. Frequently, the end product, the allergic march with atopic dermatitis, food allergy, and allergic rhinitis preceding it. You can tell these patients are allergic and identify them as such through positive skin tests and positive specific IgE. Usually, they have a marked elevation of total serum IgE.
Bloody eosinophils are variably elevated in about 80% of patients. as is the exhaled nitric oxide, which is a very good identifier for the presence of IL-13. What we really don't know is whether mild allergic asthma can progress over time, or whether it comes on with a vengeance in a certain subphenotype of severe asthmatics.
If we contrast this with type 2 asthma that's much later in onset, and typically is a group known as eosinophilic asthma, defined as a bloody eosinophil count of greater than 150 cells per microliter. In severe asthma, there are very high numbers of eosinophils that can persist despite treatment with inhaled and oral steroids. And this is something that's been shown to be very consistent over long periods of time.
These patients tend to be non-allergic. Disease comes on in their late 20s or even late 30s, much less related to both atopy and to family history. And what distinguishes this group from the allergics is it can be very severe from the outset.
very, very closely related to nasal polyps and any subgroup of patients with aspirin or NSAID hypersensitivity. And then finally, that third pathway that we mentioned in our diagram, those with low or non-type 2 asthma, often late onset, greater than 40 years of age, frequently associated with gastroesophageal reflux. These patients may also have chronic rhinosinusitis, but typically without nasal polyps. And these people may have obesity as a distinguishing factor.
And oftentimes, because they don't really have a modifiable trait that responds to steroids, they don't respond to either the inhaled or oral form of these drugs, even though many of them will end up on these drugs for long periods of time, despite the fact that they may not be very effective. Biomarker-wise, they have low blood eosinophils and a very low exhaled nitric oxide. And skin testing may be a positive, typically to things like seasonal pollens, if they have associated seasonal allergic rhinitis.
But typically, this is not instrumental or really a guiding factor in their disease course. So this, again, reiterates that from the epithelium, which really is hit upon by a number of external factors ranging from viruses to allergens to pollutants to bacteria, with the release of these alarmants, TSLP, interleukin-33, and IL-25, these three so-called alarmants have a very important impact, whether it's allergic asthma on the left, eosinophilic non-allergic asthma in the center, or non-type 2 asthma on the right, which again, can show that shows the presence of the neutrophils and the mast cells. What's also important to keep in mind is that these alarmants, particularly TSLP, can go straight to the smooth muscle, where it does have an effect on thickening and hyper-responsiveness of the airway.
How does the epithelium really impact upon all this? And the epithelium plays a critical role. And this is something we've learned over the past decade. On the left, we can see it plays a critical barrier in sensor function. It's good because we want to keep external factors out of the body.
And we can see that there is some mediation of immunity through the epithelium. Typically, with regard to the alarmins, this is more in the line of what we would call parasitic immunity, much less of an impact on bacterial or viral immunity. Where the alarmins really, I think, get in the way of asthma and cause contribution to the disease is for the induction of inflammation. which we're going to be learning a lot about today, and the mediation of long-term structural consequences, which ultimately will lead to narrowing of the airways and irreversibility of the asthma.
Some of the things that we have to keep in mind with this dysfunctional epithelium that we find in asthma are, first, there is genetic impairment of the junctional proteins. So these junctional proteins actually allow the cells over time to drift apart. Flagrin is a very good example of one of these proteins that's genetically regulated. Environmental factors, things like allergens, particularly fungi, have the ability to increase the permeability and loss of barrier function. And then finally, the airway can become colonized, whether it's the upper or lower airway.
And these bacteria will have an effect over time. Ultimately, all this leads to denonation of the epithelium, impaired epithelial repair after an injury like an infection. And then finally, spontaneous goblet cell metaplasia.
If we look at this little pictorial, we can see that. due to the effect of house dust mite, we actually see a reduction in staining of these junctional proteins. There's a proteolytic effect, so these cells become very porous and allow the external environment to penetrate much more easily. The evolving concept in asthma are, we've previously viewed this as a one-size-fits-all asthma as a single disease, but what we now understand is that there are a number of heterogeneous syndromes with a variety of phenotypes that vary enough that we really want to treat them very specifically. This shows us the GINA guidelines from 2022, and it's really as we get into more severe asthma, daily asthma with frequent nighttime awakening.
often with exacerbations that are occurring two or more times a year, that we move from level four, which is medium dose inhaled steroids and an additional controller, to level five, where we now go ultimately to the highest levels of inhaled corticosteroids, plus a long-acting beta agonist, frequently with a long-acting muscarinic antagonist, we call triple therapy, and still we're not completely controlling the disease process or symptoms or exacerbations. And this is where we get into. biologic therapies. And I think this probably applies at the very least to 5 to 10 percent of the population that have severe asthma that may be uncontrolled and really needs additional treatment besides what we typically give for standard of care therapy.
So the question is, what can we achieve with biologic treatments for asthma? Some of the things that have been consistently demonstrated are reduction in exacerbations, reduction in steroid dose, and consequently a reduction in those side effects that come from steroids, an improvement in daily symptoms, and significant improvement in quality of life. And then finally, something that we are starting to really entertain and talk about is can we modify the disease over a long period of time?
And can we prevent some of those long-term changes in airway function and inflammation? We come back to our diagram from the New England Journal of Medicine, looking at the left, allergic asthma in the middle. non-allergic eosinophilic, and on the far right, low type 2 asthma. We can see that there are boxed in yellow a number of different cytokines. We can see the very critical type 2 cytokines, 4, 5, and 13, coming from the ILC2 cells, coming from the TH2 cells, and a variety of other things on the right-handed side, which really don't relate to those type 2 cytokines.
What we'd now like to do is superimpose some of the existing therapies, what we have available to us now. and see really how does that intervene. So if we start with dupilumab, which is a known blocker of the IL-4, IL-13 receptor, we can see that there are numerous branch points in the inflammatory cascade that we can impact upon.
What we have found with dupilumab is, like many of the other type 2 biologics, a significant reduction in exacerbations and improvement in FAV1. There may be a transient increase in bloody acinophil numbers due to re-trafficking of the ESNFL, but this is something, again, that diminishes with time. And there's been a recent indication and approval for dupilumab in children down to the age of six, for children that have recurring exacerbations, with the hope being that we can not only improve their clinical course, but preserve lung function over periods of time.
If we come back to our diagram, we have omelizumab, which is a monoclonal antibody. directed against IgE, the most downstream effector molecule in allergic asthma, along with dupilumab. And we can see that with omelizumab, there's been very consistent experience with randomized controlled clinical trials that there are a reduction in exacerbations.
In the largest trial done to date, in which omelizumab was added on top of existing ICS plus second and third line inhaled agents, there was about a 25% reduction. And in real-life use, there's been a reduction in oral corticosteroids. Coming back to our diagram, the next level of medication after omelizumab and dupilumab are a class of drugs that are relatively new in the last five to six years, drugs that block anti-IL-5 by binding to anti-IL-5 or blocking the receptor. These include mepolizumab, rosalizumab, and benrolizumab.
Benrolizumab differs slightly in the fact that it It binds to the receptor of IL-5 and therefore has a very different mode of action, in which case it actually causes apoptosis of the eosinophil, which allows you to drop eosinophil counts to the lowest possible. And if we look at methalizumab as the first drug that was developed and approved for as an anti-IL-5 agent, again, we see a reduction in exacerbations roughly in the neighborhood of 50%. So, we're going to look at the We see a reduction in oral corticosteroid use.
And finally, we see an improvement in quality of life and symptoms. FEV1 has changed variably with this medication, and there has been some data showing over a several-year period of time, FEV1 improves but then comes back down to baseline over time. And these data show us the improvements that can be garnered with mepolizumab, showing reductions in steroids in patients that are taking these drugs. Restylizumab differs from the other two anti-IL-5 and IL-5 receptor drugs in that it is administered intravenously. It was never approved for subcutaneous use.
And it differs regarding the boundary of eosinophils where we typically employ the drug, typically at 400 eosinophils, which is where it's been shown to have the highest level of efficacy. At 400 eosinophils and above, there's about a 50% reduction in exacerbations. And here, what we're looking at on the left is the improvement in FEV1.
Again, I think significant. And on the right, we're looking at a reduction in blood eosinophils. And then finally, Benrolizumab, the most recent of drugs that target not only IL-5, but really targets eosinophils directly by binding to the receptor and causing apoptosis of eosinophils. A couple of studies have demonstrated that there's a corticosteroid sparing effect for patients, which is quite profound.
And as you go beyond the normal six-to-month clinical trial, which was done with the PENENTE study, that you can get to even lower or better reductions in the requirement for oral corticosteroids. And what we can see here is really on the upper, we're looking at the improvement in corticosteroid dose, and in the lower, we're looking at improvements in exacerbations in patients who are treated with benrelizumab. So again, there have been studies showing that if you switch from a drug like omelizumab to benrelizumab, that there appears to be a greater anti-inflammatory effect and a better effect. on severe asthma.
So if we look in total at the drugs that we have available to us, this excludes one very important drug, which you're going to be hearing about from Dr. Wexler momentarily. But what we've had up until the past few months is dupilumab, omelizumab, benrelizumab, mepolizumab, and ruslizumab. And we can see that there are some differences in dosing. The dosing ranges with dupilumab every two weeks administered at home, up to every eight weeks with benrelizumab given in the doctor's office. And we can see that there are some other comorbid indications in which we can use these drugs for additional benefit.
In the case of dupilumab, approval for atopic dermatitis, nasal polyps, and eosinophilic esophagitis, omalizumab with urticaria and polyps, and mepolizumab, polyp disease, hyper eosinophilic syndrome, and eosinophilic granulomatosis with polyangiitis. So that's an important thing to keep in mind. This shows us In total, again, what we've discussed in summary, the kind of reduction you get in exacerbations, typically 25 to 70 to 75 percent, depending on the drug, usually hovering around 50 percent, with variable improvements in oral corticosteroid reduction, improvements in quality of life.
And with regard to FEV1, there are some important differences, with really the lowest changes being seen in omalizumab. with mepolizumab, something I think that will become important in the future. Which now brings me to our second audience question, which is, what is the biggest limitation of omelizumab, dupilumab, mepolizumab, reslizumab, and benrolizumab?
And let me read you the possible choices. A, a lack of availability to children less than six years of age. B, lack of consistent or durable response with the medication. C, therapeutic targets are downstream in the inflammatory pathway. And then D, lack of efficacy for patients with severe type 2 low asthma.
I'm going to give you a moment to think about that. And while you're thinking about where you really see the limitations of these drugs, I want to introduce you to a topic which really is going to be the foundation for the rest of today's symposium, unmet needs in severe asthma management. And there's some observations that have been made over the past few years.
Despite significant advances with all the drugs we've talked about up until this point in our symposium, many patients do remain uncontrolled, and it's been estimated up to about 50%. Secondly, heterogeneity and pathobiology of severe asthma, something we've recognized now and understand that there is type 2 asthma, where you'll get variable responses. But then there is type 2 low asthma, where in fact, many of these patients, if not all, will not respond to any of the available agents. And then finally, current therapeutic targets are downstream in the inflammatory cascade.
We have IgE, interleukins 4, 5, and 13. And what we understand is that you may give an anti-IL-5, and we understand that you will not block IL-13 in some of the products of inflammation regulated by IL-13, such as exhalonitric oxide. And very similarly, if you block IL-4 receptor alpha with a drug like dupilumab, you will not block eosinophil ingress in the bone marrow out into the periphery and then ultimately into the lung. So with that, I want to mention.
that the majority answering the question found D to be the most important answer. Let's go back to that. And I agree wholeheartedly that it's a lack of efficacy for patients with severe type 2 low asthma. So what I'd like to do now is, Banaz or Sanaz, you recently conducted that same patient survey that you mentioned earlier.
Can you kind of bring us up to speed on what that showed in this regard? Yeah, thanks, Dr. Korn. And I would mention, in addition to the lack of efficacy, it might be just the lack of awareness from patients. So in last week's patient and caregiver program, we asked the question about who is on a biologic, and only about 40% of qualified patients had stated that they've been offered a biologic therapy. And then out of the remaining patients, so that 60% who may have qualified for one, we asked about what was the hesitancy for not starting one.
And it broke down into... about three ways. So a third said they were not hesitant and they plan to talk to their doctor.
So this is great. About a third said that they were aware, or I'm sorry, they were not aware because, you know, the conversation about the biologics never came up. And about a third said they were concerned about possible side effects.
So this does introduce the potential of talking with patients more about these. I think that's a great transition, Dr. Korn, if you want to pass it back over to the next section as well. Thank you, Sanas.
So I'd like to pass it over to Dr. Wexler, who's really going to talk about something very new, I think, and different from what we've been talking about today. Thank you, John. You know, we've spent a lot of time discussing all the amazing therapies that we have for our patients with asthma, and they've really had a huge impact in terms of reducing exacerbations, improving lung function, helping reduce oral corticosteroid dosing, and really improving patient...
quality of life. That being said, as was just mentioned, there's still some shortfalls of some of the medications we have, and not everyone who receives these therapies gets complete control. And still there's some patients where there's still some significant unmet needs, particularly the patients with non-type 2 disease, or just patients who have some airway hyper-responsiveness.
So that's what we're going to focus on right now. We're going to talk about the potential for maybe targeting some of the upstream cytokines. that are involved in asthma pathophysiology.
So as we discussed already, you've seen this figure before. We talked about all the downstream cytokines, interleukin-4, interleukin-5, interleukin-13, as well as some of the other mediators, including leukotrienes and histamines, as well as IgE, which is an important antibody. But if we look upstream, if we look at the airway epithelium, we start to recognize that the airway epithelium plays a really important role.
It plays an important role as a barrier and as a sensor, and it's really the first barrier of defense against antigens and allergens and irritants, as well as pollutants, microbes, and viruses. And one of the things that we see is that the airway epithelium not only plays a role as a protector and as a sensor, it also plays an important role in terms of its ability to produce a variety of cytokines, what we call... epithelial alarmans that work upstream at the top of the inflammatory cascade and help drive some of the downstream inflammation and pathophysiology that we see in asthma. These so-called alarmans, including IL-25, IL-33, and TSLP, they're upstream of all cells involved in allergic inflammation, eosinophilic inflammation, neutrophilic inflammation, as well as structural changes associated with asthma.
And so one of the important concepts is trying to identify whether or not targeting upstream can potentially benefit our patients with severe asthma because of the various roles it plays in terms of mediating some of the inflammation that's going on. One of the kinds that we've really learned a lot about in the last 20 years is thymic stromal lymphopoietin, or TSLP, and it's been shown to be associated with asthma in many different ways. So TSLP was first described about 20-21 years ago, and genetic studies have identified the fact that variants of the TSLP gene soar with asthma risk. Furthermore, measurements of TSLP in bronchoalveolar lavage fluid and other bronchoscopic specimens have demonstrated that the higher the TSLP level expression, the higher the likelihood that a patient has asthma, as well as the greater the likelihood that a patient has more severe asthma.
Furthermore, higher TSLP expression is associated with higher type 2 cytokines and chemokine expression, and importantly, These are associated with disease severity. So in response to all of these different stimuli, whether it's viruses, cigarettes, pollutants, bacteria, allergens, or physical injury, these can all stimulate TSLP, as well as the other epithelial cytokines, to drive the downstream inflammatory pathway that are involved in asthma. And it's been shown, for instance, that TSLP levels are associated with not only severity, but also reduced lung function, the for airway remodeling and airway hyper-responsiveness, as well as rederoid response and exaggerated response to viral infections.
So all of these are important features of asthma that are associated with higher levels of TSLP. So wouldn't it make sense, therefore, to potentially target TSLP to target more upstream in the inflammatory cascade? Well, One of the nicer, newer therapies that we've developed is a drug called tezipalumab.
It's an anti-TSLP monoclonal antibody that specifically blocks TSLP from interacting with its receptor. And by blocking TSLP, you can potentially reduce the initiation and the persistence of airway inflammation that we see downstream, as well as the role that airway hyper-responsiveness plays in terms of asthma pathophysiology. In addition, it's been observed that if you administer anti-TSLP, you get a reduction in a broad spectrum of cytokines, including IL-4, IL-5, and IL-13 key type 2 cytokines. And also, you get reduction in type 2 biomarkers, as I'll show you, with reduction in eosinophils, IgE, and nitric oxide.
Clinically, what has been shown and how does tesopelimab differentiate itself? from the other biologics? Well, similar to the other biologics, it can be administered, usually it's approved for administration every four weeks, to individuals 12 years and up.
Its only indication currently is for patients with severe asthma, but it's been approved in the United States, in Canada, and it's imminently being approved in UK and Europe. So these are very exciting times because... we've now added a sixth biologic to our armamentarium.
So why don't we take a look at the data upon which tezipalumab was approved. So this is a study that was led by Jonathan Koren, in which tezipalumab was administered at three different doses to patients with severe asthma. And these three different doses, 70 milligrams once a month, 210 once a month, and 80 milligrams every two weeks. were all evaluated compared to placebo in patients who had moderate to severe disease and who were poorly controlled. In the subsequent year, at week 52, the rate reduction of annualized asthma exacerbations was significantly reduced with all three tesipelumab doses, with an important magnitude ranging from 61% down to 71% reduction in asthma exacerbations annually.
One of the exciting things that was identified in this phase 2 study was that the reduction in exacerbations was seen independent of biomarkers. As can be seen in this figure from the study that was published in 2017 by Jonathan and colleagues, is that there was a reduction in exacerbations in patients who have low eosinophils, high eosinophils, and patients who have low nitric oxide or high nitric oxide. and in patients with a low TH2 status or a high TH2 status.
In all of these groups, there was a reduction in exacerbations, suggesting that this therapy works in a broad group of patients. This study led to the Phase III Navigator Study. The Phase III Navigator Study was a study that evaluated the efficacy of tezipelumab in a broad group of patients over a 52-week period of time. In the overall patient population, there was a 56% reduction in exacerbations, including going down by over a half from two exacerbations to less than one exacerbation per year. And one of the things that was exciting was that in patients who had low eosinophil levels, less than 300, as well as less than 150, as I'll show you, there was also a significant reduction in asthma exacerbations in patients with non-eosinophilic asthma.
Here are some of the data of all the sub-patients who seemed to respond well in terms of improvement with tesipalimab blockade with anti-TSLP therapy. As I mentioned, over the 52-week period, there was a 56% reduction in exacerbations in the overall population. But when you look at all the different eosinophil groups, you can see patients who had more than 450 eosinophils, 300 to 450 eosinophils, 150 to 300 eosinophils, or even less than 150 eosinophils, there was still reductions in exacerbations in all those different patient populations. And the higher the eosinophil count, the more likely, the greater the reduction of exacerbations a patient was to have. However, even in less than 150 eosinophil group, a group of patients for whom none of the biologics had been shown to have any efficacy, here we see that there is efficacy of 30% reduction in exacerbations in that patient population.
The same thing was shown for nitric oxide. In the patients who had higher than 50 eosinophil, per billion of nitric oxide, it was 73% reduction in exacerbations. 25 to 50, a 60% reduction.
And even in patients who had nitric oxide levels less than 25, there was still a 32% reduction in exacerbations. Lastly, the same thing can be shown with regard to allergic status. In patients who were an aeroallergen positive and who had specific IgEs, it was 58% reduction.
But In patients who were negative for any IgE to perineal aerogen, there was still a 51% reduction in exacerbations. These data suggest that there's a broad group of patients who seem to respond to tesipelimab with the important reduction in exacerbations. But not only in exacerbations, also in terms of lung function.
Here from the NAVIGATOR study, we can see that compared to placebo, there was an early improvement in lung function. that peaked out around three to four months and was sustained throughout the 52 weeks and was significantly greater than the placebo group. Overall there was a 230 milliliter improvement in lung function compared to only a 90 milliliter improvement lung function with placebo.
These improvements were early on and they were sustained throughout the study. I mentioned before that tezupilumab works at the top of the inflammatory cascade and TSLP levels correlate with IL-4, 5, and 13, as well as other marker levels. Tezupilumab was shown to reduce all three of the key biomarkers in type 2 inflammation. Eosinophil counts, toxide levels, and IgE levels all were reduced with Tezupilumab treatment over the 52-week period. And importantly, these biomarkers...
All were reduced, and this is the first biologic to show reduction, all three of these key biomarkers. Again, suggesting how broadly this therapy may be utilized. One of the other studies evaluated the efficacy of tezupilumab in patients who were on oral corticosteroids. Now, while there was positive studies with benrelizumab, with mepolizumab, dupilumab, in terms of reduction of oral corticosteroids.
This study, in which tesipelumab was compared to placebo in patients with oral corticosteroid, did not meet its primary endpoint. This is a study that I led, and what we found was, while 54% of patients treated with tesipelumab were able to reduce their corticosteroid dosing by 90 to 100%, almost coming off of steroids, there was a significant placebo response. 46% of patients treated with placebo were able to reduce steroid dose by 90 to 100 percent. For all the other strata of corticosteroid reduction, there was a significant difference.
Now we think that lack of difference may be due in part to the large placebo effect resulting from the long duration of the oral steroid reduction phase and also the multiple attempts to reduce oral corticosteroid dose that were allowed in this study compared to other studies. Interestingly, in a post-hoc analysis, Fewer placebo recipients achieved a 90% to 100% reduction in maintenance oral steroid dose at week 20 compared with placebo at week 48. This suggests that perhaps oral steroid dose reductions in uncontrolled patients, had they been not permitted, perhaps we would have seen different results. Also, it's important to look at some of the secondary endpoints. In this study, there were still reduction in exacerbations with tesipelumab compared to placebo. The steroid reduction wasn't very different.
31% reduction in exacerbations. And there was a significant improvement in lung function, FEV1, the tesipelimab compared to placebo. Furthermore, despite the fact these patients were tapering their corticosteroids, there were greater improvements in ECQ, AQLQ, and asthma symptom diary scores.
One of the other studies that was done was the CASCADE study, which was a biopsy study, which we'll talk about in a moment. But it and two other smaller studies, an allergen challenge study, and a phase two upstream study all demonstrated that tesiponiumab had a significant benefit in terms of reducing hyper-responsiveness. Now, airway hyper-responsiveness, which can be measured either with methacholine challenge or mannitol challenge, is quite a bothersome attribute of patients who have asthma. Airway hyper-responsiveness suggests that the airways are patients who react to different stimuli and In these studies, it was demonstrated that tesipalumab reduces this degree of airway hypersponsiveness, suggesting that perhaps by blocking TSLP at the airway epithelium, as well as potentially downstream at the airway smooth muscle layer, you can have significant benefits in terms of ameliorating airway hypersponsiveness as well. All of these studies demonstrate broad efficacy of tesipalumab.
But an important question with any new therapy is, is it safe? Well, in the different studies that were observed, and particularly in the NAVIGATOR study, there was no significant difference in terms of safety signals in patients treated with tezopeliumab versus placebo. In terms of the portion of patients who had any adverse event or any serious adverse event, those results actually favored tezopeliumab, although there was no statistical difference.
Lastly, there were no adverse events resulting in deaths. And in terms of... adverse events leading to treatment discontinuation, the proportion of patients treated with tesipalimab was lower than that treated with placebo. The most adverse events reported were nasopharyngitis, upper respiratory tract infections, and headaches, and these rates were comparable to that what was observed with placebo.
There were no significant differences between severe infections or malignancies between these different groups, and injection site reactions occurred in similar ways. proportions, 3.6% versus 2.6% in tesipelimab versus placebo studies. Importantly, there was also no anaphylactic reactions with this therapy. So Jonathan showed you before what can biologics do.
Well, here we are adding tesipelimab in the last column to show you that tesipelimab also has robust efficacy in terms of exacerbation rate reduction, in terms of FEV1 improvement, and in terms of quality of life improvement. In terms of oral steroid reduction, I don't think we're quite there yet. Although, given the totality of the data, I feel quite comfortable administering tezupilumab to patients on oral corticosteroid as well. So let's just summarize what we've talked about today, what Jonathan has shown us, and what I've shown you. it's clear that the response to asthma therapies is quite variable.
And one of the challenges that we face as clinicians is trying to evaluate who responds to which therapy. And so I think it's important to evaluate all of those specific features in our patients with asthma and to try to identify which therapies should we give to which patients. So We now have all these biologic therapies that can treat patients with severe asthma. So I'd like to just bring back the colleagues and let's have a brief discussion and discuss the role, the place of tesipeliumab in treating patients with severe asthma. Jonathan, I'll start with you.
What are your thoughts in terms of where to use tesipeliumab? Should you be using it first line? Is it second line for... First line.
failures? Is it for patients with non-type 2 asthma because it works so broadly? You should use them in type 2 asthma.
What about patients with oral corticosteroids? What are your thoughts? I think when you look at the biggest unmet need that we have currently, I think the audience did a great job of answering this question. It's people with low type 2, which in some case series can be 40 or 50% of patients with poorly controlled asthma, with increased symptoms, with a lot of exacerbations, maybe even hospitalizations. So right off the bat, we have a very significant group of patients that requires something that we've never had before.
And that is, I think, tesopelomab to treat this group. And you showed us very nicely, Mike, how efficacious it is in that group. The another consideration when you're trying to pick a biologic, particularly if it's first line, is what are comorbidities?
You have to always consider, as I showed in the first half of the discussion, are polyps present? Is EOE present? Is atopic dermatitis present?
You have to make that consideration. But if you were to ask me, is this drug something that you could use, notwithstanding other comorbid conditions, that somebody has severe asthma? which cohort you put it in, not only the low type 2, but I think when we look at the efficacy data for type 2 itself, whether it's allergic or non-allergic, and as the eosinophil count goes higher and higher, this is a very, very highly efficacious agent for those patients as well.
Where I'm probably going to really consider this most strongly as first-line therapy would be in the low type 2 patients and patients who have eosinophilic. allergic asthma. Because when you look at how TSLP really works, without it, you don't have the development of allergic type tubes, allergen-specific Th2 cells. So really, TSLP is instrumental in the development and sustenance of allergy.
And if we can directly address that immunobiologic problem with a specific agent, I think it really puts us way ahead, gives the patients really a big advantage in terms of... controlling the disease and maybe long-term preventing some of the complications. Yeah, I agree.
I'm just excited that we have so many good therapies. And the fact that over the last seven years, we've had five new therapies approved for asthma on top of Fomalizumab approved 19 years ago. I think it really gives us a great opportunity to treat many of our patients.
Certainly. non-type 2 patients. We don't have any other biologic therapies that are effective in those patients. So that's a no-brainer.
But I think patients who've got mixed phenotypes who aren't purely eosinophilic or purely allergic or just pure nitric oxide increases, I think for those patients, tezipalimab would be fine. And one of the other advantages is, in addition to treating based on other comorbidities, is... to, is that we can, you know, if one drug doesn't work, we can always switch and see if another drug does work. So that's another potential role is for patients who aren't responding as well as we'd like to our asthma there. So some of the factors that I utilize in choosing biologics is, well, it's tough.
And I think I recognize that and Jonathan recognizes that there's no head-to-head study. Those are needed. We definitely need to consider that. therapy we should consider for which patient. We also need to figure out how we decide when to stop a biologic and when to switch a biologic.
If it's working, when can we stop it? And if it isn't working, when should we switch? How long should we wait and to which biologic?
In terms of deciding which therapy, I generally look at the biomarkers and I look at comorbidities. Those are some of the key factors. I try to identify what's the dominant biomarker.
So certainly if the eosinophil count is high, it's over a thousand, you know, an anti-L5 therapy is going to be the right approach. If the nitric oxide is very high, again, over 75 to 100, that might be the dominant biomarker. And maybe using anti-L413 therapy might be the right approach. If there isn't a single dominant biomarker, I think that, you know, you're not going to be faulted for using any of them, or you could pretend anti-TSLP therapy.
I also think type 2 comorbidities. whether it's chronic rhinosinusitis, nasal polyps, atopic retitis, or some rare eosinophilic disorders like hyper eosinophilic syndrome or eGPA. And I try to look for all those different comorbidities before deciding which therapy to use in my patients. Lastly, as I mentioned, if it doesn't respond to an initial biologic therapy, I just consider switching them until I find the right drug for the right patient.
Sometimes it's a matter of trial and error as well. But when I think about all the different potential patients, I think, you know, you won't be faulted if you have patients who have got allergic eosinophilic asthma. Frankly, you can use any of the biologics as a starting point.
Anti-IgE would be good for the allergic component. Anti-L5 or Anti-L413 would be fine for the eosinophilic component. Or anti-TSLP, as I showed you, reduces nitric oxide levels, eosinophil levels, and IgE levels. For with allergic non-eosinophilic asthma, I think for those kinds of patients who are non-eosinophilic, you're not going to give an anti-L5.
So for those patients, consider anti-TSLP or anti-IG or anti-L413, particularly if the nitric oxide level is high. And for patients who've got eosinophilic asthma and are non-allergic or they don't respond to anti-IG or one of the other therapies, or they're out of range of dosing for anti-IG. anti-TSLP, anti-IL-5, and anti-IL-413 all seem to be effective.
And for patients on oral corticosteroids, well, the data really support anti-IL-5 and anti-IL-413 therapy. The anti-TSLP study that we did, the source study, didn't meet its primary endpoint, but we are doing another study looking at oral steroid reduction, changing the underlying schema a little bit of that study to perhaps better tease out some of the differences. versus placebo.
Other factors that I utilize are choosing which drugs patients feel more comfortable with, what are some of the comorbidities, and how frequently are they using oral corticosteroids. But as I mentioned, head-to-head studies are needed. I'm going to pass the baton back to Jonathan, who's going to lead us in the question and answer period. John, why don't you take it from here?
Well, thank you, Mike. That was really a very elegant presentation. It really brought us up to speed on... what promises to be a very important agent in treating severe asthma.
Do we, to our production team, do we have any questions at this point? Here's one. Do biologics replace other asthma medications or are they supplemental?
Mike, what do you think of that question? Do biologics replace the other inhalers or are they supplemental? I think that I'm very hesitant to replace the inhalers. I have had many patients who do so well in the biologics that they stop their inhalers.
But I think that there are a lot of benefits to the inhalers that we have, including the bronchodilatory effects of the beta agonists, the anti-inflammatory effects of the inhaled corticosteroids that work across a broad group of inflammatory processes. So I don't think that I really advocate for cessation of the inhaled therapies. You know, I think if a patient is so well controlled that they don't need their inhalers anymore, I would sooner have them continue their inhalers and think about stopping the biologics because of the cost issues.
The inhalers, you know, they cost a few thousand dollars a year, but the biologics cost $30,000 to $40,000 a year. And I think that's another important consideration. Yeah, no, I think those are some very important points to keep in mind.
There will be people who taper off of them unbeknownst to us, but I have people keep them on hand because there will be exacerbations that may require corticosteroid anti-inflammatory therapy. So Naz, can you read us the next question? Sure. The next question is, please review differential responses based on ethnicity and race based on available studies.
So how does race and ethnicity play into the available studies for these biologics? I would say that there's not a lot of data right now, but Mike is working on a study that is hopefully going to provide some really important information. Mike, are you aware of much out there that...
So for all of the biologics that we have, they've been studied in broad groups of populations. That being said, the minority of the patients who've been involved in those clinical trials were... minority groups and of different ethnicities, but there was some representation. To date, those patients from those backgrounds, ethnic backgrounds and races, they seem to do just as well as Caucasian groups that are generally studied. We've studied this not just with the biologics, but also with inhaled corticosteroids and long-acting beta-acids.
There seems to be broad efficacy in all these patient groups. One of the issues seen in those patient populations is access to care. And I think that's an important consideration, as well as education about the availability of these kinds of therapies, the newer biologic therapies, and some cultural reticence about starting some biotherapies.
Thank you. And I'll just put a plug in also. I think it's no secret for the manufacturers, for the FDA, for us as patient advocacy organizations, that there's definitely a need to increase the diversity in clinical trials. So it is something that we're all working on as well, just for the future of studies that are available.
The next question, how would you define treatment failure on a biologic? So Dr. Wexler, you talked a little bit about this. If a biologic doesn't work, try a different one.
But what considerations do you take into account before you start a next therapy? Yeah, so I think it's important to mitigate expectations and to evaluate what was the reason that you put a person on a bike to start with. So I always make note of that. Was it because of exacerbations? And were you able to reduce exacerbations?
So did they have four exacerbations last year? And did they get down to two exacerbations this year? Well, I consider that a success, although it's only a moderate success. If the reason you did it is because the lung function is low and there's been no improvement in lung function.
If you did it because the patient was on oral corticosteroids and unable to reduce the dosing. If you did it because the patient was having persistent symptoms despite combination therapy and the patient still had symptoms. So you want to try to evaluate what was the reason that you put the patient on to start with and keep track of that in some kind of objective way.
You can use that. do that using, you know, the asthma control test, looking at lung function measures, looking at exacerbations. Sometimes some improvement is better than no improvement.
And you have to acknowledge that, that getting down to two exacerbations from four is a good thing. But going from four to four suggests that the drug isn't working. And I would add to that, that some of the low-hanging fruit that we can look at pretty early during our treatment with biologics.
are things like asthma control questionnaires and symptoms and even quality of life, along with FEV1. And when you showed us the data for tezopilumab, we could see within two or three weeks, you get a very nice improvement in FEV1. And we've seen this with some other drugs as well, with dupilumab certainly.
So I think if you really want to take a good look at that patient early on, if you don't see any change in the first couple of months, you may want to continue the course. only because exacerbations may be one of the endpoints you're trying to affect. But certainly if a patient has a lot of symptoms, and that's one of the goals of therapy, we should be seeing that within the first couple of months of treatment.
Did you bring us to the next question? Thank you both. Yeah.
And one of the questions we get pretty often is about the application or the future of biologics for pediatrics. So we know that a lot of the biologics were starting out to be available for 18 and older. Some have been brought down to the pediatric age six to 12. But do you guys anticipate the future of biologics for under the age of six for asthma? Well, we have three drugs to six now, which would be mepolizumab, omalizumab and dupilumab.
I'm sure this is something that will be coming forth as well with tezopilumab. But we also know that these drugs seem to be pretty safe. Dupilumab has an indication in the first couple of years of life now for atopic dermatitis. One of the advantages of dosing children early on is, particularly if you were to treat for atopic dermatitis, could you stop the allergic march?
Or if you had a child with asthma coming on at age two or three, which is when we might start to see allergic asthma, might you be able to preserve lung function and lung growth to a much greater extent? if they were not responsive to existing treatments. So I think certainly we've already pushed that boundary down to six and I expect it to in all likelihood go lower. Yeah in fact there's a study going on now looking at omalabs called the PARCC study it's led by Wanda Pipitanical at Boston Children's in which they're registering omalizumab versus placebo in kids at high risk of developing asthma starting as low as age two to see whether or not you can prevent asthma down the road. And another important question is whether or not these biologic therapies, can they prevent airway remodeling?
Can they result in complete remission if you give them for long enough to the right patient? Thank you both. I'm going to squeeze in one more question and then we'll close out the program.
So do you guys routinely perform phenotesting? I know we talked about the exhaled nitric oxide. And especially when measuring biomarkers and things like that.
Do you guys routinely perform the phenotesting for patients on biologics? I do. I check phenol really just about every asthma patient. I think it's a useful biomarker. The same way I check FEV1 at all my visits.
And the same way I check vital signs. The same way I do a physical exam. It's all part and parcel of this whole approach. And I think it's a... useful biomarker that gives you a sense of IL-13 mediated inflammation.
It's not expensive and it's very easy to do and you get a quick result, you know, within minutes. I would second that. And I would remind the audience, it's probably most critical.
Where Gina puts this is really when you have a patient where you start to escalate inhale therapy and they're not really getting better. That's critical then to get a blood eosinophil count. And if you can, an exhale nitric oxide. And I think allergy testing is something that should come even way before that, because certainly if you have somebody with allergic rhinitis, as most of these people do, and they're developing even mildly increasing asthma, you should always think about. doing allergy immunotherapy, which is one of the only disease-modifying treatments we have.
Well, this has been a fantastic opportunity to present a lot of this very interesting data. So what I'd like to do is really show the audience one more important slide, which is the companion patient session entitled Breathe Easier with Severe Asthma, the Role of Current and Future Therapies in Reducing Exacerbations. and gaining control of your symptoms. And this is available on demand at medlive.com.
So I'm going to give you a chance to look at that for a moment and jot down any of that information if you need to. But otherwise, this has been a great session. I want to thank Michael and Sanaz, and I want to thank the audience for giving up your own time and listening to what we had to say and offering us some really important questions.
And finally, I'd like to thank AstraZeneca for their support. support of this really important educational activity. Please remember to complete the post test at the end of the session to secure your CME credits. And then finally, please visit immunologylive.com to view everything that we went through today, along with potentially other sessions on demand that you may have interest in.
So I wish everyone a good night and hope to see you again.