Video Neutrophil-Based Targeting in Non-Cystic Fibrosis Bronchiectasis (NCFBE)Focus on Inflammation and Disease Activity Play Pause Volume Quality 1080P Fullscreen Captions Transcript Chapters Slides Neutrophil-Based Targeting in Non-Cystic Fibrosis Bronchiectasis (NCFBE)Focus on Inflammation and Disease Activity Overview TAKE CME TEST Back to Symposium Hello and welcome to this session on neutrophil-based targeting in non-CF bronchiectis. My name is, uh, Professor James Chalmers. I'm a pulmonologist and a clinical researcher at the University of Oxford in the UK, um, and I've, um, spent much of my career doing research into the role of neutrophils in bronchiectasis, uh, and so very excited to take you through some of the latest developments and how this impacts on our clinical care for people with this disease. Before we begin, these are my disclosures. I do a number of research studies with pharmaceutical companies in the field of bronchiectis. Some of these are focused around some of the new anti-inflammatory drugs targeting, um, neutrophilic inflammation, so it's important that you're aware of that. As we start to think about the concepts of disease activity and the concept of uh treating inflammation in bronchiectis, I thought it was really good to start with a case so we can apply these principles in real life clinical practice. So here's a case of a 45 year old lady presenting with a known diagnosis of idiopathic bronchiectis. She reports a two year history of persistent cough, she's coughing up perium sputum. This is the, the classic typical presentation of bronchiectis. The cough is severe, it's impacting on her daily life, um, and she's also describing breathlessness, limiting exercise capacity. She's got two exacerbations in the last year, um, and a typical presentation of those exacerbations is that she gets carrizal type symptoms, which progresses into severe cough, malaise, fever, and an increase in sputum purulence. Uh, and these events are responsive to antibiotics. She's practicing airway clearance but hasn't noticed a great benefit from that, and so our, uh, request here is for a second opinion. What else can we do to help this, this patient? So CT is the, the cornerstone of diagnosis, but it also helps us to understand a bit about the severity and activity of bronchiectasis, and in this case, it's reported as showing mild bilateral basal cylindrical bronchiectasis. Um, there are 3 types of bronchiectis, as I'm sure you know, cylindrical, varicose, and cystic. Cylindrical is generally the more mild, um, but here there's widespread mucus plugging and inflammatory change, so a lot. Of inflammation in the lungs. She has an FEV1 of 110, 111% predicted. Sputum culture is positive for Haemophilus influenza. The eosinophil count is not elevated, uh, and Aspergillus serology, immunoglobulins are standard tests for, uh, other problems in bronchiectis are normal. So I want you to keep that case in your head in terms of uh that presentation of severe symptoms, two exacerbations, idiopathic bronchiectis, mild, um, radiological bronchiectis, but with a lot of inflammation and preserved lung function. Um, this is a very common presentation to my clinic, um, and I'm sure to yours as well. And the question is, what's the best way to manage this patient going forward? Um, so key questions that I would ask for this kind of a patient is, why does the patient have bronchiectis? Is there, uh, an underlying inflammatory process, are there other things going on? How severe is this patient's disease? Have they already accrued a significant amount of damage? How active is the disease? I'm going to introduce to you the concept of disease activity, uh, and what are the. Treatable traits, and therefore what treatments could we offer to this patient that could improve their quality of life and reduce the impact of these exacerbations. So over the next, uh, 30 to 40 minutes, we're going to try and answer all of these questions, uh, and give you a framework for the best possible management of people with bronchiectis. And we're gonna start with the question of why do patients develop bronchiectis. You will be aware, I'm sure that there are many diseases that can cause bronchiectis, many roads leading to the same destination. There's over 100 conditions that are, uh, known to be associated with the increased risk of bronchiectis, but they generally can be put into one of the 4 buckets that we see in the vicious vortex. The vicious vortex includes Epithelial dysfunction, inflammation, which is typically neutrophilic, infection, and structural lung damage. In the inflammatory bucket, we can talk about both, um, autoimmune and, um, eosinophilic inflammatory processes, so ABPA causes mucous plugging of the airways and, Uh, ultimately dilation, rheumatoid arthritis, Sjogren's syndrome, and other connective tissue diseases are associated with an increased risk of the disease, as is inflammatory bowel disease. Alpha1 antitrypsin deficiency leads to uncontrolled neutrophilic inflammation that also drives bronchiectis, and there's a strong overlap with asthma and COPD. It's important not to miss the genetic causes of bronchiectis, and we'll talk a bit about that later. Primary ciliary dyskinesia and cystic fibrosis are the two most common. There are some primary issues with lung structure that can result in bronchiectis, uh, including the Mounier-Koon syndrome, tracheobronchiomegaly, and then severe infections can cause bronchiectis, um, including TB and NTM infection, uh, and. Primary and secondary immune deficiency likely cause bronchiexis through recurrent infections, uh, and they're very important that we don't miss. So on this slide is the most common, but there are many others, uh, and so it's important that we have a comprehensive evaluation of patients when we first see them. And also reevaluate as we find more information uh and patients' condition changes. A good framework for the evaluation of patients initially, like our, our 45 year old lady, is the European Respiratory Society guidelines, which were published in December 2025. Uh, at the time that I'm speaking to you, they're the only international guidelines that are available, uh, and were put together by representatives from 16 countries, uh, and contain comprehensive recommendations around investigation and management. They recommend specific tests to identify possible underlying causes. So when you see for the first time somebody like our 45 year old patient, uh, who's got severe uh symptoms and exacerbations, you would want to ask yourself, is there an underlying condition? All patients should get full blood count, electrophoresis, aspergillus serology, immunoglobulins, and sputum for NTM. Why? Well, the, the full blood count, the electrophoresis, and the immunoglobulins let you identify if there's an obvious primary or secondary immune deficiency. Uh, the Aspergillus serology identifies ABPA and the NTM sputum obviously identifies NTM. All three of those, immune deficiency, ABPA, and NTM are treatable. They change your management, and so they're very important that you don't miss them. Patients who have childhood onset bronchiectis or have any of these other features, um, should be investigated for genetic causes of bronchiectis, so severe chronic rhinosinusitis, uh, infertility, uh, obviously situs inversus, which is a strong, uh, signal that the patient has primary cellular dyskinesia, chronic otitis media, these are things to think about, um, testing for genetic causes. We don't test everyone for genetic causes. Um, and then extended immuno immunological testing may be considered in patients that have strong features suggestive of, uh, immune system problems. So this gives you a framework for both primary testing and more extended testing for people with bronchiectis, and I strongly recommend referring to these guidelines. So, let's assume our patients had all of these tests. We've given them the label of idiopathic, and we've done that correctly because we've gone through all of these tests, and Not found another cause. That's very common. About 40% of patients in the, the massive international embark registry have, uh, idiopathic bronchiectis. The second most common is post-infective. 3rd and 4th is asthma and COPD. Around 25% have those rarer causes. So those rarer causes are very important to test for because there's a lot of them. Um, but it's not uncommon that we're in this scenario that we're in with this lady, um, that she's got idiopathic disease. The other thing I'll point out is I, I pointed out this lady has normal spirometry. She's got an FEV1 of 111% predicted. Bronchiectis is often thought of as an obstructive disease, but it's actually really common to find patients with normal spirometry. In the embark registry, just under a third of patients had normal. Spirometry. Um, so that's, that's an important finding. Suggests the patient has disease at an earlier stage. It's not a crude, significant airflow obstruction from lung damage, but doesn't mean the patient has a low burden of disease, because as, as identified in our patient, she's terribly symptomatic. So why does our patient have bronchiectis? We do extended testing, we've not found an obvious cause. We're now looking at an idiopathic disease case, which means that we need to think, uh, outside of underlying cause for how we treat the disease. The next question is how severe is this patient's disease, and I've started to allude to that in terms of the, the lung function, but there's other aspects to the severity of bronchiectis that we need to think about. We often start with radiology. We define bronchiectis by radiological abnormalities, and that's absolutely right. That's how we make the diagnosis. The diagnosis of bronchiectis is made by the identification of dilated airways that are larger than the adjacent vessel. This is a nice example of that cygnet ring sign. You can imagine. Uh, the, uh, the dilated airways being the, the loop of the ring with the stud being the blood vessel, clearly, um, uh, an elevated BA ratio, bronchial arterial ratio. This is bronchiectasis. Um, this is mild cylindrical bronchiectasis, which is, as I mentioned earlier, uh, the earliest stage of the disease. As we get more severe, you get cystic and varicose bronchiectis, and you can see here these areas that almost look like cavities. This is cystic bronchiectis, uh, this is. A more varicose type bronchiectis. Um, this is much more severe, indicating much greater lung damage, probably greater length of time that the patient has had the disease. And actually, this is an example of a patient who has turned out to have cystic fibrosis, uh, a more severe phenotype of the disease. Uh, and then the most severe type of bronchiectis that you can find is where the lungs, uh, virtually completely destroyed. Uh, and this is an example of that here where, uh, the lung is, uh, the normal lung anatomy is almost completely absent, and this was a patient, uh, with a previous history of tuberculosis. So we have, uh, cylindrical varicose and cystic. Bronchiectis, but we also have to take into account the extent of the disease, how many lobes are involved, um, how widespread is the disease, and what other features do we see? Bronchial wall thickening, mucus plugging can be signs, not necessarily of severity of disease, but that that there's a lot of active inflammation going on, and we'll talk about that later. From a clinical point of view, the manifestations of the disease can also give us an indication that the patient has more advanced disease. The bronchiexis severity index has been around for a long time, we published this in 2014, it's really stood the test of time, it's in all of the major guidelines, uh, as an important way to evaluate the disease, and it's included in all of the big randomized clinical trials. Um, so it's something that should be part of our evaluation of patients. So very severe bronchiexis leads to loss of weight, which is why BMI is a feature. It leads to loss of lung function, which is why FED1 is a feature. Hospitalisations in particular, the exacer frequent exacerbations are also signs that the disease is more severe. Breathlessness, uh, comes on because of lung destruction. Uh, and that is therefore a feature of severity of disease. As the disease becomes more severe, you're more likely to be, uh, infected with organisms, and Pseudomonas in particular, is one of those key organisms, and then radiological severity. So you add all of these things together, and you get a score, a score of 9 points or more is, uh, severe bronchiectasis. So an example of that would be somebody. With severely impaired lung function, um, a patient who's got MRC dyspnea score of 5, and a patient with pseudomonas, regardless of anything else, would get 9 points. Age plays an important role because this, uh, index was decided, uh, was developed in order to predict mortality and hospitalisations, and those are outcomes that are very strongly associated with age. So, if we apply this scoring system to our patient who's got, um, Uh, our 45 year old patient who's got idiopathic bronchiectasis, um, they actually score very low on the severity scale. So they're 45, so they get nothing for age. They've got a normal BMI, they've got an FEV1 of 111% predicted, so nothing there. They've not had prior hospitalizations. They're having 2 exacerbations per year, so they get 0 points on the exacerbation scale. Their breathlessness is not so bad that they get points for MRC dyspnea. They don't have pseudomonas, they do have Haemophilus, they get a point for that, and they get, they've got less than 3 lobes involved because it's involving the right and the left lower lobes only. So they get 1 point, and anything 4 points or less is mild bronchiectasis. So this is a patient that doesn't have very severe disease, but they've got a terrible burden of disease. They're very symptomatic, 2 exacerbations a year. So there's a disconnect here, isn't there? There's a, there's a disconnect in this term that we're using, severity. And what we're really talking about here is severity is how much damage has been done. And our patient is at an early stage of the disease. There isn't a huge amount of damage done yet. But the disease is very active, so our next question is how active is the disease? And I guess also as part of that, what do we mean by activity of the disease? So let's go through that. What do we mean by disease activity? Well, this is a well established concept in inflammatory diseases, and the, the, the originator of this idea is, is rheumatoid arthritis, where disease activity scoring is really a key part of, of management. It indicates the. extent of inflammation and symptoms. So we're not talking about damage, we're talking about how rapidly is that person progressing to damage. So if we think about that in terms of the hot, the hot red joints, these joints are not yet damaged or disabled, but without treatment, they're going to become damaged and ultimately remodeled, and you get the, the classic, uh, burnt out rheumatoid, uh, with deformity because the joints have been destroyed. So the activity of the disease indicates that patients are at higher risk of progression to disease and irreversible damage. So our patient who's 45 and has preserved lung function, but a lot of symptoms might be thought of as being currently undamaged, but on a fast track to getting severe lung damage if we don't do anything. So what causes that damage? So I, I just made the analogy with rheumatoid arthritis. Rheumatoid arthritis is an autoimmune, intensely inflammatory disease where immune cells such as neutrophils rush into the joints and cause a lot of tissue destruction. You can think about bronchiectis in the same way. In bronchiectasis, you get lung damage, you get, um, epithelial injury. These cells called neutrophils. Rush into the airwaves, um, they explode in the airways, forming these things called neutrophil extracellular traps, where webs of DNA come out, and those contain chemicals, which are very damaging to the lung, and some of those chemicals include neutrophil elastase, protease 3, cathepsin G, myelop peroxidase, pregnancy zone protein, azuricy, resistant. You don't need to know all of those, but it's important. To know that some of those are proteases, so they're chemicals that cut, uh, proteins and directly destroy the lung. Some of them cause oxidant stress, some of them disable normal function of the immune system. And so the intersections here that you see are, uh, with disabling of the normal mechanisms that would control bacteria, and so you're more susceptible to infections like Pseudomonas. Lose some of your body's natural antibiotics, because these are destroyed through the process of the release of these chemicals. And very important for bronchiectis, the main driver of release of mucus from your epithelial cells are these, these neutrophil proteins. So you make too much of these mucins, including the, uh, the pro-inflammatory mucin Mach 5AC. And you get more secretory cells, more goblins. Cells that release mucus. So that all results in significant epithelial damage, uh, and ultimately, progression of the disease. So that's the vicious vortex in, in reality. And it is all initiated by an inflammatory process. So it's not unreasonable to think of, uh, bronchiectis as an inflammatory disease and to use these kinds of inflammatory disease concepts like disease activity. So that is the vortex, uh, and the vortex is interconnected, meaning that all of the different components amplify each other to lead to disease progression. But we've got ample evidence that neutrophils are central to this. Uh, if we take just the inflammatory component, we can measure markers of inflammation in the airways through sputum, for example. In 2018, we published this paper where we measured sputum. Neutrophil elastase and we were able to show that patients that had higher levels of elastase, had a higher frequency of exacerbation, uh, compared to patients that had low levels, proving that neutrophilic inflammation was an important driver of exacerbation. People who have more severe disease as reflected by higher exacerbations, more hospitalisations, worse lung function, have different proteins in their airways, and those are those neutrophil extracellular trap proteins that I mentioned before, including neutrophil elastase, um, azurocybin, uh, the the matrix metaloproteinases, and others. So there's a key link between inflammation, disease activity, disease severity, risk of exacerbation, and outcomes. Uh, inflammation is key. apart from that direct measure of inflammation, what other markers do we have of disease activity? Well, we've done studies using CT scan, uh, as I mentioned earlier, CT is central to our assessment of people with bronchiectis. In this study, we had CTs. From all over Europe, the Netherlands, Italy, UK, Israel, Belgium, France, uh, and after filtering, we ended up with 524 CT scans that underwent scoring with an algorithm, uh, which included assessment of, uh, multiple factors including mucus. This is what we saw, so this is a, uh, a graph where 100% of the lung, uh, is scored, uh, and obviously most of the lung, even in a patient with severe bronchiectis is healthy, thankfully, but the disease goes from patients that have very small amounts of disease, meaning just small amounts of airway is abnormal, through to people that have almost the whole lung, uh, damaged. But what grabs your eye here is the yellow color, doesn't it? And the yellow color is mucus plugging. Um, there's loads and loads of mucus plugging on these scans, uh, and that's abnormal. You shouldn't see lots and lots of mucus plugging. So, um, uh, there's, this is a, a core feature of bronchiectis. There's also a lot of inflammatory change that's not mucus related. Uh, they tend to go together, and I'll show you that on the next slide. We looked at factors that were associated with these inflammatory changes, uh, and what this shows is, uh, Total bronchiectis, mucus plugging, and total inflammatory change. What you see is that many groups of patients have a lot of inflammation, even if they don't have markedly more bronchiectis than anyone else. Primary ciliary dyskinesia, the genetic cause of bronchiectis, they have impaired mucus clearance, so maybe not surprising they have more mucus. People who exacerbate have a lot more mucus and inflammatory change. Likewise, people with NTM. Um, people with pseudomonas, you can see, uh, more bronchiotaic, uh, still a lot of mucus, but not quite so, so dominant. The longer you've had the disease, you have more mucus plugging, um, and so on. So there's a, even after adjustment for age, sex, uh, and other factors, you find groups of patients, exacerbators, certain etiologies, certain infections that have a lot of mucus plugging, uh, and infective change. So the CT scan. Identify patients that are more likely to progress and do badly. Uh, and I mentioned in our case presentation that despite having mild radiological disease, our 45 year old lady had severe, uh, mucous plugging, suggesting lots of inflammation. What else can we use to evaluate inflammation in these patients? Well, uh, an obvious one is the prior history of exacerbations. We know that the best predictor of future exacerbations is prior exacerbations, and that was shown nicely in this study that was recently published from the Embark registry, which includes over 20,000 patients, a real powerful resource for observational research in bronchiectis. Um, so using patients with zero exacerbations at baseline as the reference, you can see that your chance of having another exacerbation markedly increases the more exacerbations you had in the previous year. So you're 3 times more likely to have an exacerbation, uh, if you had 5 exacerbations in the last year than if you had 0. not, not rocket science makes sense, but it tells you that prior exacerbations are a predictor of the future. But even if you take into account prior exacerbations at age, underlying cause of disease, and so on, the severity of symptoms also predicts exacerbations. This is the quality of life bronchiexis score. It's a questionnaire that asks about symptoms like sputum, uh, and cough. Uh, 100 is, is no symptoms at all. 0 is the worst symptoms you can imagine. Uh, and so it goes all the way up from 100 to 0. And what you. See is as the symptoms get worse, the number of exacerbations increases, uh, independent of prior exacerbations. So a patient who comes to you, like our 45 year old patient who's coughing up lots of sputum, feels really awful, that patient's going to do badly and have lots of exacerbations regardless of any other factors. Uh, symptoms. Indicate disease activity. How are they linked to inflammation? Well, I told you in a previous slide, what's happening is those neutrophil proteins are driving the body to make more mucus, that's presenting as lots of mucus symptoms and cough, and so you've got a direct link here with inflammation, higher scores on this questionnaire means more inflammation. You don't just have to take my word for this, this is actually recognized in the international guidelines. The ERS bronchiexis guidelines for 2025, uh, included for the first time this concept of patients at risk of exacerbation, and they identified subgroups of patients that are more at risk, and those include certain etiologies like COPD, PCD, and rheumatoid. People infected with pseudomonas and other gram-negative infections, patients with a high prior history of exacerbations, patients with severe symptoms, NTM infection, and ABPA, and all of that, I've shown you the evidence that supports that all of these groups of patients are at higher risk and tend to have more disease activity, and that's what we're talking about in all of this is disease activity. So to put all of this together, in previous years and in previous guidelines, um, we would have said we should be initiating treatment on patients that have low lung function, that have 3 or 5 exacerbations per year, um, that have very bad radiological disease. We were very focused on severity. So if you draw a plot here of disease severity, which is uh marked by reduced FEV1, extensive varicose or cystic bronchiexis, things like pseudomonas infection, or disease activity, which is very much symptoms, exacerbations, inflammation. Obviously patients that are already very severe but also very active are a priority for treatment, they're gonna do badly. We also tend to aggressively treat those patients that have high severity, even if they've got low activity. You could argue those patients are less likely to respond to treatment because much of the damage has already been done. The group our patient falls into is low severity, high activity. They're like the rheumatoid arthritis patient that still has their joints intact, but their joints are hot and red, uh, and being damaged. They arguably are the patients that are most, uh, at risk and therefore should be the top priority. For therapy, because we have a chance to prevent them ever becoming in the red group. Um, and so we tend historically to have focused our attention here, and I really think we should also be focusing our attention here on patients like our 45 year old, um, that I presented at the beginning of this lecture. So our patient has high disease activity and is at risk of progression. So having identified that, we now have to ask ourselves the question, beyond airway clearance, which our patient is already doing, what can we do to help her? Well, we go back to our vicious vortex and our path of physiology model. We've got 3 key components of the disease that we want to target. There's an infective component, and that's historically been the focus of a lot of our, uh, therapeutic development and a lot of our research. We have an inflammatory component that we think is absolutely central, and then we have the mucus, uh, and our patient has terrible mucus symptoms, we're doing airway clearance, and it's not helping. So what can we do across all of those areas? Well, the, I go back to the ERS guidelines, which have very helpful, uh, algorithms for what you can do across these. Different components. Our patient has Haemophilus influenza infection, um, so they have an infection problem. The guidelines recommend strongly, 2 ticks means a strong recommendation, 1 tick means, uh, a weak recommendation, cross means, uh, recommendation against, uh, and the quality of evidence is indicated by the number of crosses. It the, the guidelines recommend inhaled antibiotics, but primarily for people with pseudomonas, and our patient doesn't have pseudomonas. The guidelines recommend pseudomonas eradication with a conditional recommendation. Our patient doesn't have that. So, uh, at the moment, it doesn't look like this box helps us very much. What about inflammation? Well, we really lack good quality non-antibiotic anti-inflammatories, or we did until. Recently, inhaled steroids have no clear role in bronchiectasis. Long-term macrolides have good evidence, and I'll talk about them, them in the next slide. Um, they have an anti-inflammatory effect, um, so they may be an option here for our patient. Our patient's already doing airway clearance. Mucoactive drugs can be helpful in severe refractory cases, but there's recent trial data showing very limited effect, uh, and we don't use recombinant DNAs. Pulmonary rehabilitation can be very helpful to reduce symptoms of breathlessness, but it's not going to change the trajectory of this patient who's got lots of inflammation that we need to tackle. So the best evidence that we have up until recent years has been the, the long-term macrolides. The amount of data's not huge, it's only about 350 patients' worth, uh, but they did show a marked reduction in exacerbations across 3 trials that were pulled together in an individual patient meta-analysis. Inhaled antibiotics also work predominantly for people with pseudomonas, uh, and they have been tested in more than 16 trials with a just under 20% reduction in exacerbations, um, despite high heterogeneity. So these drugs do have a role, um, and may be an option for our patient. The algorithm that we have in the ERS guidelines, uh, suggests, firstly, optimizing bronchiectis management, which, which I emphasize is very important. Including for our 45 year old patient, you would want to make sure she's doing airway clearance correctly. You would want to treat any underlying etiologies, which we've talked about, comorbidities, make sure they're up to date with their vaccinations, um, to prevent, uh, respiratory infections. You might also want to treat things like chronic rhino sinusitis, gastroesophageal reflux disease. These are common accompanying symptoms or comorbidities in people with bronchiectis. Our patient is at high risk of future exacerbations because she's having 2 exacerbations per year, and she has severe symptoms, so she's identified as a patient at increased risk. Uh, and then the algorithm asks, does she have pseudomonas, and she doesn't have Pseudomonas. So the first line therapy here would be a long-term macrolide in the guidelines. Um, but there's lots of caveats to this. Uh, macrolides are not suitable for everybody. About 1 in 5 patients may experience gastrointestinal symptoms. Some patients, uh, have hearing problems with macrolides, and they're not suitable for patients, uh, who are at high risk of having NTM because of the risk of inducing resistance. For many patients, this will not be an option, which leaves us with very limited other options in a patient like this. Um, until recently, this was the extent of the The therapeutic options that we had. So the field has been crying out for more effective, not, uh, and non-antibiotic based anti-inflammatories. To enter, uh, the power of, of research and the power of clinical trials, the power of experimental medicine, bronchiectasis in the last 10 to 15 years has experienced a surge in clinical research that has led to important breakthroughs. The Recognition of the disease as an inflammatory disease that needs to be targeted with anti-inflammatory therapy, or I like to say immunomodulatory therapy, uh, has transformed how we think about the disease. The DPP-1 inhibitors, are also known as cathepsin C inhibitors, are the first disease-specific therapy that has been approved for the treatment of bronchiectis. As you can see from the graphic, there's many others. Mechanisms that are currently in clinical trials, uh, or theoretically could be used to target the inflammatory process in bronchiexis. But with the centrality of the neutrophil proteases and the, the granule proteins to the disease, and their link with mucus production, etc. uh, they are an excellent candidate for an anti, uh, neutrophil targeting, uh, disease modifying therapy. So we're gonna focus on uh where could we find the role for these um anti uh DPP one inhibitors. What is DPP1? Dipeptidy peptidase one, is a, uh, a protease that activates the other neutrophil serum proteases during neutrophil maturation in the bone marrow. So as neutrophils are maturing, Uh, the serum proteases are packaged into granules, um, and they're activated at the point at which they're being packaged because they're very toxic. The body wouldn't want to make them as they're activated. And so if you block that process using a DPP1 inhibitor, the neutrophils are released into the blood, but with less of these proteases available. The neutrophils will then migrate into the lung, uh, because the patient has bronchiexis, but they'll be less inflammatory, and so it calms down that excessive inflammatory response and therefore resets the immune system to a more normal state. And that's why I like to call them immunomodulatory because they don't suppress the immune system, um, there's no evidence at all that they increase the risk of infection. What they're doing is calming down, uh, an exaggerated immune response. And so, um, the DPP-1 inhibitors have been tested in a series of clinical studies, um, globally, uh, and the one I'm going to focus on is the phase 3 aspirin trial because it's by far the largest, and it's the one that has led to the approval of renzakib as the first. Disease modifying therapy. So this was a phase 3 double-blind placebo controlled study over 52 weeks of two doses of renzicattib, 25 mg and 10 mg once daily. It was tested against placebo. Patients were randomized 1 to 1 to 1. Uh, it was, uh, stratified by pseudomonas infection, number of exacerbations and geographical region, and the primary outcome was the frequency and exacerbations over the 52 week period. This trial followed on from a successful phase 2 trial called the Willow Study, which had shown a significant reduction in exacerbations at both doses. So if we look at the primary outcome on the left hand side, what you see is a significant reduction in the frequency of exacerbations of both the 10 mg and the 25 mg dose compared with placebo. Uh, the magnitude of the effect is approximately 20%, and there's no meaningful difference between the 25 mg and the 10. And that mirrors what we saw in the, uh, the Willow study, and it's consistent with what we know about these drugs. What I will say is because the drugs work in the bone marrow and it takes time for new neutrophils to come out of the bone marrow, these drugs take some time to work. Look how the curves don't separate until about 16 weeks, so they separate late. That's probably important when we're thinking about using these drugs, that we have to counsel patients, that they're gonna take a bit of time to work. If we look at the lung function though, we do see a difference between the 10 and 25. We didn't see any difference in the um exacerbation frequency, but we see here, firstly, key message, bronchiexis is a progressive disease, look how the lung function gets worse. Over the 52 weeks in the placebo group. A reduction of 62 mL is far more than you would expect in the general population. So, bronchiectasis is a progressive disease, we learned this, uh, uh, in a very, very high quality data set from the Asmin trial. There's no difference here in the 10 mg, it's not slowing down progression, but there is a clear slowing of progression in the 25 mg dose. Uh, the between group difference is 38 mL, which I think is clinically relevant. We also saw differences in the exploratory endpoint of forced vital capacity. So that suggests that the 25 mg dose is giving us some benefit. Um, these results led to the approval of renzacatetib, uh, both by the European Medicines Agency and by the FDA. Interestingly, the FDA approved the 10 and the 25 mg, whereas based on those lung function data, the European Medicines Agency only approved the 25 mg. I really do think if I was uh going to be using renzakib, I would want to be on the 25 mg, not just because of the lung function benefit, but also because of the secondary endpoint and exploratory endpoints of symptoms showed a benefit of the 25. This is a daily diary that was done during the, uh, the, the Aspen trial. The first trial to do this, and it's really beautiful data, um, it's called the Best Diary. Uh, it takes about 28 days for the full effect of those new neutrophils washing through into the lungs to happen. And so look at what happens with the symptoms here. So the 10 mg, the placebo, and the 25 are exactly the same for the first month. And then at about exactly 4 weeks, exactly when you expect the, the treatment to kick in, the new neutrophil effect to kick in, you see a reduction in symptoms, but only in the 25 mg group. And that continues for the rest of the trial. So there's a clear effect on symptoms that fits with the pharmacology of the drug, but only at the, the, the dose that's having the largest effect on neutrophilic inflammation, and that's the 25 mg dose. So, uh, again, I think the message is that there is a benefit of, of taking the 25 mg versus the 10 mg. With any new, uh, with any new treatment, safety is a key consideration, and there are some cautions with renzakib, but in general, it's safety profile is very reassuring. The, the overall frequency of adverse events was very similar between the renzicib treated groups and the placebo groups. There is a rare genetic syndrome called Papillion LeFevre syndrome, which is caused by loss of function mutations. in DPP1, so it gives you a prediction of what would happen if you completely inhibited this enzyme, which renzakib doesn't do. So we look very carefully for these side effects. Um, these are hyperkeratosis, which is thickening of the skin, periodontitis, inflammation of the gums, or severe infections. We see no signal on severe infections at all, you can see pneumonia is most common. In the placebo group. For periodontitis, there's no signal, the highest number is in the placebo group. The one side effect that does happen is hyperkeratosis. Uh, it's rare, um, in the, uh, even at the 25 mg dose, there's only 17 cases in 574 patients, and only in one case did it lead a patient to discontinue the treatment. But it is something that we're gonna have to warn patients about with these medications, because skin effects do happen. They're manageable. Patients don't have to stop the drug, um, they often will go away by themselves, or if they don't go away, a short interruption to treatment seems to allow them to go away, and then if you restart the drug, the, the skin effect often doesn't come back. So that's all very important from a clinical perspective. What are these drugs really doing? They're obviously highly effective. I started this uh this presentation with the story of the disease activity, whereby inflammation drives mucus obstruction. Well, that's what these drugs are doing. Really nice translational research shows that. So there are, uh, important components of the immune system that are involved in mucus. Uh, this protein. Called azurocybin paralyzes the cilia, the hairs that clear mucus from the airways. So high levels of this mean more mucus obstruction. And look, renzicib takes away that protein. It goes back, uh, almost to normal once you stop the drug, between 24 weeks and 28 weeks, the drug's being stopped, but for the period you're on the drug, it's stopping that impairment of ciliary function. And then MachC5AC is that pro-inflammatory mucin that I mentioned earlier, and again, this goes down, uh, in both renzicid doses, but particularly at the 25 mg dose by week 24 in the phase two trial. So maybe the reason that the 25 mg dose is better for symptoms and lung function is because it has a bigger effect on mucus. I think that's potentially really important. Do we have any? Any other evidence that that's the case? Well, there was a small CT substudy within the Aspen trial. This is where patients had a CAT scan at the beginning and the end of the trial. Uh, and within that, we were able to use that same 0 to 100% scoring system to look at mucus plugs. And this is bronchiectatic airways with mucus plugs change over 1 year. You can see the placebo group gets worse. The 25 mg dose. The dose gets a lot better. And that's also the case for healthy airways that have mucus plugging, where the 25 mg dose really made a bigger difference, and that results in more healthy lung in the 25 mg dose. So the CT study, although it's small, it's 100 patients, supports this idea that the 25 mg dose is having a bigger effect on mucus, and that may make it a disease modifying therapy, which is really important. So we're arriving at a new, uh, a new era for therapeutics in bronchiectasis. It's not just the fantastic results with renzakib that have led to, uh, approval. Uh, we've also got another compound called verducatib, uh, BI 1291583, that's now in phase three, trials as of this year, uh. And a further compound that's called fluensicaib, that's just entering phase 3 trials now. Um, and so, we've gone very rapidly in bronchiexis from recognizing this disease as, as primarily an inflammatory problem, to now having FDA approved therapies. And hopefully it will be the, uh, renzicib will be the first of many. We do still have a number of unanswered questions about DPP-1 inhibitors, so I, I think our patient, going back to our 45 year old patient who's got very high disease activity, frequently exacerbating, they would be a great candidate for this therapy because of the, the potential effect to preserve lung function and prevent their exacerbations without using antibiotics, but we do have a number. Of, uh, a number of unanswered questions. We still don't know which of the groups of patients that respond the best. Um, our subgroup analyses within the Aspen trial showed almost every group behaved the same. The one exception was patients from, uh, East Asia who did extremely well, and we, but we don't know the reason why they have a, a greater effect, and up to 60% effect. Uh, the Kaplan-Meier curves, which I showed you earlier, um, they tend to separate late, we don't know why. We know the effect in the bone marrow takes about 28 days, but it takes about 3 months for the drug to have their biggest effect. We don't really know why. Um, we need more studies in very early disease because all of the patients in the aspen trial had to have at least 2 exacerbations at baseline, uh, so is there a benefit in patients with even earlier disease than that? Um, and the one other big unanswered question is what happens to infections in patients who are on these drugs long term? Do we see less pseudomonas, do we see lessenophius, because we're managing to normalize, um, the inflammatory response. So there's lots of really important research still to be done in this area, uh, and it's great we'll be able to do that because, uh, these therapies are now advancing into further, uh, further clinical studies. So the way I want you to think about bronchiectis is as a, as a chronic inflammatory disease, uh, where severity of disease is important, that means how much damage has been done to the lungs, but our goal should actually be to prevent damage to the airways. We should be looking, uh, at patients like our 45 year old, uh, as an opportunity to prevent patients leading to end stage lung damage. Uh, the analogy. I always use is of the house that's on fire. Um, once the house catches fire, it progresses rapidly through the house, and eventually the whole house will be burnt down. The earlier you put the fire out, the less damage that will be done. The neutrophils are the fire. The neutrophils are the driver of inflammation. Uh, and so the best approach is to target the neutrophils, uh, with these novel anti, uh, neutrophil targeting drugs. So it's an exciting time for bronchiectis. My, my concluding slide is that, um, clinical trials have never been more important for people with bronchiectis. So the other thing that I always discuss with my patients, uh, in addition to these novel therapies, uh, and our existing therapies, are to participate in clinical trials because that's the way that we will get more. uh, licensed therapies for this disease. And it's a really exciting time that there are dozens of, uh, active clinical trials with novel anti-inflammatory therapies, uh, currently in trials in bronchiectasis. Um, so I think bronchiectasis will be held up in future years as a, uh, an area where respiratory medicine has really advanced because Of translational science, translational medicine, uh, which is really now being translated into, uh, benefits for our patients. Um, so with that, I'd like to thank you very much for your attention, uh, and for participating in this, uh, this webinar on anti, uh, inflammatory therapy for bronchiexis. Thank you. Published July 20, 2026 Created by Related Presenters Professor James Chalmers Professor (Clinical), Molecular and Clinical MedicineSchool of MedicineUniversity of Dundee School of MedicineDundee, Scotland, United Kingdom
