So our, our current therapies for bronchiectis up until this point have really been focused around two things, antibiotics and airway clearance, mucoactive drugs to help with mucociliary clearance. Airway clearance is fundamental to managing the disease, we teach patients to clear their mucus, uh, more effectively, but this is a palliative treatment, it doesn't break the cycle, it just makes patients feel better and reduces the risk of mucus obstruction. So it's not, not going to change the course of the disease, it's palliating the symptoms. And so most of the therapeutic development until recently has been different types of antibiotics, mostly delivered through inhalation. Uh, infection is an important component of bronchiectis, uh, but it's not the primary driver in my opinion, and that's been demonstrated through all of the, the studies that we've done with antibiotics. They reduce the frequency of exacerbation somewhat, they improve symptoms somewhat, but the results are often inconsistent because in. is an important player in some people, it's a less important player in others, uh, and in all cases, even when you manage to clear the infection with a high dose antibiotic, the underlying pathology, which is neutrophil driven inflammation and mucus hypersecretion, are not fully addressed, in fact, they're, they're, uh, addressed to only a very limited extent. Uh, and so the absence of a therapy directly targeting the underlying driver of the pathophysiology, which is the inflammation, uh, has been the major gap, uh, and so our, our reliance on antibiotics has led to an ongoing very high burden of disease. Probably the most effective treatment that we've had up until this point is long-term macrolide therapy, um, azithromycin, uh, and that does, Reduce the frequency of exacerbations, the evidence supports that, and it probably does so because it works through a, an anti-inflammatory mechanism that includes some effects on the neutrophils, but it's much less targeted uh than some of the more novel drugs, azithromycin is still debated exactly how it works, uh, and so although that's an important part of our therapy that we use for very severe patients who are having frequent exacerbations. Um, it's not, it's not a disease modifying therapy, it's not one that directly targets the neutrophil, uh, and it's not something that can be used very widely because of the risks of antimicrobial resistance, adverse effects, uh, and, and risks such as driving resistance in non-tuberculous mycobacterial infection. So although we've had a large number of therapies that we use in bronchiectis. Um, none of them quite fit the bill in terms of what we've been looking for, uh, to try and modify the course of the disease.
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