Well, good afternoon, everyone. I'd like to uh welcome you uh to Vienna, both in person and uh remotely. Uh I'm going to talk uh a little bit about several aspects of managing uh mac lung disease uh including uh trial based advances uh in treatment for high risk patients and uh those with refractory mac lung disease. These are my potential conflicts of interest. First, I wanna talk again about predicting mac disease progression and there are uh four areas uh where that might be accomplished. There are clinical predictors, microbiologic predictors, immunologic predictors and then molecular uh predictors. Time to culture positivity is the time for inoculation of a liquid medium culture bottle in an automated mycobacterial culture system to the first detection of growth in the bottle. So, this was a recent meta analysis looking at several studies that had identified possible predictors of disease progression. And I I think it's important to point out the ones that were most helpful in this model. It was a consolidated pattern on radiograph or chest ct leukocytosis. The presence of a cavity being older. A FB smear positivity, a history of tuberculosis and the isolation of mycobacterium abscessus. Uh I think these are, these have all been previously identified, but this solidified their utility in predicting uh both mortality and progression of mac lung disease. There's also recently published a scoring system. We're looking at the severity of uh NTM lung disease and the prediction of progression. Uh It involves BM I age cavitation, uh erythrocyte sedimentation rate and uh gender. Um and each one of these is assigned a point. And as you can see on the slide that the probability of five year mortality goes up dramatically. If you have a score of five, it is interesting that uh in the scores between one and four, there's not a lot of differentiation, but once you reach a score of five, both mortality uh and disease progression are very likely an important microbiologic technique for predicting who will need therapy and who will uh respond to therapy is the time to culture positivity. That is the time for inoculation of a liquid medium culture bottle and an automated mycobacterial culture system to the first detection of growth in the bottle. And basically how this works is the shorter the time to culture positivity. The more likely uh patients will have progressive disease and require therapy. Conversely, the longer the time the it is less likely that they will require treatment. So this is a study of 100 and 25 patients with positive sputum cultures for mycobacterium avium. And as you can see, looking at disease presence. A FB smear positivity treatment initiation at either three or six months. There is a highly significant difference in those patients who had time to culture positivity less than 10 days and those with time to culture positivity greater than 10 days. The conclusion was that time to culture positivity is associated with bacterial burden and infection severity and increases in response to treatment in this study. A threshold of 10 days or less was useful in predicting significant uh disease progression. This is another time to culture positivity study looking at who will respond to therapy. This is data from the Alice convert trial. It involves 71 participants. The median time to cu culture positivity at screening was longer in those participants who achieved culture conversion versus those who did not. And individuals with culture conversion by study treatment, six were more likely to have a screening time to culture positivity greater than five days compared to those who did not. And the conclusion was time to culture positivity prior to and on treatment is associated with microbiologic treatment response. So this is a very good method for predicting who will need treatment and who will respond to therapy. This is also a relatively easy technique. It doesn't require any special equipment or reagents. Uh almost any lab that does liquid media cultures can uh provide this data. This is particularly exciting. It was recently uh published uh serum cell free DNA based detection of MAC infection. So this is a technique that uses CRISPR technology. That's a technology that was developed to modify the DNA of living organisms. But it can also be used to detect cell free DNA uh concentrations in the serum uh including MAC cell free DNA. So in this trial, mac of cell free DNA concentrations were measured uh in patients with a diagnosis of Mac or who had bronchiectasis and uh COPD. It was also measured in MAC patients on treatment. Uh And this is I I think really compelling data uh on the left. Uh It shows uh comparing control patients with individuals with Mac Pulmonary Disease. What's remarkable here is that there's almost no overlap uh and prior uh efforts to measure biomarker differences between disease and uh control, uh there are significant differences but there's also significant overlap. This is quite remarkable. And then in the uh graph on the right uh shows uniform decrease in Mac cell free DNA in uh patients who are on therapy again, uh inc incredibly uniform uh data. So the CRISPR Mac essay uh detected Mac uh cell free DNA in Pulmon Mac Pulmonary Disease with 97% sensitivity and 97% specificity. Uh again, quite remarkable. Uh and uh cell free DNA concentrations markedly decreased with therapy. Uh This is preliminary data. They have yet to uh publish uh any data about using this on uh an elderly elderly patient with bronchiectasis who has one positive culture but uh I feel confident that that data is forthcoming. Now, I wanna turn to treatment of patients with refractory Mac uh Pulmonary Disease and talk specifically about inhaled liposome uh inhalation suspension. Uh This graph on the right uh is from the uh critical paper that described a significant improvement in sputum conversion for refractory patients with the use of uh Alice uh versus continued uh guideline based therapy. And in the guidelines from 2020 it states in patients with Mac Pulmonary Disease, uh who have failed therapy for at least six months of guideline based therapy, we recommend amicas and liposome inhalation suspension or Alice uh to the treatment regimen. That was the only strong recommendation uh for Mac in the guidelines. Now, uh in addition to the initial improvement, uh there is also benefit uh while on therapy and then after therapy. So uh sustained culture conversion uh while on therapy was uh better with uh Alice but did not quite reach statistical significance but uh durable culture conversion uh at three months and at 12 months was highly significantly better. Uh with Alice in the in the regimen. I think uh this is part of the convert trial uh that doesn't get a lot of attention, but because there are so many microbiologic recurrences in our current approach, uh This may have a significant impact when uh Alice is available for uh initial therapy. This is uh one last aspect of the uh convert trial uh for those patients who did not receive Alice during the randomization period. Uh they were given Alice and uh a third of those patients converted their sputum uh similar to uh the prior response of uh Alice naive patients. But even more interesting is that patients who had had received Alice and did not convert their sputum. Almost 14% of those patients did uh have sputum conversion with continued Alice you. So uh Alice is recommended in the 2020 guidelines. Uh It's the only strong recommendation for Mac therapy in those guidelines. Uh And so far is not recommended uh for initial Mac therapy. And in my opinion, it is the most significant change in NTM therapy recommendations between the 2007 and 2020 guidelines. And frankly, I I think the FDA made a big mistake uh by not allowing Alice use initially, I can think of no other mycobacterial disease where you wait for your best drug. In this case, macrolide to fail before adding the second best drug, which is Alice, that is a recipe for acquired mutational resistance to both drugs and e it, it's easy to see the optimal use of Alice would be including it in the ini initial map treatment regimen which brings us now to the arise uh study. Uh uh This is the abstract title uh from the uh data that was presented at the American Jurassic Society meeting in May. Uh And basically this was a randomized study looking at uh Alice plus azithromycin plus a than Beal. And the comparator arm uh had a uh placebo plus azithromycin. I have to point out that the primary objective of this study was validation of a patient reported outcome instrument. It was not microbiologic. The microbiologic endpoints were secondary endpoints. Uh The uh some of you may not be familiar with these uh uh patient reported outcome instruments. In this case, it was the Qolb respiratory domain uh which is part of a larger uh pr O evaluating bronchiectasis patients. Now, this, this particular PR O is validated for bronchiectasis but has not yet been validated uh for NTM. Uh And the uh patients in this trial uh filled out the respiratory domain which contained nine items out of uh 37 total items uh in the whole QOLB. Now, comparing uh QLQOLB uh scores between uh patients in the Alice arm and the comparator arm overall, uh there was not a significant difference. Uh There was a trend uh in favor of the Alice arm. But as I say, uh it did not reach statistical significance. I need to point out also that a the higher the change uh in score uh the better uh for the patient and uh with decrease in symptoms. But if you looked at uh comparing uh patients who received Alice and those who converted uh by month six or by month seven, there was statistically significant difference in those qolb uh scores in favor of the patients who had culture conversion in terms of the microbiology. Um At month six, the Alice Arm uh had uh I had better culture conversion than the uh placebo arm, but it did not reach statistical significance. But at month seven, again, there was a higher culture conversion in the Alice Arm versus placebo. Uh And at month seven, that difference did reach statistical significance. Also um in looking at patients, the proportion of patients who uh converted their sputum by month two, there was significantly higher number of those patients uh in the Alice arm versus the placebo arm. So again, the arise study aimed to establish that the qolb uh respiratory domain is a reliable measure uh of respiratory symptoms in patients with mac lung disease. As I mentioned, uh it is validated for bronchiectasis but not yet for NTM disease. But the secondary microbiologic uh objectives uh were generally met. There was higher culture conversion in the uh Alice arm versus the comparator arm. Uh culture conversion was achieved earlier in the Alice arm. Uh As I mentioned, there was greater uh improvement uh in the qolb score within the Alice arm versus the Comparator arm. Um and greater improvement in qolb uh in Alice converters compared to Alice non converters. I want to conclude uh with this study which looked at the impact of the time between diagnosis and treatment for NTM Pulmonary disease. Uh And the bottom line is that the, the bottom bullet, they found no association between the waiting period and six months. Culture conversion or death. But however, they did find that six month culture conversion was associated with a significant negative correlation with death. Uh And in the subgroup treated more than 12 months, 12 month culture conversion was also associated with reduced death. So what this study suggests is that for patients treatment or F factory at six months, if there is an intervention that results in sputum culture, I want to close with this study which looked at the impact of time between diagnosis and treatment for pulmonary disease on culture conversion and uh mortality. The six month culture conversion showed a significant negative correlation with death. And in those patients who were treated for more than 12 months, if they had culture conversion at 12 months, that was also associated with decreased mortality. So what this study suggests is that for patients treatment refractory at six months, that an intervention such as Alice not only improves sputum conversion for treatment refractory patients, but it could reduce mac disease mortality. Similarly, the study suggests that if Alice improves sputum convulsion conversion with initial therapy, that that also might be associated with decreased mortality. Thank you.
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