Video Risk Stratification and Therapeutic Targeting for NCFBE Guideline-Based Strategies and Emerging Novel Therapies Play Pause Volume Quality 1080P 720P 576P Fullscreen Captions Transcript Chapters Slides Risk Stratification and Therapeutic Targeting for NCFBE Guideline-Based Strategies and Emerging Novel Therapies Overview Hi, my name is Dr Kevin Winthrop. I'm a professor of infectious diseases and epidemiology here at Oregon health and Science University in Portland Oregon. I'm pleased to give you a quick overview of bronchi ethicists and some of the therapeutic targets that we are using to prevent exacerbations and progression of rocky exorcists. Uh these are my disclosures and I'd like to say this work was funded by a cmI grant from instead. So bronchitis is literally, I tell patients this is a a greek, a greek and latin prefix or suffix all stuck together and bronchial is latin for tube and I think ethicists is greek for stretched out. So it's literally an area of stretched out air tubes as I call it to patients. And you can see this in the graphic here that you see a normal bronchus or airway on the left. And you see one that is now dilated to stretch out and actually full of the mucus here with law, cecilia are normal clearance mechanisms present in the airway. And uh you see the build up of mucus. And this this is a process driven by inflammation whereby the airway wall thins and the airway expands and becomes um often full of mucus plugging and secretions and of course debris from the environment, both pathogens and pollutants. And so this process of bronchi exorcists of course can start quite mildly but it can progress to to various worse informs, you know, visually visually, you can see varicose bronchi exorcists and really the ultimate or the the end stage of this process is cystic bronchi exorcist, which is seen here in the ct image below. So what drives this process? It's been variously called a vicious cycle, a vicious circle uh more recently by my friend Patrick flume a vicious vortex. Uh and you can see these diagrams here, do you know, displaying the vicious cycle on the left and the vicious vortex on the right. It's largely the same concept here, and it's where um neutral filic inflammation, which we've learned more about the last few years. That is, it's a chicken or egg phenomenon really, you know, the bacterial colonization probably drives the neutral filic inflammation, but the neutral filic inflammation perhaps drives the airway destruction and the compromise ation of structural integrity of the airway wall uh and leads to poor mucus, cilia clearance. And this is just a circle that keeps going uh In Patrick Fleming's version over here, it's basically the same thing. But again, Salieri dysfunction and destruction and more of, you know, there's there's more going on than just the neutrophils. But there's clearly this this ongoing relationship between certain pathogens and the microbiome of that airway and the immune system that that we are trying to now target as ways to diminish this cycle. So, by diminishing both targeting both both the pathogens of interest as well as the immune system and perhaps at the same time. This this might offer new and improved approaches to Controlling this disease in terms of the epidemiology, this is still considered a quote unquote orphan disease in the United States whereby there's less than 200,000 individuals with it. I think in truth it's it's higher than this. If we C. T. Scanned everybody in the U. S. Of course we would find many more cases of mild bronchi excess that haven't shown up clinically yet. But you know, our more recent estimates estimate just under 200,000 primarily adults that are over age 65 with this disorder. Um But but we do start to see it outside of inherited and you know uh you know, specific instances like cystic fibrosis or um you know primary facility dyskinesia in a few other inherited diseases. We tend not to see this in young people except for an association with certain infections like tuberculosis for example, and other conditions that lead to airway destruction. But again it tends to be a disease of more elderly. And you can see this study here estimated 190,000 adults in the over age 65 population. We do see increases of between five and 10% of incidents per year. At least this using early data in the US from the 2000 to 2007, the symptoms I think you all know, you know, people tend to have chronic cough, not everyone's productive but many people have productive cough. Um Eventually patients developed dystonia and decreased exercise tolerance, more weakness and fatigue. And what drives all of this is recurrent exacerbations. And we know that the more exacerbations or flares that someone has, the quicker the progression of disease, the more symptoms uh and and eventually earlier death. So let's talk about the pathogens of interest first. So I put up the things that I tend to deal with in clinic here on a day to day basis. We tend to see gram negative organisms often associated with more advanced and more severe disease primarily. You know, pseudomonas is the one we always talk about. But again, a chroma back to standard trope Ramona's alka legions and others. They also can be associated with quite severe disease. H flu is very common. Some gram positive cox and of course staph aureus, both methicillin, susceptible and resistant. Atypical pathogens such as non tuberculosis. Mycobacterium, no cardio. We see frequently as a colonizer. It's really rare to cause infection. NTM primarily MAC of course can be a colonizer but we see a lot of disease in this setting. And of course aspergillus is very frequently a colonizer, rare to cause invasive parang camel infection. The frequency and colonization really really varies based on the studies. This is anna donald's Review paper from actually 10 years ago, there's not a ton of review papers out there since actually where or or studies but I just showed this to give you a flare there. You know, some of these studies show 30% of people colonized with pseudomonas for example To 11% in the study on the right. And it really depends on what centers doing these studies or what population is chosen. But again, these are usually institutional-based studies where there's microbiology data president. And you can see the range of colonization, you know, between you know, single digits and double digits for a number of the bugs. I just mentioned. One of the richest sources of information we have in in europe is the embark registry in the U. S. It's uh the COPD foundation funded bronchi ethicists registry and research for both bronchi exorcist and NTM. Uh This is a collection of a dozen plus centers in the US where we enroll patients into uh this longitudinal observational cohort study. You can see here that a number of patients are colonized with either NTM or pseudomonas. This is a graphic I'm showing to point out to the phenomenon that has been seen several times. And and I say this to patients to that, you know. NTM or MAC primarily MAC Mycobacterium obsessed this as well. But but 80, of NTM in this country is Mac. Um Mac and pseudomonas tend to play off one another. We we know that they both inhabit the biofilm of the airway. They probably compete with each other from a resource standpoint. And when we look at patients colonized this, MAC were less likely to find pseudomonas and the vice versa is true. And this is illustrated here if you look at the percentage of patients colonized with pseudomonas, you can see in the patients without NTM it was 41% as compared to 23% in the patients who had NTM. So again, illustrating my point that often those those flip oftentimes we treat someone's MAC it goes away and then we see pseudomonas is more of a dominant problem later and again, vice versa is true as well. Um to point out that there's data from all around the world that is TB rates decline, which is the two lines above. NTM rates are increasing, which is the line below. And we see that pretty much in every epidemiologic study in the last 10 years from most regions of the world. Some of this might be diagnostic bias, some of its environmental. I think some of it's just also that we have more people living longer lives. So we have more patients with chronic underlying lung disease and primary bronchi exorcist is putting them at risk for pulmonary NTM. And just to point out this is Oregon data from several years ago that, that NTM is definitely a uh an issue of age and it closely mirrors the incidence of bronchi texas which marches up steadily During agent. About 80% of patients with NTM have brought yet bronchi ethicists underlying. So it is a very strong risk factor. And again. NTM slightly more common in females. As you can see in the red versus blue for males here. As and again the rates steeply increasing as age rises. So um again we know chronic colonization with various organisms drives the progression of bronchi Alexis. I just spent some time talking about MAC primarily in terms of the gram negatives and a few grand positives. Again I've mentioned some of them. There's no question pseudomonas is intricately involved in um in worsening this disease as are some of the other organisms I mentioned. This is James Chalmers work from a number of years ago and it was really instrumental showing that you know, if you're colonized with one of these pathogens of interest, you are more likely to have both exacerbations. Hospitalizations in your quality of life is is worse. So you can see this in the colonized category versus the non colonized group for your mortality is higher in those colonized with one of these bugs below more exacerbations, more hospitalizations in a higher S. G. R. Q. Score. Which means the lower quality of life. The S. G. R. Q. Is is like golf. You know the higher the score. The worst she did. So you see that here um Once and exacerbate er always an exacerbate er I I like to say. And this is also from James work in 2000 and 18. Um He uh you know his group. You know he's one of the leaders in embarked registry and they they're able to to crank out quite a bit of a population based research as well as institutional based research. Um This is uh some of his work again following up on the theme from below the more exact from before the last slide. The more exacerbations you have, the worse off you are over time. And you know if you're someone who is a frequent exacerbate er you tend to always be a frequent exacerbated unless we do something about it so you can see that you know over time these are the these are people in buckets uh people who had really one or two or three or more exacerbations in the last year. If you follow those groups over time again the frequent exacerbations tend to uh maintain themselves as frequent exacerbate ear's over the five year time period and they have decreased survival as compared to those with less frequent exacerbations. And again that the issue with hospitalizations being shown here as well more exacerbations equals more um more hospitalizations and earlier death. And this jibes with the data that was presented in the slide before. Now I show this this is some of our data. I mean just to point out that it's complicated, it's not just like bugs get in there into the airway and they just you know hang out and evade the immune system. I think some of that is happening but there are also issues perhaps of even auto immunity that are driving issues of colonization and we were able to show this in non siete bronchi exorcists. Other investigators have shown it in cf that the bacterial permeable permeability um enzyme, the anti the B. P. I. Which is is there to kill pseudomonas that the patients who are colonized with pseudomonas are more likely to actually have auto immunity antibodies that actually are directed against that uh that enzyme. So unfortunately the bacteria cycle permeability, increasing protein BP I. That is there to kill pseudomonas and prevent pseudomonas colonization. The patients who have it are more likely actually to build antibodies that then negate its effects. So there is this issue of auto immunity somehow pseudomonas is able to break tolerance and promote this auto immunity that then probably then allows uh pseudomonas to hang around much more effectively. We don't see that in other groups who are not infected or even groups with NTM there were no more likely to have these autoantibodies. And patients with pseudomonas. So so I think it's a complicated story and I present this as evidence of that. So we need further work to understand how this mechanism arises and and maybe there's something to do about it. Um in terms of diminishing those human responses against our own um protective enzymes. So um let's let's talk about some targets and you know, the neutrophils become the hot thing the last five years based on a number of people's work James Chalmers and others. Uh they've they've really shown that nutri fill the last days and the attempts of the neutrophils to kill whatever pathogen is there can potentially really be driving the the worst thing of this disease and ongoing progression of bronchitis system tissue destruction. So one of the targets now is cap thep sincere ak di pepped it'll pep. Today's this is a enzyme that's uh used by the neutral in in the bone marrow during neutral film maturation. And it's it's it's basically put inside the neutral and it's what is used later to activate All these Syrian protein eases that the neutral dumps in response to pathogens. So neutral lasses protein kinase three caps, Catholics and G. These are Syrian protein eases that are released from neutrals in an effort to kill pathogens. And so we need this di peptide. It'll pep today's to to release those and so there is now a target here. If we can blocked by peptide peptide days, it will block the incorporation of of these enzymes in the neutral so that later on when they're in the circulation airway, they lack the ability to release those Granules. Um you know theoretically this could diminish the neutrals ability to protect us against infection or fight infection. But it also on the flip side could diminish the amount of destruction inflammation that is triggered by the presence of those pathogens. So it has been shown by a number of investigators that the more neutral last days that is present in the sputum for example. Um the worst off patients are and there's a number of lines of evidence here and I'm going to go through them first. We see a difference in the microbiome the higher than neutral last days in dispute them. The less diversity there are are of organisms in the airway and this is shown here by three different measures of um microbiome or or sputum micro diversity and the Shannon index. I'll just show you here. But you can see the line going down the meaning, there's less diversity in the airway. The higher than neutral elasticity is content. We see this also looking at specific organisms, you see very intimate relationship with sputum neutral last days were any and pseudomonas, the higher than neutral last days, the more likely and the more pseudomonas there is in the airway. We don't see those same relationships with all these pathogens. We should see somewhat of an inverse relationship with streptococcus on the right and fairly flat relationship with staphylococcus down here, for example. So again, a very intricate relationship with pseudomonas which we know is a marker of more severe disease and more likelihood of exacerbation. It is related to the speed of neutrophils lasts count. We can also see that it correlates with bronc excess severity, which is what I was just saying essentially. This was actually a diagnostic kit that was evaluated that that can that can take um sputum and and measure neutrophils classes and you can see again higher levels with patients colonized with pseudomonas as compared to other infections in the middle. You see you know mild, moderate severe bronc exorcist grades again associated with severity and again the more neutral assets president the worst F. U. V. One which was present. So all of these track together, they're all kind of measuring similar things in terms of severity and F. U. B. One here. But again the point being neutral molasses correlates with severity. And then of course one would surmise. It would correlate with outcomes, particularly survival and the time to the next exacerbation. And this is shown here in a large european cohort study also showing that you know the higher level neutral last days which is the lower line here has less time to their next exacerbation and there's a dose dependent effect here really. The higher the worst you are, the lower the better you are. And this is also seen with mortality that this real high group here has higher all cause mortality. So who are they? They're people with more severe bronchial axis more likely to be colonized with pseudomonas and they have more exacerbations and they have less length of life. So um this this is a nice story so far being told although again I will say it's it's a bit of a chicken and an egg right? There's a sumo this being their first promote this of course it probably does. But there must be probably some protective effect of neutrophils last days and we have to probably find the sweet spot in terms of modulating it. Um This is just showing that that again that the the neutral Alaska's activity also varies with exacerbation recovery. So this was nicely shown that at the start of exacerbation you can see from a point of stability. You see the neutral last days rise the patients treated you see a decrease um and you see this again rise up when when there's another exacerbation. So um neutral last days. Again it's not a static thing but it does depend on the amount of colonization in the airway, private organism in the airway. And again how active that processes. The last concept I'll talk about very quickly our our nets these are neutral filic um uh These are neutral filic traps, so to speak that are actually put out by the by the neutral Phil um It's really an extra cellular trap. That's what any T stands for. And it's a matrix really of Cro magnon DNA, his stones, bacterial saddle proteins like neutral last days and others that I was mentioning. And this is a defense mechanism and it's uh you know should enhance abilities, ability to trap pathogens and allow the neutral to destroy the pathogens as well as other mechanisms. And you can see that that nets are are just like neutrophils last days I think we're measuring primarily the same thing here. It's the same process but their highest and bronchi access. You can see that, you know, they're higher on the right here with patients with more history of severe exacerbation. They do um They do uh correlate with severity of bronchi axis, you know, having, you know, people with more severe disease having more nets. Um So again, very similar story to neutral last day is really nothing different. And here's the outcome data very similar to the neutral last days data I showed you before. But the people with more net formation or high net formation is measured by um the presence of nets. You know, they are more likely to have exacerbations and and also less likely to survive over time. So the same story here, the question is, is this a viable target? Um are we going to increase the risk infection or make things worse or are we going to calm things down? This is an anti inflammatory approach certainly. Um and I and I will want to talk about that in just one second. Um and another approach is targeting the S NFL and there are studies that are starting to do that. There's clearly a subgroup of patients who have high ES NFL's and um they're they're um they're not the large percentage of patients, it's probably between 10 and 15% of patients depending on what study you look at. But this group definitely has high in the east center fills and sputum. This graphic on the left shows that these coordinate with or correlate with the bloody assassin affiliated hospital meus cinephiles goes with bloodiest cinephiles. And on the bottom you can see based on your blood eosinophilic count or sputum. Eosinophilic count. You would see the same thing that you see decreased survival and then more exacerbations decreased survival with the higher es NFL counts. The graphic on the right to make the point I'm color blind so I can't even tell you what it shows. But I did figure it out that you know that that also there are microbiome differences or colonization differences in terms of organisms present based on the proportion of the essentials that are there. Um And again here outcomes based on blood es NFL's. I just showed you this is just a different study showing the same thing. Again the probability of death rises with the higher higher us NFL counts. So um let's talk about the research and the treatments and the targets. So I would just say that that we don't have guidelines in the U. S. We have an effort by some investigators that was part of this group where where we did bring together patients and experts have come up with a research roadmap. Most of this was around treatment and you know how do we prevent exacerbations of progression disease. Uh There are a number of things we can do. They have been laid out in terms of management by the european respiratory society quite recently in the last few years. We don't have guidelines in the US but but I think most of us agree with most aspects of these guidelines. Not all of them, but but a lot of us practice similarly on both sides of the pond. Um The first thing to talk about and this is the very practical aspect of my talk harmony hygiene. You can see various modalities here. You see all capella valves down here on the right, You see a vest here. Um there's nebulizer kids. So so many of us, you know, reinforce. This is the first speech we give patients. It's what are you doing in terms of airway hygiene and the speech consists of exercise. There's no question that exercise, cardiovascular aerobic exercise promotes appalling hygiene. And on top of that these mechanisms can as well. And when I say hygiene, I just mean trying to keep your airways uh free of mucus as possible fewer mucus plugs, less secretions, etcetera. Um It probably does decrease the risk of exacerbations. We have data from cf showing that we don't have a whole lot of data from the non cf bronchial justice world supporting the use of these modalities. But I would say that, you know, my practical experience is that most patients at least feel better doing some of these things. Um and I will say that the normal saline, you know, I I don't have any data to show you there's very little data supporting the use of hyper tonic sailing in this setting. There's some data from the cf setting. This supports its use there, although it's it's fairly limited in the non cf bronchi exorcist setting. We just don't have the data. We're doing a study presently with with hyper tonic saline, trying to collect some of that data. And I know some others are as well. So, so again, we often have people inhale hyper tonic sailing, thinking that will promote clearance uh and cleanliness of the airways, so to speak. But but it's it's hard, I'm hard pressed to show my patients data proving that um beyond exercise and pulmonary hygiene or clearance. We have other options for people who are still having recurrent exacerbations. Azithromycin is is a good option. Uh It has anti inflammatory properties. Some of this may involve modulating neutrophils activity. Um, there are at least two positive randomized controlled trials. And non CIA bronchi accepts patients with the Zithromax and there was also a positive RCT with erythromycin is and so we have three for three. Uh they're hitting 100% the macro leads. Uh they're really actually quite safe. You know, the sudden cardiac death risk. I think people don't really worry about that anymore. Um certainly you can't see tinnitus and hearing loss with prolonged use of these agents. Um the big issue for us is really uh mycobacterium avian given the high risk most bronchi excess patients have of having uh MAC particularly the time of the bronchi excess diagnosis. You really need a culture as people repeatedly to ensure that they're they're negative for NTM before you put them on Zithromax because you certainly do not want to promote the the evolution of MAC allied resistance in Mac if the patient has underlined max. So so I often culture these patients 34 times over the course of a year before. I'm really convinced that they don't have MAC before I consider using his infirmities and and I have to be honest I have a hard time sometimes doing it anyway because I look at their CT scan and I I see what sure looks like MAC. To me it might not be. But so that this can be, it can be complicated. Although again we do use it particularly after repeated negative cultures. I will mention inhaled corticosteroids or I. CS here uh you know, these are mentioned in the guidelines as an option. There also mentioned that there is no data supporting their use and they potentially have adverse event issues. There is data showing that you know use of I. C. S. In this setting does increase the risk of subsequent NTM disease or infection. Uh It does there is data of course showing that they do increase the risk of pulmonary exacerbations. We published some of that data. This was actually a study that we looked at in direct comparison to materialize. We took patients who either started zip through medicine as a suppressive or immune modulating therapy as compared to those who started inhaled corticosteroids. And we certainly did see a decreased risk um of hot respiratory infection with Mac allied. So actually this is flip this is showing the higher risk of hospitalized restaurant infection. And those on I. C. S. As compared to America leads. Um And again you see a higher risk mortality and hospitalization. So again the reference group here is Mark collides. But I I think it's it's very clear if you had the choice between one or the other you would certainly want to choose the medical ID and not the inhaled corticosteroid. So um the currently approved therapy is a non cystic fibrosis uh brock texas. So N. C. F. B. Um which we have now drifted to just call him bronchi exorcists and you can see the slide is empty and it is it's still empty. We don't have any improved therapy. Um We do have some therapies that have shown promise and I truly believe they work. So in in terms of targets let's talk about targeting the pathogen. First I I guess as I take a step back I think probably in the end we want to target both the pathogen and the neutral or the immune system probably simultaneously. And that when you do one without the other it may not be optimal but that's of course something we need to study in the pure targeting the microbial pathogen arena we have several large R. C. T. S. That have shown promise It has not led to a drug approval yet. Although I think we're getting close to that. This is one of the best studies. This has inhaled gente mayes and it was the first one really where someone took an inhaled antibiotic and continuous therapy. Some of the early trials really adopted the CF trial mentality of 28 days on 28 days off. And I think that was part of the problem. There's no question in my mind that continuous therapy works better than intermittent therapy. I use a lot of inhaled Jeremiah's and based on this very positive study where the gent group had a decrease time um or the decreased incidence of exacerbation as evidenced by longer time to exacerbation here. They had fewer mean exacerbations and they improved in their quality of life. Um and so again this is a viable alternative for patients who are having more than two exacerbations in 12-month period. I I tend to offer this as a therapy Colston probably also works and I'll show you some data from an older trial here that Charlie Hall worth did with a number of investigators and clearly the patients in in the per protocol analysis meaning if it works it works if you actually use it. So the patients who actually use the drug they did see a positive effect. They saw a decreased risk of exacerbation and they saw improved quality of life. Unfortunately in the in the analysis that took all comers, uh you know, the the intention to treat analysis, uh, there was no statistically significant benefits. So again, the people who actually used it. Yes, it worked. But the people overall, it was not a positive study and so hence it was not approved at that time. There are at least two inhaled floor queen alone trials. Both ended up quote unquote negative and uh no drug approvals. However, when you look at the data, they were both quite positive. They just were discordant or not positive enough for, for regulators to approve them. You can see that in one of the face Cipro DP I trials, that's dry powder inhaler, you see a decrease um, in exacerbation frequency and in, in incidents in the patients on on Cipro as compared to the pool placebo arm. Um, you know, in both the Cipro 28 day on and off, super 14 day on and off their bodies, both of them look similar and they look better than placebo. So when you pull the two phase three trials, this is what you saw when you looked at them independently, one was positive, you saw this and the other one was not as positive. So the pool data look great. But the individual trials didn't didn't look as good and so it was not approved if you look at the other inhaled Floor Quinlan. Very similar story if you pull the data to see a positive effect. So I think there's no question in my mind that inhale floor Quinlan's would work. Um The question also regulators and experts had was around resistance. We did see some patients develop gram negative resistance uh and other resistance in that experience. And that of course is a trade off of the use of any inhaled antibiotics. So suffice to say we don't have access to these therapies but I think it's evidence that targeting that the pathogen works. Uh This study did not work though it wouldn't support my my statement that you know as training um this was done. Alan barker, a close friend of mine did the study and despite showing a reduction of bacterial load when the patient was on drug um we did not see any benefit in either quality of life or an exacerbation uh frequency. For instance you can see that the time the first protocol defined exacerbation was the same in the Austrian army group as a placebo group. The hazard ratio there is 1.26 big confidence general across one. So there was really no benefits. So um at this point I think there's good evidence showing gentle minus and works. There is good evidence showing that inhale Floor Quinn alone would probably work and there is good evidence showing that inhale Colston uh probably works. And now we have even better, better evidence is presented just very recently E. R. S. By charlie hall Worth. Ah And this is the promised one trial. Clearly showing that patients on Colson had a higher likelihood of staying exacerbation free so you can see their hazard ratio of 0.59 and the survival curve. So again patients on the lower line placebo, these are patients they're more likely to exacerbate sooner after about day 60. You see these curves separate and when you look at the micro data he presented also showing it makes sense that you see a decrease in pseudomonas in patients. And again this was an anti pseudomonas trials. These patients colonized with pseudomonas. You see a decrease in pseudomonas growth and it sustained wilder patients on continuous Colston. This is not 28 days, 28 days off. This is continuous. And you see this throughout and it tracks with the decreasing exacerbation frequency And now we have a new mechanism. This is Phase two data that was very exciting. It was published in New England Journal by James Chalmers at all trial I was involved with and many of us were involved with and this was a trial between two doses of Brown's executive and this is a anti DPP one inhibitor. So this should stop the packaging of those Granules. The neutrophils Alaska's Granules that I showed you in the bone marrow maturation process of the new travel. And so it should lead to diminished intra airway inflammation. Uh And in this experience, that's exactly what we see. This is just showing the characteristics of the patients that were similar between placebo and the two bronze aka to groups great. And now we have some of the outcomes of those trials were also phenomenally successful. And that both those in groups of 10 mg and 25 mg group showed statistically significant improvement in terms of decreased risk of exacerbations. So in the survival curve, you see the proportion of patients with no exacerbation uh being shown here. And you can see the lower line below as placebo by day 1, 69 there are many fewer patients still exacerbation free in the placebo group as compared to the two um study drug groups. Uh and what was really nice to see to is it didn't matter where these patients were, how old they were, um whether they use Michaelides, whether they were colonized with pseudomonas or other pathogens etcetera. All these subgroups showed benefit um with uh with the study drugs. So, so it seemed to be a very clear win in this Phase three trial. So, of course, now there is a very large phase three trial, ongoing looking at the safety and efficacy of this drug and I will just comment that the safety in the Phase two looked quite good. We did not see an increased risk of infection in patients on the study drug groups. And actually this is the placebo group here on the left. This is the 10 mg and 25 mg Groups for for the study drug, 10 mg here, 25 mg here. And you can see the number and percentage of patients with adverse events was actually lower in the study drugs that's probably cause they were having fewer exacerbations. Um and you can see other infections like pneumonia. We're no different between placebo and the study drug groups also no difference in skin events like dermatitis or periodontal disease, both potential adverse events of special interest with this drug. But we did not see um really more of those things necessarily in the study drug groups as compared to the placebo with the exception of maybe some increase periodontal disease. So that is something we're checking in the phase three trial. So we'll just have to see where that goes. But but again, I thought what was most important was no increased infection. So despite, you know, calming down the neutrophils, so to speak, we don't see an increased risk of infection. In fact, we see a decreased risk of of flair. So in conclusion I I covered a number of the co pathogens of clinical importance today within bronchi axis, primarily pseudomonas and other gram negatives. We talked about N. T. M. That's a whole nother talk on its own how to manage that gram positive such as staff clearly prevention of exacerbation, which is really what I focused on today is key. We need more evidence around um clearance and hygiene. I I beg someone out there listening if anyone is to do a randomized controlled trial of 7% hyper tonic saline uh to see the actual benefit of of that intervention. We have evidence of Fc for a number of inhaled antibiotics and uh you know some very positive trials recently. So I am encouraged that some of them will get approved for for the actual use, you know FDA approved Auriemma approved for use in this setting. And then now we have this neutrophils target um with the anti DPP IR Brent succeeded. We'll see where the phase three trial goes. But again encouraging evidence from phase two and then as the or as its demise. And I mentioned some of the difficulties around using it but certainly very good RCT evidence behind it. So again, screen your patients for NTM prior to using it in management exacerbations I didn't even get to That's the next talk. Um We have really little data on how to you know, optimize the management of exacerbations. What data we have suggests sometimes the susceptibility results of the organisms that play don't necessarily jive with clinical outcomes. So anyway, that's the next talk but I guess we don't even talk about it if we focus on prevention and actually prevent those exacerbations. We don't need to even go there. So anyway, good, good luck with your patients. Uh and stay tuned in the next couple of years because I think we'll have some exciting new developments in terms of access to therapies for for these individuals. So thanks very much for your time, cheers. Published March 21, 2022 Created by
