Dr. P.J. McShane from University of Texas, Tyler, Dr. Chuck Daly from National Jewish. Our colleague, Dr. James Chalmers, because of unexpected personal occurrence, won't be here today, but he'll give us a chance to go a little bit deeper into a couple of the topics that Dr. McShane and Dr. Daly have in particular. So again, welcome and glad folks are here. Name of the session is What's New in Non-CF Brachiectasis and NTM Lung Disease, a World Brachiectasis Session. I would share with you that a lot of this is coming off the heels of a very successful, well-attended and robust program, World Brachiectasis Conference held in New York City, hosted by NYU in July of this year. A couple of housekeeping issues for everyone. Reminder, all sessions can be evaluated through the mobile app and or on the online program. Don't forget to evaluate this session or course in faculty when done. 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So let's go ahead, and I might just as a plug as well, just share that the Presidential Honor Lecture following this at 8.15 in room 323C will also feature topics on bronchiectasis by our colleagues, Dr. Jerreen O'Harris from NYU, who's the current CHESS president, and Dr. Ann O'Donnell from Georgetown. So with that, I have the pleasure of sharing some perspectives about the U.S. Bronchiectasis Research Registry, and we'll move forward. I participate in a number of clinical trials, but all my money and support goes to my employer, the Mayo Clinic. This is an exciting time for bronchiectasis. It's beautiful. It's a new age of bronchiectasis and NTM lung disease, as you're gonna hear from my colleagues, and so there's a lot of opportunities at hand, and this isn't done with just a single effort, but with a lot of folks and lots of support in there. In this next 10 or 15 minutes, I'm just gonna share just a little bit of background information, little information about the U.S. Bronchiectasis and NTM Registry, some ongoing activities as far as education and collaboration. Again, it's working with partners not only here in the U.S. and North America, but globally, and then leave you with a few summary thoughts. Let's first talk about background. Like most things, it's really important that there's a mission defined if there's gonna be success with any project or effort that we make. The registry is certainly no exception. In the bronchiectasis, U.S. Bronchiectasis and NTM Research Registry is a consolidated database of adult patients with bronchiectasis and or NTM lung disease, not associated with at least classic cystic fibrosis for major clinical and research institution. It's designed to support collaborative research and assist in the planning of multicenter clinical trials, whether it be investigator-driven, pharma-driven, or otherwise for bronchiectasis and NTM lung disease. And it's designed to provide better insight into the diagnosis, pathophysiology, endotypes, natural history, and management approaches of the different types or phenotypes now of bronchiectasis. Let's talk a little bit about the registry update. And this is, again, a different perspective in the sense that this is a growth phase. It's a great time, a beautiful moment to be in this space, not only with investigators that have been at this a while, but bringing on younger people to grow and make this certainly a much more enriched space. With respect to the registry, this is data taken from a little bit earlier this year. The active sites are now 24, participants just under 6,000, almost 20,000 clinical visits. We've been at this 15 years. The cohort, for the most part, biased as it may be because this is primarily from referral centers, is mostly women, white, few Hispanics, and the average age is 66. 96% have been diagnosed with bronchiectasis, and as mentioned, some of the individuals enrolled have just NTM disease without bronchiectasis. 34% pneumonia, over half had either a past or current NTM isolate or infection, and then 16% with pseudomonas. There are comorbidities, but this is a registry that patients are being enrolled with a primary diagnosis of bronchiectasis or NTM, not COPD, not asthma, or GERD, but they do have these comorbidities that are not uncommon. We are diversifying geographically throughout the U.S. into the Midwest and Southern areas of the U.S. The numbers, again, earlier this year, end of quarter 2023, 5726, and we're now knocking at the door of 6,000 with the growth phase actively increasing. It's been rewarding to have publications come of this. 2023 has been no exception with both manuscripts and abstracts highlighted at the major meetings, ATS, the World Bronchiectasis Congress, ERS, and then submitted to CHESTA as well. I wanna share just a little bit with you to give you a perspective about an ongoing work. In summary, looking at the five-year outcomes amongst patients in the registry, and this is directly taken. We're looking and analyzing exacerbations, hospitalizations, lung function, and mortality across five years in patients with bronchiectasis with or without NTM at baseline. Again, over the time of the analysis, 5,300-plus patients, 1549 with NTM at baseline, 1,000 without. And when we look at these two groups of with and without NTM, they do look different, as many of you are probably very familiar with in your clinic. The age, for example, in the individuals without bronchiectasis is a little younger, more women with NTM, pseudomonas more common in those without NTM, BMI is a little lower in those with NTM, and then the FEV1's lower in those without NTM, as you would expect and probably are familiar with in your clinic. Likewise, exacerbations and hospitalizations also differ between these two and are more common in those without NTM at baseline. This is within the two-year period of enrollment into the registry. Comorbidities as well, as you would expect, are more common for the most part in those without NTM than NTM. But they are, again, they look differently from an endotype. Now, what that really means clinically, we're in the process of trying to analyze and drill down on, but again, this has been a consistent signal that not only us but other investigators globally have come to appreciate. The number of exacerbations over this five-year period, surprisingly, is really durable, and although there's more exacerbations and hospitalizations in those without NTM disease, it stays consistent pretty much through this five-year period, and that holds true for the hospitalizations as well when we look at this data over this five years. And then one of the aspects I found particularly interesting is, although the FEV1s and pulmonary function of those without NTM disease started at a lower level, the rate of decline is similar. There's no statistical difference whether patients are with or without NTM disease, and the rates, as you can see, varied between about 35 and 40, which are not that significantly different from what most of us think of, that age-related change in spirometry, about 30 cc's per year in both FEV1 and vital capacity, and that, too, has been durable over that five-year period. When we look at mortality charts, also with or without NTM, the mortality did not appear to differ over that five-year period. Probability of death estimate based on the imperfections of the data was estimated at about 12%. Cause of this would be all-cause mortality. We didn't have the granularity to be able to sort out whether this is death related to NTM and or bronchiectasis, but again, probably a little bit lower than what's reported in a lot of other series, both in the US as well as Europe and globally. For most of you, there aren't many patients that we admit with exacerbations of NTM. A lot of them with their comorbidities can be very sick, and those with bronchiectasis as well, but the overall five-year survival, about 12%. In multivariable analysis, should be rather than multivariate analysis, again, pulmonary function tests jumped out as people that were more likely to die over that five-year period. That is starting out with more severe lung disease, not surprisingly, older group. If they've been hospitalized in the past, they're more likely to be hospitalized and have exacerbations, lower BMIs, again, presumably as a biomarker reflection that it's a sicker population, and males more so than females, probably related to the comorbidities. When we look at the BSI and the FACET scores, the BSI in the top panel, the FACET score. In the lower panel, the FACET score appears to be a little stronger predictor of who's gonna survive over that five-year period, starting out with baseline numbers. So in summary, as far as the registry goes, the outcomes, including exacerbations, hospitalizations, rate of loss of lung function and mortality were similar across five years. That is durable in this way. In patients with bronchiectasis with or without NTM, even though they look different at the start, patients with bronchiectasis and NTM fared no worse than patients without, at least by the estimates of this analysis. What are some of the ongoing activities? With the registry, we're in the process of trying to do some linkage studies to try to firm up the data, to try to drill down, get a little bit more robust and enriched assessment. There's a biobanking network being developed, and then lots of work by many investigators with translational research looking at the microbiome, diagnostic treatment outcomes, not only in bronchiectasis and NTM, but as I think Dr. McShane's gonna share with you, PBB, or P-B-B, it should be not P-B-B, but P-B-B, and protracted or persistent. Protracted is the term used by the pediatric space, and whether you say persistent or protracted, I'll defer to Dr. McShane, bacterial bronchitis. And then growth and enrichment of the registry to, again, drill down. This has been, as I say, now a 15-year project, lots of support and development, and we're very grateful to all those that have supported over the years as this has grown and developed. There's been a World Bronchiectasis Day. I would encourage you to direct your patients or even yourselves. There's a great set of resources with a lot of global partners, almost 20, looking at different ways to raise global awareness, share knowledge, and discuss ways to reduce the burden of bronchiectasis for patients and their families, primarily through collaborative research. The impact of the World Bronchiectasis Day, and we're still working on the 2023 numbers, but in 2022, which was the inaugural launch, reached almost 800,000 patients. Lots of social activity that was shared, and it highlighted patients from around the world with bronchiectasis, looking at video interviews, and so, again, it's a very rich source of information for you and your patients. There's lots of educational programs on this site as well that you can share with patients to enhance and enrich your practice, take some of that burden off the time component as well. There are caregiver kits that are available in different languages across the world. Again, in lots of different languages, English, Spanish, French, Japanese, Portuguese, Italian, Arabic. We're continuing to increase those as well. This last World Bronchiectasis Day was scheduled and was much akin to one of those New Year Day recommendations that is a one kind of around the world with a timeline. There were live sessions from around the world with different groups and colleagues all presenting their activity. So, in summary, this is a beautiful time to be in this space and you're gonna hear some more of the specifics from Dr. Daly and Dr. McShane, and we will have some time for, I think, additional discussion and questions at the end. I'd be remiss if I didn't say thanks to all the investigators from within the registry. And this is a list from active individuals now throughout the US. But like a lot of things, this isn't just about the investigators, of course. And the people that really do make this happen can bring the magic on us, our patients. They're a very motivated, inspiring, and really an engaging group of individuals that help us with this. Shout out to all our study coordinators who tirelessly work through abstracting data and entering this into the charts. We couldn't do this without collaborations and especially our industry partners. We've had Richard Scarborough Foundation, the Kellen Foundation, and the Bronchiectasis and NTM Industry Advisory Committee, which are critical to the success of this. Without these resources, we wouldn't be able to do what we've been able to do. And then as a last shout out to the team at the COPD Foundation who helps oversee the Bronchiectasis and NTM programs, Delio Oliver, Ruth Talsinger, Jean Wright, Amanda Brunton, Christine Hunt, Radha Choit, and Jenny Thompson. And with that, I'm gonna stop. And I'm gonna defer any questions as far as the registry and what's going on in the US. If there's interest by any of you in potentially getting involved with not only the registry, but there's interest in developing a care center network, come on up afterwards or during our discussion and we can talk more of that. And again, Dr. PJ McShane from University of Texas, Dr. McShane. Thank you so much. I'm so always enthusiastic about my job and my patients. And so it's a pleasure to be here to be able to talk about this. And this is an exciting evolution in bronchiectasis. When I was a fellow, bronchiectasis was really thought to be a chronic infection and this inflammation has been sort of uncovered and more acknowledged in the recent years. This is my disclosure slide. It's a really exciting time in bronchiectasis and NTM and to help with these clinical trials has been very rewarding because I feel like I have something to offer the patients now. This is going to be somewhat of a fast and furious discussion and much of it is data you know, but I do want to review that bronchiectasis is an inflammatory disease as much as it is chronic infection and perhaps maybe even more an inflammatory disease. I want to give you an update on anti-inflammatory drugs for bronchiectasis that are in the pipeline and you know, we can just see the light at the end of the tunnel when the data might be available and then review what we have available now to treat our patients. So here is an explanted lung of a patient with very severe bronchiectasis and as you look under the microscope on this patient, it's really, it's undeniable, this is an inflammatory process. You see copious amounts of submucosal lymphocytes and the intraluminal airway is just inundated with neutrophils and as you know, the neutrophils just assault that normal epithelium and turn it into epithelial necrosis which destroys the anatomy, ends up with a host of other downstream effects and leads to the bronchiectasis that we see on CT scan. I'm going old school, well not old school really but this is going all the way back to 2001. This was an elegant study that looked at BALs from patients with bronchiectasis who had microbiology or pathogenic organisms in the BAL versus those who did not grow pathogenic organisms in the BAL and then compared the inflammatory markers within those two groups plus control subjects and you can see that in the patients in the center column who did not have pathogenic organisms in their BAL still had neutrophilia beyond what was seen in a normal control. So this is a inflammatory disease, a neutrophilic disease in the absence of infection and the cytokines IL-8 and IL-6 were also increased in these patients despite not having bacteria there. I'm gonna take a tangent here and just mention, Dr. Aksamit mentioned persistent bacterial bronchitis. I didn't actually include that in my talk today but it's referred to now as PBB and I think you'll hear more about it and this is a identification of a group of patients who you probably see in your clinic who come to you without bronchiectasis but they're coughing up copious amounts of sputum and they're getting sick frequently and this is sort of along the lines of these patients have neutrophils in their airways and perhaps this is a precursor. So that's just a little bit of a teaser for I think what hopefully will come to be more commonly mentioned in the adult presentations, in the adult literature, this PBB entity. The pediatrics, especially like Ann Chang from Australia refer to it as protracted bacterial bronchitis which I find kind of hard to get out of my mouth and the adults, thank goodness, have called it persistent bacterial bronchitis. Anyway, this could be a precursor and it's sort of related to this slide so I thought I would mention it. Okay, now, so this neutrophilic disease which we have, then subsequently a nice paper was published by Betty and I also wanna say a disclaimer that James isn't here in person but he is certainly here in spirit because every single slide that I have references a paper that is either, if not first authored by James Chalmers, is senior authored or co-authored, driven or engineered or supported by James Chalmers. So we have him to thank for a lot of this data that we know about bronchiectasis today. Okay, so what this paper showed is that neutrophils are not productive members of society. They are not killing the bacterial the way they're supposed to be, impaired phagocytosis. They're not dying the way they're supposed to, delayed apoptosis. They're running around like zombies, not dying, not helping out and they're releasing these searing proteases and enzymes that are damaging and causing epithelial necrosis. James Chalmers further went on to show us that specifically neutrophil elastase correlates with more severe disease in bronchiectasis. That is, it is a marker of disease in bronchiectasis. So on the y-axis, that is just an assay for neutrophil elastase. And as that goes up, the severity of bronchiectasis increases as measured by the bronchiectasis severity index. Also, higher levels of neutrophil elastase correlate with lower lung function in bronchiectasis. And importantly, high, if you separate neutrophil elastase into like lower, medium, yellow bar, high, red bar, you can see that those patients with very high neutrophil elastase have a lot of exacerbations. The exacerbation-free survival is on the y-axis there. So high neutrophil elastase correlates with disease. It's a disease marker, and so it would be precision medicine, so to speak, to identify how we can tamp down this neutrophil elastase. Subsequently is a paper here that is really informative and speaks to the imbalance between serine proteases in bronchiectasis. Now this is an extremely active figure, but really it's what we learned in medical school. These are the downstream effects of the serine proteases up there. Believe, let's see if I can use this without my, I guess I cannot. Yeah. So at the top of the slide is the cathepsin C. That's an enzyme that activates cathepsin G, protein A-C. But I think you, thank you, Tim. I think you all see though that the enzymes are at the top. The serine proteases are the cathepsin C, protein A-C, protein A-3, and neutrophil elastase. The point of the paper is that the downstream effects of these guys is completely imbalanced in bronchiectasis. So I've shown you that, yes, they do clear pathogens, but in sort of lighter area arrows that's meant to depict that the degradation is far outweighs the pathogen clearance in our bronchiectasis patients. So this heavier arrows is meant to demonstrate the imbalance of what these enzymes are doing. So to tamp down the effect of these enzymes is potentially going to alleviate some of the bronchiectasis development. Now there has been an early phase one trial of a neutrophil elastase specific drug. There is of course well described use of alpha-1 antitrypsin deficiency. Replacement is well described to help those patients. But now we have an inhibitor that inhibits the dipeptidyl peptidase or cathepsin C. What's cool about this, you guys, is this does this in the neutrophil precursor. So this dipeptidyl peptidase inhibitor inhibits the activation of the serine protease way early, sort of like I guess what you intend to do with your children, like teach them what to do, don't do bad stuff when they're kids, so that then when they mature to be a mature neutrophil and they spit out their granules, those granules aren't carrying as much activity of the bad serine proteases. So not surprisingly, as I know you all know this, a dipeptidyl peptidase called brenzocatib, and I know if James Chalmers was here he would call it brenzocatib, but that did reduce exacerbation frequency and was published in the New England Journal of Medicine. And that was really exciting. And what this forest plot shows is that it didn't matter what the age of the patient was or whether they came in on mamacrolide or whether they had pseudomonas, that brenzocatib reduced exacerbation frequency in all patients. So that was super exciting, and now the phase three trial has recruited, reached its enrollment. Let me tell you, it surpassed its enrollment goal, and I think 712, I just heard, patients haven't been enrolled, and this included some adolescents. The primary endpoint of this trial was rate of exacerbations over 52 weeks. The last patient has been enrolled, it is no longer enrolling, and the patients who have been in the trial are now on a continuation phase to look at safety data. I couldn't be more excited about being involved as a PI in that trial because I felt so excited to be able to offer my patients something. Furthermore, there is now another dipeptidylpeptidase inhibitor in bronchiectasis. This is a phase two trial, but it sort of functions as a, it's a 2B, sort of functions as a phase three because the primary endpoint is time to first exacerbation. This was slightly different in terms of enrollment criteria. The brenzocatib trial enrolled people who had two exacerbations in the prior year. This trial, a patient could get in if they only had one exacerbation plus a really high St. George respiratory questionnaire score, over 40. And the idea behind that was that patients who have poor quality of life, that kind of predicts exacerbation. This too has met its enrollment trial, its enrollment goals. Patients who have finished their time receiving the study drug are now enrolled in a continuation phase, but we're now in this little bit of a time of anticipation because both of these trials will hopefully provide their data in mid-2024, yet at the same time we can't enroll anybody because the data is not out yet. So I'm going to be very eager to find out what we find from these trials. Well, that couldn't be more exciting, but what can we do now? And as you know, I just wanted to make a quick review of the macrolides. You all remember the BAT, the BLESS, and the EMBRACE trials. These were relatively small, although they seemed big at the time, of macrolide use in patients with bronchiectasis. And then, so this slide, you know, there's a lot of information there, but I know you remember this from when these papers were initially published. But that sort of gives you the whole summary of the number of patients, the exact macrolide treatment there, whether it was azithromycin 250 daily, erythromycin, or azithromycin 500 milligrams three times a week. Anyway, so then James Cheps steps in again and does a meta-analysis, but this is an individual participant type of meta-analysis, which as you know, sort of gives more substance to the result of the meta-analysis. And demonstrated that yes, in truly the macrolide use in bronchiectasis patients reduces exacerbations. It improves quality of life, and if you want to nitpick that that's not a big enough change in the quality of life. More people who are on the macrolide have the big significant change in the quality of life St. George Respiratory Questionnaire. And I am sorry about this forest plot. It's a lot there, and it didn't exactly, the numbers aren't big, but let me just tell you that once again, looking at any subgroup of patient, old or young, BMI, how many exacerbations they had, FEV1, you can see that the benefit is all shifted with macrolide therapy. At Tyler Texas, I do a lot of non-tuberculous mycobacterial clinical work. So I feel very obligated to say that you must, must, must rule out non-tuberculous mycobacterial in your patients before you put them on the macrolide. This is a one patient who I have. She's a 57-year-old lawyer. She is a mother of three, and she has macrolide-resistant MAC lung disease. You can see the resistance pattern in the upper left. Her FEV1 is very low, and her CT scan is just horrific, and it's just not a lot there to manage her best, especially when she doesn't tolerate the amikacin due to hearing adverse events. Okay. Now I'm going to go into my absolute favorite, and I hope I'm not running too late, but I'm going to make this real quick because I can't talk about bronchiectasis without my favorite topic of airway clearance. Mucins are the proteins within the mucus that are the very important proteins within mucus that sort of give it the properties of trapping the bacteria and being anti-inflammatory. But in bronchiectasis, those mucins are too high. The concentration is too high, and specifically the type of mucins is imbalanced. And this obviously, as you know, overwhelms the ability of the cilia to clear. The higher concentration of mucins correlates with lower lung function, and it correlates with higher bronchiectasis severity. And not surprisingly, here is a correlation coefficient data on the percent solids or the total mucins or the specific type of mucins. The inflammation is all higher with this higher mucin content in our patients with bronchiectasis. And what's super cool about this patient, about this paper, is that it was independent of pseudomonas. So there again, this inflammation has its own sort of feedback loop and cycles that are not necessarily always dependent on the bacteria. So the point that I want to make about all of this is that in this same study, they analyzed their patient cohorts who had the sputum. And this is the BLESS. They used BLESS trial patients, and they validated it with a UNC cohort. And in cases in which the sputum was induced with saline, hypertonic saline, the mucin content came down by 25%, which is not that surprising. But my point is that if using hypertonic saline in your patient has the potential to reduce the mucin concentration and therefore reduce the inflammation. Once again, if lovin' hypertonic saline is wrong, I don't want to be right. Okay, last point here is that just kind of like PBB, another subgroup of our patients is the eosinophilic bronchiectasis. And this is becoming more and more discussed and covered. About 20%, at least in the EMBARQ trial or the EMBARQ data, 20% of patients have eosinophilic inflammation, and an opportunity there to improve their outcomes. In these patients looking at their level of eosinophilia, patients who had higher eosinophils, not surprisingly, had higher exacerbation frequency. And Stefano Alaberti looked at these patients, separating them into low eosinophils, 150, and above 150. And I found that patients who were treated with the inhaled corticosteroids had an improved quality of life. Now that can become a little gnarly, because you've gotta, you know, there's some data that demonstrates or suggests that the NTM risk is higher in patients with inhaled corticosteroids. But that's sort of the fun of what we do. It's not just cookbook medicine. We have to consider these patients individually. They're not all the same, and that's what makes our day interesting. So in summary, bronchiectasis is an inflammatory condition, not just chronic infection. Inhaled corticoelastase inhibitors are promising and exciting data to come soon. And currently, we can use our macrolides, inhaled corticosteroids, and airway clearance. Thank you very much. Thanks, BJ. What a great way to kind of set up for the next discussions. Yes, I think most of you, while we're getting the slides up, you can appreciate that we've transitioned, for those of you who've been doing this a while, from infection talking just about pseudomonas maybe 10, 15, 20 years ago, to now we're talking about inflammation. In the coup de gras, as Dr. McShane had said, that I think ties that third leg of the three-legged stool together, is the mucins, is that mucociliary clearance that we know has been so important for our patients, but we understand. And I think that you're going to hear a lot in the next couple of years about the MUC5 gene expressions. And again, what happens? We understand that things like macrolide have a huge impact on mucin itself, on the quorum sensing between organisms. And again, we'll bring together the infection that we've done for 20 or more years, the inflammation, as Dr. McShane has, and then now this third leg of mucociliary clearance vis-a-vis MUC5. You'll hear a lot more about that and what's going on in the biofilms. So with that, I'm going to, again, I express my thanks for Dr. McShane for an absolutely fantastic talk. And we're going to try to call up Dr. Daly's talk, and very much looking forward to hearing what's new in NTM lung disease. Dr. Daly. Okay. Thank you. My title is going to be Innovative Therapies for NTM Infections. Basically, I'm putting together what were a number of lectures at the World Congress into 15 minutes. So you know who I am. These are my disclosures. I include consultancies, advisory board membership, data monitoring committee, and contracted research. Two learning objectives. Basically, at the end of this, I hope you recognize some of the new drugs that are coming down the pike, and as well as some of the drugs that you can reach for now that might help you treat your patients with NTM. So I'm going to start off looking at some antimicrobials, both new and repurposed. First we'll look at some drugs that are already approved for other indications, so you actually can try to access those to treat patients. Drugs that are in phase two trials, omatocycline really fits in both categories. It's approved already, so you can get your hands on it, but it's also in a phase two trial. And then a few non-antimicrobial approaches, such as inhaled nitric oxide, inhaled GM-CSF, and phage therapy. So let's start with dual beta-lactam. This is something that we have been using more and more at National Jewish, and I know another of other centers. The reason is because mycobacterium abscessus has a beta-lactamase, and it's called Blamab. It's pretty resistant to beta-lactamase inhibitors. There are two drugs that we use to treat patients with abscessus, imipenem and sulfoxetine, and people wonder why those are the only ones that seem to work, and it's probably because they slowly hydrolyze this particular beta-lactamase inhibitor. Now there are studies that have shown if you inhibit this beta-lactam with a beta-lactamase inhibitor, it improves the efficacy of imipenem. There are also now data with meropenem, and this has been shown in multiple models, in vitro, intracellular models, as well as zebrafish embryos. There are also studies that show that you don't have to use a beta-lactamase inhibitor to improve the activity of a carbapenem, for example. You can just combine two beta-lactams, like imipenem and ceftaroline, and that shows synergy, and that has also been shown in multiple models. This is a study we did with Khalid Dussa and Robert Bonomo, a couple of studies. This is looking at the activity of imipenem, ceftaroline, and the combination. So first, the background is that imipenem and ceftaroline tend to bind the same targets, but imipenem preferentially binds those targets, and what looks like we see is a transformation that opens up the binding site and allows the ceftaroline to bind better. Because by itself, you'll see, ceftaroline has very little activity, and then if you add a beta-lactamase inhibitor in this setting, it was Relobactam, it did not improve the activity. So if we look at the figure on the X-axis, we're going from very low MICs on the left, moving to the right, an increased MIC. So you can see with ceftaroline alone, it's not very active. The MICs are pretty high, and if you move to the left, you see imipenem, the MICs are more active in the range that we would use this drug to treat someone, but when you combine imipenem and ceftaroline, look how that MIC shifts. So now it becomes very active, in fact, synergistic, and it doesn't matter if you add a Relobactam or not. The beta-lactamase inhibitor doesn't do much. So my take on this and other studies is that really, the bang for the buck are two beta-lactams, but if you can't put in two beta-lactams, maybe you can't get one or they have allergy, then if you add a beta-lactamase inhibitor, you will also get synergy, but you don't necessarily need to do that if you have two beta-lactams. So I think you'll see more and more use of this. Now imatocycline is a drug, it's a newer cycline. It's approved in the U.S. for the treatment of pneumonia and skin infections. It seems to be better tolerated than tigacycline. Tigacycline is very active against obsessives, but it's kind of a pukagenic drug. I mean, half the people get sick, and that's very tough if you want to try to give this for months on end in someone with obsesses. So imatocycline gives you the oral option as well as the IV option and seems to produce less nausea in clinical trials when it was compared head-to-head to tigacycline, significantly lower rates of nausea and vomiting in both the IV and the oral. And most of that nausea and vomiting was during the loading phase, and we won't need to do a loading phase in NTM. There's no reason to load for a chronic infection. So we hope that those side effects will be less. Now, this is a drug that is quite active against imobsessives and its subspecies. These are a number of studies, mostly small. But if you look at the MIC 50 and 90 for imatocycline, you see it's pretty low. And you go, okay, it's low, but how does it relate to tigacycline? They're almost exactly the same. The MICs between imatocycline and tigacycline are very, very similar. And then there's another one out there, iravacycline. This is in only an IV form. It looks like it's about a dilution, even more active. So all three of these cyclines have significant in vitro activity. What we need to learn is which one is best tolerated and which one actually works in a clinical trial. Now, because imatocycline is actually available in the U.S., there are now case series that are developing. Most of these are small, but they show good clinical and microbiologic success. I'll highlight the last one. This was a larger one that a number of us in the U.S. put our cases together. And Dr. Mingora at the Medical University of South Carolina published this recently. Basically about 30% had an adverse event, and 22% had to discontinue. And one of the most common adverse events was nausea. When you look at the efficacy side of this, it doesn't look too positive. But most of the patients were still on therapy, so we really couldn't say very much about the efficacy. So this really was focusing more on the tolerability. And in this setting, remember, all of these patients are on multiple different antibiotics. It can be difficult to determine which side effect is being caused by which drug. But ultimately, most of the patients did complete their treatment with this, and there is clearly some activity. And that activity is going to be shown soon, because it is in a Phase II clinical trial. So let's move to some of the drugs in development. This is a clinical pipeline for NTM drugs, looking at Phase I through III. You know, Phase II drugs are usually looking at the activity of that drug. And at Phase II, we might be looking at a microbiologic endpoint, as well as quality of life measures, PRO instruments. When you get to Phase III, a microbiologic endpoint is not considered a primary endpoint, so it has to be some type of PRO or quality of life. And usually in Phase III, what we're looking at are regimens, not a drug alone, whereas in Phase II, you can do monotherapy studies. Now these are some of the ones that are in Phase II trials, or soon to begin, and ones that I will briefly update you on. So e-petroboryl is a very interesting compound. It contains a boron molecule. It has an interesting and fairly unique mechanism of action by inhibiting the protein synthesis enzyme leucyltransfer RNA synthetase. These are data that were presented last year at ID Week, and next week my lab will be presenting some updated data on abscesses in e-petroboryl. But what's out there now is mostly MAC. Here we can see they use two different culture media comparing the activities of e-petroboryl with two other important drugs, clarithromycin and amikacin. You can see that the e-petroboryl was very similar to clarithromycin, so very active and more active than what we see with amikacin. So for MAC, this looks like to be an active drug, one of the most active drugs. We also have data looking at this in a chronic mouse model, which is, I think, the activity is even more impressive. So what you see on the y-axis is the CFUs with different dosing. So the first here is the control. If it's going below the line, there's a reduction in the CFU. So in the control, the organisms are growing and actually increased. Then they gave clarithromycin, again, for MAC, this is our drug. And you can see a significant decline in the CFU. And then from there on, we see increasing doses of e-petroboryl until we get to here at about 250 milligrams, which would be about what we would be giving an equivalent dose in humans. And you can see that compared to clarithromycin, up to that point, each of these doses, this is very impressive, statistically significant increased activity. So very active when you compare it as a monotherapy to clarithromycin. But of course, we're not going to do that. We're not going to give monotherapy. So they also looked in a model. Here they looked at four strains and recognizing these are small, but they're showing you kind of the same thing. But what they did here is they gave standard of care therapy. So that's right here, your three-drug regimen. You can see it works. There's a reduction. But when you just added e-petroboryl to standard of care, look how much more active it became. And these are four different strains of MAC. And in each one of these, just simply adding e-petroboryl to standard of care greatly enhanced the reduction. So from an in vitro and mouse model, this looks very potent. Another drug in development, SPR-720. This is a non-fluoroquinolone, gyrase B inhibitor. It is converted to SPR-719, which is the active moiety. This has been also studied in multiple models, in vitro, hollow fiber models, mouse models. And what has been shown is it has very good activity against slowly growing NTM, particularly mycobacterium kanzasii. And it's orally formulated. So there are multiple studies that have looked at the activity of this. Here you see both slow growers and rapid growers. If we look at the top here, these are slow growers like avium, intracellular, and look at the MICs to kanzasii. That's unbelievable. This is incredibly active against kanzasii. Simiae is always a tough bug. It's a slow grower, but very resistant. And then here are abscesses and mycelians, not a lot of activity. So as you're going to highlight something, this thing is impressive against kanzasii. So impressive that it's the kind of drug that maybe would allow us to shorten therapy. So just a reminder, all three of those drugs, epetroboryl, imatocycline, and SPR-720, are all enrolling now in phase two, and the epetroboryl is actually a phase two, three study. You can find out more on clinicaltrials.gov if you have patients that you might want to refer to a local site to get into one of these studies. But all of these look very active in vivo and other models. Now let's talk about some non-antimicrobial approaches. Inhale nitric oxide. So these are a couple of phase one studies. One was in healthy adults. The other is CF patients. They got treated pretty much the same. Inhaled 160 part per million of nitric oxide for 30 minutes, five times daily for five days in the healthy study. Well tolerated. No SAE, no AE. And the upper panel shows you the percent methemoglobin, because this is the possible downside, is that with nitric oxide, when it combines with hemoglobin, it produces methemoglobin, which of course is toxic to humans. So by giving it, though, intermittently at the doses that they give, they don't reach toxicity levels or don't sustain them. And you can see here during the treatment period here, right there, there was a rapid increase in methemoglobin, but it very quickly drops down to almost nothing so you can give the next dose. In the next study, it was a small group of CF patients, similarly dosed, little variation. Here they did have some AEs, but it was basically dry mouth. And this just shows another type of outcome, which is their FEV1 was increasing during this time. And this is regardless of the pathogen. This is just showing that maybe there's some anti-inflammatory effect by giving this. So also interesting findings. And this is a recent study, Patrick Flume and Kevin Winthrop published this in Respiratory Medicine this year. This is a small study, but they took 10 patients who had pulmonary NTM, nine of them had been on long-term antimicrobial therapy, but they had been failing therapy because they were persistently positive. They were treated with NO gas, a little differently than the others, 50 minutes, three times daily, five days a week for three weeks. So they got a total of 15 treatments. 40% of them culture converted, but three of those, once the treatment was stopped, reverted back to positive, and then the treatment was well-tolerated with no discontinuations. And that's probably the main measure so far, because these are all early phase studies, is that it looks to be safe. And we certainly see a microbiologic effect in some patients during the time that the gas is present. So again, more to learn about this. And a study just completed this past year in Australia, and we're waiting to see the results of that trial. There's been a lot published about the immune system in the airway and cystic fibrosis patients. One of the areas that has been studied are the function of alveolar macrophages. And there are multiple ways that these can be impacted in the CF airway. There are also some mouse studies that have shown that alveolar macrophages from GM-CSF knockout mice, they exhibit basically defect of phagocytosis, bacterial killing. And also, there's mouse models of M. abscessus, and they tend to be more susceptible than wild-type mice. So it looks like that the macrophage function is an important immune component to fighting NTM, and I would say not only in CF airways, but any airway. So what happens if you improve that macrophage function? Well, that's been attempted by giving inhaled GM-CSF to people who have refractory NTM. This was a study by Rachel Thompson in Australia, 32 patients who had chronic culture-positive refractory NTM, 14 of them were on treatment, antimicrobial treatment, 18 were not. They got 300 micrograms a day over 48 weeks. So let's say 16% did achieve culture conversion, of which it was durable in 2, meaning it persisted after treatment was stopped. Among 29 smear-positive, there was conversion in about 38% of those. There was no difference in conversion between those on antimicrobial therapy and those not on antimicrobial therapy. One of the things, maybe a down point here was, so we're seeing a microbiologic effect, but there were no improvements in the clinical endpoints that were being evaluated. That's important for drug development, because you're not going to get a drug approved by the FDA based on culture conversion. And then the SEAs were generally due to pulmonary exacerbations and worsening. So again, it looks like an agent that has some microbiologic activity, looks to be safe, but we need more information. And let me finish with FACE therapy. This is a patient of ours that we published under the leadership of Jerry Nick, a 26-year-old man with cystic fibrosis. He had had chronic MRSA and Pseudomonas infections. He was treated for MAC about five years ago and now has subspecies obsessus. He had every drug that I could come up with or Jerry could come up with to treat him with, but he remained culture positive with declining FEV1. This is a busy slide, but it kind of tells the story. So what you see on the y-axis is his FEV1 percent, and you can see it's just falling over these years. At the top are his cultures. The red ones are positive, the black notches are negative. And so during this time frame, he had lots of positive cultures. And if you look, this was while he was getting all of these regimens, all the ones I just talked to you about and more, and we could not convert him. But because of this decline, you can see where he got to. He got to transplant time. But he would not be listed for transplant unless we could convert him and get control. So we talked to him and said, you know, we don't have any more drugs for you. Let's try something else. So this is when he got dosed with a phage. And you can see what happened at the top. The red became black. We converted him for the first time in all of these years. He converted his cultures to negative. He never grew abscesses again, and he was transplanted. And even after transplant, he did not grow it. He unfortunately died a couple of years later from rejection, but he never had abscesses again, and in the explanted lung, there was no abscesses. So this did convert him to negative for long term. We looked at other things because we're trying to figure out, was this helping him? And we looked at clinical things like radiographic improvement. You can see this cavity in the top closed. This nodule resolved, resolved, got bigger, then resolved. So we see radiographic improvement that was pretty impressive. And these are biomarker changes. This is part of a biomarker study in CF patients. The top panel is showing sputum DNA, an in-house assay, sorry, an in-house assay. You can see it was elevated prior to phage, then it spiked after he got the phage. So why would that happen? It would suggest we're releasing DNA. The organisms are breaking apart. And then it went to undetectable. This was urinary lamb. We can see it was elevated, spiked. Why did it spike? Because we believe that the phage disrupt the cell wall of organisms. And that's why the DNA was released. So we have two things suggesting that we're destroying the organism and then went to undetectable. And these were in-house IgA and IgG, elevated, started falling after phage therapy, and then almost undetectable thereafter. So biomarkers also demonstrated what we thought clinically we were seeing, is that this in fact converted this person. So we think phage therapy is also something we should be looking into and more excited about. So I'm going to just mention that more than our patient has been given phage, 20 patients have been given phage by Graham Hatfield. That's who we work with at University of Pittsburgh. And if you look at those 20 patients who got phage, there was a clinical, let's call it favorable outcome in about 11 patients. In eight patients, they did not have a good outcome, and they developed neutralizing antibodies against the phage. So something we need to learn is how do we prevent that from happening? Because we think that's going to have a negative impact on the outcome. So anyway, it's very exciting, I think, data. This is my summary. I will leave it up for you to read for sake of time so we have some questions. Thanks very much, Chuck. Thank you.

non-CF bronchiolitis

NTM lung disease

research registry

multicenter clinical trials

dual beta-lactam therapy

mycobacterium abscesses

epathroboral

ematocycline

SPR-720