Video Early Intervention, Reducing Exacerbations, and Emerging Evidence for Oral Therapies Based on DPP-1 Inhibition in NCFBE Play Pause Volume Quality 1080P Fullscreen Captions Transcript Chapters Slides Early Intervention, Reducing Exacerbations, and Emerging Evidence for Oral Therapies Based on DPP-1 Inhibition in NCFBE Overview Click to take Test Back to Symposium I'm Michael Loebinger. I am one of the host defense consultants at the Royal Brompton Hospital in London and also work at Imperial College in London, and I'll be talking today about non-cystic fibrosis bronchiectasis and in particular, focusing on the neutrophil-based targeting as part of the management for that. I'm going to split the talk up as follows. I'm going to start just giving a little bit of background with regards to bronchiectasis and then move quite quickly into a case history which I want to use to illustrate some of the issues with management and some of the things that I then want to go on to discuss. I'm going to then talk about disease activity, which is a rather new concept which has come up over the last year or two with regards to deciding on which patients to manage with bronchiectis and when. And also tied intrinsically with this is, is the concept of inflammation and bronchiectis, which I will also talk about um as as a major part of the talk. OK, so what is bronchiectasis? So as you know, it is the irreversible dilatation of the airways, and this causes manifestations clinically with cough, sputum production and recurrent chest infections. It used to be diagnosed with the use of bronchograms, which used to provide these really nice pictures that you can see on your screen there. But for many decades now, has been diagnosed with enlarged um dilated bronchi on cross-sectional imaging CT scan. And in fact for the diagnosis of bronchiectis there was a consensus group which was published in The Lancet Respiratory Medicine a few years ago, talking about some of the criteria that you would need both radiologically, which um leant on some of the Fleischner guide Society guidelines previously, but also the need for clinical suspicion of bronchiectasis with some of the symptoms that I mentioned before. It is becoming much more important and hand in hand with that, with that is the increased prevalence, which is understood now. So, a decade ago, it was thought that the prevalence was about 50 per 100,000, but actually more recent studies have suggested that the prevalence is 10 times that and actually about 500 per 100,000, and so about 0.5% of the population may have conflict. OK, so moving on for the, from the background, let's talk about this clinical case which I want to use to illustrate simple things. This is a 48-year-old female who was well as a child. She started to develop for the first time cough and sputum at about the age of 35. And she went and had some cross-sectional imaging that you can see there on the panel and was diagnosed with mild bronchiectasis. She had an etiological screen that I'll talk about in the next few slides, but no cause for the bronchiis was found, and her general management was essentially physiotherapy. She had no specific growth of uh particular microbes in her sputum, um, and really suffered with about 2 chest infections per year which were treated with acute antibiotics. She then, when I started seeing her, started to become a lot more symptomatic. And so that brought on the questions of what to do, and the first thing is how would you assess a patient like this, both perhaps originally, but also when they start to deteriorate. And in thinking about the assessment, I think about different types of investigations to do, and I think it's important to think about doing an updated CT scan, spirometry, and then to think about whether perhaps other investigations such as an echocardiogram might be necessary. This is to both update some of the baseline investigations, also to look for any evidence of objective deterioration to go with the increased symptomatology and to perhaps correlate some of the symptoms to changes in some of these test results. Blood and sputum are also important. Firstly, to make sure that there are no underlying etiological causes that haven't been looked for before that may be causing or driving the bronchiectasis, but also to make sure that there's nothing new which has developed, a new microbe, for example, or the development of perhaps ABPA on top of the bronchiectasis. The underlying etiology is important, and this is something that I've mentioned a few times so far. This is the etiological pie chart from the Embark registry, which is about 15,000 patients across Europe, and you can see that the majority of the time, actually, the cause of bronchiectis is termed either idiopathic, we don't know, or thought to be. Secondary to infective causes, but other than that, there are a range of different possible causes of bronchiectasis where the treatment may differ substantially. So immunodeficiency, for example, ABPA, bugs, for example, non-tuberculosis mycobacteria, all those would have very specific managements enhance if somebody isn't doing well or doing less well, it is important just to think about this again. And this is nicely shown in, in this table from the recent European Respiratory Society bronchitis guidelines that were published at the end of last year, which shows that when you are thinking about bronchiis patients and the cause of bronchitis, it's important to do some of these tests in the blue panel, particularly looking for things such as ABPA or immunodeficiency or NTM causing it. And then if there are very specific features in the history, perhaps that may be suggestive of cystic fibrosis or PCD or autoimmune disease, then to perhaps go on and do a more specialized tests on it. Anyway, these assessments were done in this patient, and really the main thing that came out was the deterioration or the change in her CT scan. So you can see the original diagnosis CT scan on the left and then on the right, you can see there's a lot more in the way of mucus plugging, the walls of the dilated bronchi are much thicker, and there's um some uh tree and bud and nodular change on top of that. In the other tests, there was no sputum growth still, so no specific microbe. And so from a management point of view, she was watched quite carefully. Her physiotherapy was optimized, and she was started on long-term azithromycin. So it is worth thinking about the management of this patient through the lens of the recent ERS guidelines, and they nicely provide this diagram showing the vicious vortex here. where management can be split into the various different areas that can drive the pathophysiology of bronchiosis. So infection, inflammation, impaired mucociliary clearance, and lung damage. And within this patient, you will see that we thought about the impaired mucociliar clearance by optimizing the physiotherapy. They didn't have from an infection point of view of specific. Specific microbe and specifically didn't have pseudomonas, but we did want to do something within this inflammation and infection sphere and that's why we use uh long term macrolides or azithromycin which have both an inflammatory or anti-inflammatory rather impact but also um er er an antimicrobial impact as well. So that's how we, we manage that patient. But it is interesting if you think about this patient and when you start thinking about actually the severity of the bronchiectasis, the severity of the bronchiectasis as termed by some of the uh the criteria and here is the bronchiois severity index, would have been very low. If you look through this, her age was less than 50, so no points. She had a normal BMI, so again no points. Um, her FEV. One was normal, um, she didn't have any hospital admissions. She had 2 exacerbations per year. Um, Her MRC dyspnea score was, was low. She didn't have pseudomonas or other organisms, and actually she just had lower load bronchiosis. So you could quite easily get a score of 0 or very low uh bronchiectasis severity score, despite the fact that she wasn't doing that well or had become more symptomatic. And it's interesting actually if we look back on the previous guidelines, because the previous guidelines would have suggested, these were the ERS guidelines from 2017, and they would have suggested long-term antibiotic treatment or macrolide treatment like we gave only for patients who have had three or more exacerbations per year. So strictly using the old guidelines, even though we decided to give this patient azithromycin, strictly using the old guidelines, she wouldn't have um met the criteria. And what's changed is really the concept of activity and the activity of the bronchiotis, so less, I suppose the severity, which is what was being measured by the bronchiotis severity index, and more how active the bronchiotis is at any one time. And going back to her CT scan, I'm sure you will agree. That this is an active looking scan. The wall thickness, the nodules, the, um, the uh nodular consolidation, the tree and bud, all, all hint and all look towards quite a, an active process and one that is on the move and needs something doing for it. And this has been nicely illustrated through these pictures of a house on fire in relation to different bronchiectasis scans by Marretta Long in The Lancet respiratory Medicine article. And you, you will see that the concept of severity is thought of as like a burned down house. So there was a lot of damage to that house on the right panel, a lot of damage to the CT scan above, whereas actually, perhaps the time when you need to actually be. Intervening is when the house is on fire, when you can actually do something to stop the irreversible change, and that's what is meant to be illustrated in the middle panel with the burning house, but also in the panel with the active looking CT scan, not dissimilar to our patient. And you can see this nice matrix here whereby severity is highlighted by disease on the scan by FEV1, whereas activity is more uh denoted by things like sputum purulent, yes, frequency of exacerbation, but also the severity of daily symptoms, which is what was getting worse in this patient. And that's really led to a change um in the present guidelines, so these ERS guidelines from 2025, um, as I mentioned, whereas previous guidelines recommended them for 3 or more exacerbations per year, the present guidelines at the bottom here are for patients at high risk of exacerbations, including patients with 2 or more exacerbations. or one severe exacerbation, or, and importantly for this case, one exacerbation plus severe daily symptoms, which is what she had developed with the other high risk groups mentioned here in this table, and you can see the two or more exacerbations or 1 severe exacerbation and the severe symptoms, both leading towards the patient being denoted as high risk. And some of that concept of high risk for patients with high levels of symptoms was based on this paper uh that was also published last year. In the lantern respiratory Medicine by Oyel Sabila's group, and they showed, uh, both within the EARk cohort, but also as a post hoc analysis with the three macrolide randomized controlled trials, um, that, um, patients with high symptom loads uh actually had just as high relative risks of exacerbations in the future as those who had had previous exacerbations, and that's some of the evidence on which these new guidelines are based. So look, going hand in hand with both what that scan looked like, but also with this concept of activity and active disease and trying uh to actually manage patients at the correct stage of their development is, is, is this concept of inflammation. And you will have seen inflammation on the vicious vicious vortex um diagram um previously um from the guidelines, but um, certainly in the past, the majority of studies and randomized control trials were done predominantly looking at the reduction of infection as opposed to inflammation. Now we know that inflammation is important to the bronchiois. We know that there are high numbers of neutrophils in the airways, and we know that these can produce extracellular nets. They can produce the release of neutrophil serum proteases as shown in this diagram here, such as neutrophil elastase, Capsin G, protease 3, and that these can cause damage to the airways in multiple ways. They can cause extracellular matrix degradation. They can cause an expression of B 5 AC and goblet cell hyperplasia, so more mucus secretion, they can impair ciliary function, um, and they can also reduce, uh, the host events as well. And we also know that patients with higher levels of inflammation here measure those higher levels of neutrophil elastase, one of the neutrophil serum proteases, that that can also be associated with severity and outcomes here shown in exacerbation. It, uh, related to different levels of neutrophil elastase. So it's always been a target which has been of interest and certainly some of the early work here looked at drugs aiming at reducing the number of neutrophils by targeting chemotactic factors uh to stop neutrophils going into the airways, um, and a couple of studies there actually, um, had shown, um, some negative results and seemed to impair the immune response to infection. But actually targeting the release of these NSPs may have been a target, and there was some early work um there that was done with an oral neutrophil elastase inhibitor, which had results which were quite difficult um to interpret, but. What, what has uh has happened within this field within the last couple of years or so was the use of DPP1 inhibition, which actually targets the process much, much earlier, much further upstream. So DPP1 is interesting, it's a cysteine protease which, uh, its key function is to cleave dipeptides from the M terminus of proteins. And this is significant in relation to these neutrophil serving proteases because as they mature, um or as neutrophils mature in the bone marrow, NSPs are synthesized in an inactive form, and they require this cleavage by DPP one in order to become active before they're packaged. And so if DPP one is blocked. As you can see in the cartoon here by a DPP1 inhibitor, then these neutrophils, when they mature, do not contain active um NSPs, they don't contain active neutrophil elastase, peptin G, and proteinase 3. So the neutrophils themselves still work, but when they release some of these damaging proteases, they um uh are non-activated. And because of that, there has been over the last year or two, lots of interest in clinical trials, and the main one here, uh, which I will talk about is the Aspen trial, uh, which is from the New England Journal of Medicine, and that was a phase 3 trial looking at the DPP1 inhibitor benzacatin. And there have also been a couple of other DPP1 inhibitors in the phase 2 stage which I will also mention. So talking now about the benzacatetib study, uh this was a phase 3 trial which randomized 1 to 1 to 1 for adults um into 10 mg of benzacateb, 25 mg of benzacateib or placebo. The treatment period was for 52 weeks with enough treatment of 4 weeks. To be included in the trial, patients needed to have bronchiectasis, they needed 2 exacerbations per year, uh, they needed to have muc equivalent or prevalent sputum color, and they needed for COPD or asthma to not be the primary diagnosis. And what did this show? Well, this met its primary endpoint, the main primary endpoint was the uh significant reduction in exacerbation rates over the 52 week period with uh the magnitude of effect um on the frequency of exacerbations was similar here between the 10 and the 25 mg group with about a 21% reduction, um, uh, in the 10 mg and the 19% in the 25 mg group compared to the placebo. They also both had a significant improvement in the time to first pulmonary um exacerbation during the study. There was a significantly increased number of patients that had no exacerbations during the study. And then there was also some intriguing spirometry results. These were significant just in the higher dose in the 25 mg arm where you can see that the reduction over the 52 weeks of the FEV1 here um in patients was significantly reduced compared to both placebo and the and the 10 mg arm. There was also some nominally significant improvements in quality of life um QOLB in the 25 mg um arm as well, those effects were not seen with the 10 mg dose. So moving on to the other phase 2s that I mentioned. So the second one was with um a different type of DPP1 inhibitor and the inclusion criteria were slightly different here. So here you needed two exacerbations or similar to what I mentioned with regards to the guidelines before, one exacerbation but a high symptom load. And there were no COPD or asthma restrictions within this, and you can see much less numbers of patients. It was about 1600 patients in the phase three study because this is a phase two, there's only 322 patients here. Different doses, 1 mg 2.5 mg, and 5. Milgram and this also uh met the primary endpoint. The primary endpoint in this study was quite complex. It was a dose response analysis which showed a significant dose dependent benefit of the IMP on prolonging the time to the first exacerbation um up to week 48. Um, the magnitude of the benefits was about 30%, which was similar to the phase two, Brenzatib study in Willow. Interestingly, several secondary endpoints, including frequency of severe exacerbations, lung function and symptoms appeared more favorable. With the 2.5 mg dose rather, rather than the 5 mg dose and it's the 2.5 mg dose which has gone forward into, into the um activity uh phase three study um um labeled as verduated or or sorry termed as verdu cat. The final study was a DPP-1 inhibitor which was again done as a phase two. Here the inclusion criteria was the same as the Brenza Katib study, 2 different doses, one placebo, 1 to 1 to 1 ratio again. Here the treatment period was only 24 weeks, um, and it was just um in patients in China. And here there were very significant uh results, so in 210 patients, the reduced exacerbation frequency was 48% and 59% over six months with uh both the 20 and the 40 mg um uh um IMP versus placebo respectively. Uh and there were additional benefits also which were observed. There was a reduction in sputum volume at both doses but no significant effect on lung function or quality of life questionnaires. So overall, with these three studies together, there were no significant safety signals. Um, they were well tolerated. There was a small increase in skin related AEs in the main phase 3 study, there was a slight increase in hyperkeratosis, um, in the active arms which were predominantly mild to moderate, with only 1 case leading to, uh, discontinuation. There was no increased infection signal in any of the studies. And the phase 3 study has led to the first licensed drug in bronchiectasis, the Brenzoti study. Um, it's now labeled as rinsuri, and you can see the different labels here. So the FDA label is quite broad. It's indicated for the treatment of bronchiectasis in those aged 12 and older at. Either the 10 mg or the 25 mg one. The EMA and and MHRA um guidance is for those with two or more exacerbations with bronchiectasis, um, in the prior 12 months. Um, um, so slightly different and it's just at the 25 mg, um, dosage. So, when should we be using, which patients should we be using, uh, these, uh, DPP-1 inhibitors, the anti-inflammatory agents in the future? So, the phase 3 study, the Aspen study tried to look at this. This is not meant for your reading, but it's meant to show you all the predetermined analyses that were done within the various subgroups and to show that everything to the left hand side in the blue bar showed that it was positive or favored the use of Gwentate within the different types of subgroups on the Left on side and the same with the Purple Armor as the 25 mg, and just to point out some things, um, it seemed to benefit patients whether they had three or more exacerbations or just two, whether they were on antibiotics before as chronic use or not, whether they were on maintenance before or not, whether they had pseudomonas or not, and irrespective of the um severity, and that was shown through some of the other studies as well. So didn't really help to definitively define a subgroup of patients that may benefit but the benefits seem um to be wide. Then obviously what this has done is it's opened up the whole area of inflammation to other potential targets. So you will see um in the top, well, it's sort of in the middle at the top, um the DPP1 inhibitors and how they impact um on the. Uh, on the protease, uh, on the NSP releases, but there are various other studies now also looking at different things. So, uh, there's PDE 3 and, uh, 4 inhibitors, uh, that are being studied. There are anti-IL 33, um, inhibitors, so lots of different areas now that can be looked at looking at inflammation and the concept of management for bronchiectasis. It is important, however, I've spent a lot of this talk talking about uh inflammation and particularly neutrophil driven inflammation, but it is important not to forget the other part of the vicious vortex, um, and infection. And just to slide on that, um, it is, it is important as an etiological cause, it's important with burden of treatment, and it's also influenced with regards to severity and mortality. We know that about 20 to 30. 30 % of our patients have Pseudomonas, and we know through a whole variety of studies that Pseudomonas is harmful to end points, both with regards to morbidity, also with regards to mortality. And so having some of these microbes is important. We also know that the higher the bacterial load, the more that there is inflammation. So you don't just want to target inflammation, sometimes infection driving that is also important as well. And with that, probably the most recent study um published a year or two ago now was that those studies um for premixing, um, the Pro one and two studies, and, um, they were, uh, two similar studies. Promise one, showed a significant reduction of 39% of exacerbation rates, which obviously is, is quite a large reduction in the. Concept of some of the other numbers I've been talking about, or 59% of severe exacerbations with improved quality of life and pseudomonal density. Unfortunately promise two was non-significant, however there were issues with the running of the study, uh particularly over the course of COVID and how that impacted on the patient population and the way patients behaved. There are other studies that are also going on which are looking at the use of ages um as uh anti-infective treatments and also um the use of uh monoclonal antibodies against specific virulence factors within Pseudomonas is a whole new area uh for treatment in the future. So the bronchiosis pipeline is rich and it's a really interesting area and it's a really active area to be involved in at the moment with studies looking at all of these four drivers that I mentioned with the vicious vortex. I've spoken a lot about some of these areas within inflammation and also in infection, but it really is an area where there's a lot of interest from industry and from academic partners alike, and it's likely that bronchisis management. is gonna change significantly over, over the next few years, not only with the concept of when to treat with um activity, but also how to treat and with what. So let's go back to the patients and, and back to where we started. So this patient actually did well on Mac therapy, the uh CT scan reduced much further down to baseline, it looked much less active. She was also clinically less active and she had no issues uh with tolerance. Now, in the future. Um, a patient like this may well be a good candidate for these DPP-1 inhibitors. Now, um, from England, they're not, uh, presently available, they are licensed but they haven't gone through, um, a, an assessment with NICE, a cost assessment, and so they're not something that, that I'm able to prescribe on, um, the NHS and it, it may be, um, obviously the license, um, for it, um, is for two or more exacerbations within the uh within the previous year. So exactly where they are gonna fit within my uh patient population I suppose is yet to be decided, but proba probably they would be a good fit for this kind of patient with uh active disease in the future. So, let me summarize. So for patients with bronchietis, assessment is critical, both at the beginning but also throughout. Part of monitoring a patient is ensuring that nothing new is happening and certainly if patients start deteriorating or start becoming. Um, active, then it is important to reassess them with a CT scan, perhaps with spirometry and certainly with bloods and sputum. It may be in the future that we even do further assessments of their activity. Perhaps we will look at for the last days in their sputum as well. Then when you have assessment of the activity of their bronchiotis, when and who to treat starts becoming a bit easier. And then from therapies, I've talked about the present ERS guidelines, I've talked about these new anti-inflammatory agents and how they may fit now and how they may fit in the future. But I've also talked a bit about the pipeline of future therapies. So I hope that was helpful, thank you very much. Published Created by Related Presenters Professor Michael Loebinger, MA, FRCP, PhD Director of the Lung DivisionClinical Director of Laboratory MedicineRoyal Brompton & Harefield HospitalsLondon, UK
