Video Focus on Bronchiectasis Patients with Recurrent Exacerbations Despite Standard Therapies Play Pause Volume Quality 1080P Fullscreen Captions Transcript Chapters Slides Focus on Bronchiectasis Patients with Recurrent Exacerbations Despite Standard Therapies Overview CLICK HERE FOR CME CREDIT Back to Symposium Hello, uh, my name is Dave Griffith. I'm a professor of medicine at National Jewish Health in Denver, Colorado, and today we're gonna talk about neutrophil-based targeting and non-cystic fibrosis bronchiectasis, and this will be a case focusing on patients with recurrent exacerbations despite standard therapies. This is a 58-year-old woman who has bronchiectasis and recurrent exacerbations despite standard therapies. She's been on long-term macrolide therapy. She's been on inhaled antibiotics and still with those two interventions has more than 4 exacerbations per year. Her management involves both nonpharmacologic and pharmacologic therapy. The non-pharmacologic therapy of bronchiectasis is the essential basis for any effective treatment of bronchiectasis. Uh, our airway clearance regimen generally includes a vibratory positive expiratory pressure device and nebulized hypertonic saline. If those are not optimally effective, then chest wall oscillation with a percussion vest. Is an important next step and finally, uh, a newer intervention is lung expansion therapy which also can be uh quite effective but uh again square one for any patient with bronchiectasis is adequate airway clearance um I should add that these patients frequently benefit from pulmonary rehabilitation. They frequently have nutritional deficits, so addressing those nutritional needs is very important, and, uh, gastroesophageal reflux disease is very common in this population. Uh, that certainly exacerbates bronchiectasis and addressing that, uh, can also be quite helpful. Now traditional pharmacologic therapy for bronchiectasis includes the aforementioned mucolytic therapy. We favor 7% hypertonic saline. I know that some people like 3% hypertonic saline, but we generally don't have any problems getting our patients to use the 7% saline without problems. The next step is anti-inflammatory or immune modulating therapy, and the most common immune modulating treatment is macrolide treatment. Macrolide is effective. It does diminish the frequency of exacerbations in these patients. The problem, of course, is that for patients who have mycobacterial disease. It raises the risk of developing macrolide resistant mycobacterial infection. And for patients who have chronic pseudomonas infection, inhaled antipseudomonas therapy is also effective for decreasing. Bronchiectasis exacerbations due to Pseudomonas. Now, quickly, uh, what is a bronchiectasis exacerbation? There is a definition, and I, I wanna go through this, uh, at least briefly. This is an international expert consensus, uh, definition. Um, an exacerbation is diagnosed when a patient experiences a deterioration in 3 or more. Of 3 of these key symptoms for 48 hours or longer cough, uh, increased sputum volume, or change in consistency, uh, sputum purulence, breathlessness, or reduced exercise tolerance, fatigue or malaise, and, uh, hemoptysis. Now a critical element to this. If the patient has these symptoms, the clinician must determine that a change in bronchiectasis treatment, typically starting antibiotics is necessary. If all of those elements are present, then a patient can be diagnosed with a bronchiectasis exacerbation. I want to emphasize one thing starting antibiotics is not a requirement. So that a patient can be diagnosed with an exacerbation even if an antibiotic isn't prescribed. It just needs to be documented well in the note that an intensification, say, of airway clearance was recommended rather than starting an antibiotic. So let's go back to our patient and I'm, I, I have sort of facetiously asked what's wrong with this picture. Um, this patient has bronchiectasis. She is a recurrent exacerbator despite standard therapies, and those include, uh, adherence to airway clearance, long-term macrolide therapy, inhaled antipseudomonal antibiotic therapy, and yet she still has more than 4 exacerbations per year. So she also uses mucolytic therapy. She has anti-inflammatory therapy, uh, in the form of, uh, macrolide and antipseudomonal therapy in the form of an inhaled, uh, antibiotic. So what, what are we doing wrong? What additional intervention is available to this patient that is effective? So framing the question a little bit different, this patient is receiving every intervention we know to make for a patient who has frequent bronchiectasis exacerbations, and yet she still has frequent exacerbations each year. So Just a reminder, bronchiectasis is a disease characterized by chronic self-perpetuating bronchial inflammation, and by that I mean there is no specific stimulus for the bronchial inflammation. It is a Auto stimulatory or self-perpetuating process. The new anti-inflammatory medication brinzaccadib is an anti-inflammatory drug that is not a steroid and not related to other familiar over the counter anti-inflammatory drugs such as ibuprofen. Now, brinzicattib has no direct effect on the lung, lung, and um Somewhat interestingly, it has its effect in the bone marrow. Brenzicata blocks the activity of the enzyme dipeptidal peptidase 1, also known as cathepsin C. By inhibiting DPP-1, brinzicatta prevents the activation of neutrophil serine proteases, most notably neutrophil elastase and proteinase 3, which are overreactive in inflammatory lung diseases such as bronchiectasis. Brinzicatti affects maturing polymorphonuclear or PMN cells in the bone marrow. So they release lower levels of these NSPs at the site of inflammation, such as when they are recruited into the endobronchial inflammation and bronchiectasis. So in bronchiectasis they result in less intense inflammation within the bronchial tube, and here's the critical element less potent recruitment of other PMNs that would then augment the inflammatory response and in turn recruit more PMNs. This is the pivotal phase 3 trial of DPP-1 inhibitor brinsicaddi in bronchiectasis patients that was published just over a year ago in the New England Journal of Medicine, and I want to go through a little bit of the data from this pivotal article. It described a phase 3 double-blind trial of bronchiectasis patients who were randomly assigned in a 1:1:1 ratio to receive brinzacat of 10 mg or 25 mg once daily or placebo. The primary endpoint was the annualized rate of adjudicated pulmonary exacerbations over a 52 week period. Those exacerbations, by the way, were, uh, followed the diagnostic uh criteria that we mentioned earlier. Important secondary endpoints were the time to first exacerbation during the 52 week period, the percentage of patients remaining exacerbation free at week 52. The change in forced expiratory volume in 1 2nd or FEV 1 on spirometry. The annualized rate of severe exacerbations and Change in quality of life. A total of just over 700 patients were randomized and received either brinzacadeb or placebo. The rate of pulmonary exacerbations was as follows and as can be seen with the P values for 10 mg and 25 mg of brinziccaib per day. The rate of pulmonary exacerbations was significantly lower in both brinziccaib dosing groups compared to placebo. Similarly, the time to the first exacerbation again compared to placebo was significantly longer with the both doses of brinzicate compared to placebo. The authors also looked at how many patients remained exacerbation-free throughout the 52 week period of the study. And both brincicata 10 mg per day and 25 mg per day were associated with higher numbers of patients who were exacerbation free than placebo. Again, these differences reach statistical significance. This slide demonstrates. Changes in post bronchodilator FEV1 from baseline over the 52 weeks of the study. What it shows is that there was a significantly lower decrease in FEV1 with the 25 mg per day dose of brincicadib compared to placebo. The 10 mg per day dose of Brincicada did not reach statistical significance uh in terms of the difference in change compared to placebo. I think this is a very important slide. The changes in FEV 1 are relatively small. But maintaining pulmonary function in these patients is extraordinarily important. And at the 25 mg per day dose of brinziccata, that was achieved. So the authors concluded that among patients with bronchiectasis, once daily treatment with brinzakat of either 10 mg or 25 mg per day. Led to lower annualized rate of pulmonary exacerbations than placebo, and the decline in FEV1 was less than placebo with the 25 mg dose of Brincicadem. This is a pivotal study, and this study of Brincicata resulted in demonstrating to the FDA that the drug can decrease the frequency of bronchiectasis exacerbations for some patients. And can be associated with maintenance of pulmonary function versus placebo in some patients. Both the 10 mg and 25 mg per day doses diminished the frequency of exacerbations, but only the 25 mg dose was associated with the maintenance of lung function. Side effects are generally infrequent and generally mild. They include infections in the nose and throat, headache, increase in blood pressure, skin reactions including hyperkeratosis, dental and gum issues, and allergic reaction. Now we're going to go into this in a little bit more detail. So it's important to keep in mind this is the first drug approved by the Food and Drug Administration. Specifically for treatment of bronchiectasis, and let's pause for a moment. Bronchiectasis is basically an ancient disease. As long as there's been tuberculosis, there has been bronchiectasis, and there has never been treatment for bronchiectasis. My career spans approximately 40 years treating bronchiectasis patients, and I have never been able to give patients anything that specifically targeted their underlying disease, that is the bronchiectasis. The label given by the FDA for bronchiectasis simply reads, Uh, indicated for patients with non-cystic fibrosis bronchiectasis. I think it's important to remember the FDA made no stipulations about or requirements for a certain number of bronchiectasis exacerbations within 12 months of the prescription. And this is also the only medication known to protect pulmonary function in bronchiectasis patients, at least over a 12 month period. I think it is also very important to remember this is the only FDA approved drug with an anti-inflammatory mechanism that brinzakadeb has. So let's dive a little bit deeper into adverse events. Now, as we talk about these adverse events and these uh percentages, remember this is compared with placebo that in the study, uh, these adverse events occurred at a higher uh rate than placebo. But there was no statistical analysis done to say whether or not that difference was significant. The FDA required that any of these side effects, if they occurred more frequently than placebo, had to be listed in the label. So we mentioned hypertension. Uh, the dermatologic lesions can, uh, can vary. Hyperkeratosis is perhaps the, the one that is the, the most, uh, uh, attention getting. Um, under gastrointestinal, there is the, uh, periodontal adverse reactions, uh, and gingival adverse reactions which are, which are rare, uh, actually in the phase 3 study, uh, there was not a significant difference, uh, between placebo and brinzicata, uh, in the periodontal or gingival problems. Uh, now I would, I think it's worth noting here. You notice there are no other gastrointestinal side effects listed here. That is a rather remarkable finding. Patients are generally attuned to GI problems like nausea, vomiting, and diarrhea, but they are not part of the spectrum of adverse events with this drug. Um, hepatic, uh, there are, uh, patients with increased AST, uh, uh, and ALT as well as alkaline phosphatase. Um, as far as we know so far, uh, there is no risk for, uh, fulminant hepatic failure. Um, headache is also a potential problem, uh, particularly for people who have, uh, a history of headaches. The respiratory side effect of upper respiratory tract infection is very interesting. It's not really a side effect because these respiratory tract infections were due to mostly viral infections. They also occurred with a relatively high incidence in the placebo group. Uh, but I think it's worth noting this does not have anything to do with immune dysfunction. So I think another few important observations. There are no known fatal side effects of the drug. Side effects are reversible after discontinuation of the drug. As I mentioned, there are no GI symptoms or side effects. Uh, now this, uh, this next one is quite remarkable. There are no known major drug-drug interactions and no medical contraindications to the drug. And as I mentioned, brins academ administration does not result in immune suppression. Or compromise. So from this case, um, what are the takeaways? Well, persistent exacerbation despite optimized care. Are uh uh highlights of inflammation as an independent driver of the disease. And neutrophil modulating agents such as brinzacab may break the infection inflammation cycle and reduce exacerbation frequency without adding antibiotic burden and as important without creating a state of immune suppression. So I'd like to thank everybody for their attention, and I hope you found this useful. Published September 29, 2026 Created by Related Presenters Professor David E. Griffith, MD Professor of MedicineNational Jewish HealthDenver, Colorado, USA
