Video Applying New Trial-Based Evidence, Guidelines, and Individualized Approaches to Real World Management for MAC Lung Disease Play Pause Volume Quality 1080P 720P 576P Fullscreen Captions Transcript Chapters Slides Applying New Trial-Based Evidence, Guidelines, and Individualized Approaches to Real World Management for MAC Lung Disease Overview CLICK HERE FOR CME CREDIT Back to Symposium Hello everyone. My name is Dave Griffith. I'm a professor of medicine at National Jewish Health in Denver, Colorado, and I'm going to talk about translating results of new MAC lung focused trials, evaluating quality of life improvements, time to culture positivity and microbial conversion metrics to optimize antimicrobial drug selection. These are the topics for today's talk. Rapid diagnosis of Mack lung disease, recommended treatment regimens for Mack lung disease. Treatment of refractory Mack lung disease, US and European guidelines for prescribing Amacain liposome inhalation suspension, the AISE study, which is Amacain liposome inhalation suspension as first line treatment for Mac therapy. Including patient reported outcome results and microbiologic results. I also want to introduce the topic of anti-inflammatory treatment of bronchiectasis. Uh, Time to culture positivity or TTP is the time it takes from inoculation of a liquid medium mycobacterial culture bottle to when it becomes positive. The shorter the time for positivity, the more likely a patient is going to have progressive disease and is going to need animycobacterial therapy. There are two studies that have looked at this technique for evaluating patients either before treatment or while they are on treatment. So the first study showed that the time to culture positivity is associated with bacterial burden, meaning smear positivity and infection severity. It also increases, which is a good thing, in response to treatment. A second study, which was part of an Alice trial, uh, showed that the time the culture positivity prior to and on treatment was associated with microbiological treatment response in patients with pulmonary disease. The beauty of this particular technique is that any laboratory can do it. It does not require any special equipment. It only requires knowledge of the time between the bottle is inoculated and when it becomes positive. A second technique which I think is very exciting involves serum cell-free DNA-based detection of Mac infection. This is CRISPR technology. This CRISPR-AC assay detected MAC cell-free DNA and MAC pulmonary disease patients with an almost 98% sensitivity and 98% specificity overall, which are extraordinarily remarkable. Serum Mac cell-free DNA concentrations markedly decreased after Mac directed treatment initiation in patients with Mac pulmonary disease, who demonstrated MAC culture conversion. This study provides some exciting preliminary evidence for the utility of a serum-based CRISPR Mac assay to rapidly detect Mac infection and monitor the response to treatment. These are the recommended treatment regimens for pulmonary disease from the 2020 Multi-society NTM treatment guidelines, uh, for nodular bronchiectatic disease, the preferred regimen is a three-time weekly regimen with a macrolide, uh, rifamycin, and a sambuttal. With cavities, the recommended regimen involves uh macrolide, uh, arithromycin, and a Sambutal on a daily basis. And intravenous ammocain 3 times weekly. For refractory disease, which is defined as culture positivity after at least 6 months of guideline-based therapy, the recommendation is daily azithromycin, rifamycin, and habutal, plus Amicain liposome inhalation suspension or Alice. You can use intravenous aminoglycoside 3 times per week in place of the inhaled ammocasin. This slide summarizes the data supporting the use of AI for treatment refractory pulmonary disease. And in this trial, this was the pivotal trial that allowed the Food and Drug Administration to approve Alice. It, it was shown that patients given Alice plus uh guideline-based therapy had significantly more sputum conversion at 6 months than patients who received only guideline-based therapy. So the guidelines state in patients with pulmonary disease who have failed therapy after at least 6 months of guideline-based therapy, we recommend addition of Amica and liposome inhalation suspension to the treatment regimen rather than a standard oral regimen only. This was the only strong recommendation for MAC treatment in the 2020 guidelines. There is a little wrinkle in this, uh, in that there is a difference between the US recommendations and those from Europe, which we'll talk about in, in a few minutes. In patients who achieve culture conversion by month 6. Culture conversion is sustained, meaning patients remain negative while on treatment, more often with Alice plus uh background therapy than with background therapy alone, although the difference was not significant. But the culture conversion is also durable, meaning once treatment is stopped, patients were more likely to have continued, uh, culture negativity with Alice compared with background therapy alone, and that was highly significant. And that durability was noticed both at 3 months and 12 months. There were patients in the convert trial who had Alice for 6 months and did not convert their sputum. And on the right, you see if you continued the ERA case, about 14% of those patients did eventually convert their sputum. Now on the left is the group of patients who uh did not receive Alice during the convert trial, but then after the trial was completed, they were given Alice, and you can see. That about a third of those patients did convert their sputum, which is close to the uh response initially for patients assigned to the Alice arm of the study. So in summary, uh, Alice, uh, as noted, is recommended in the 2020 guidelines. For refractory disease on the basis of two large randomized prospective trials. There are no other similar trials for treatment of Mac disease, and Alice is the only strong recommendation for Mac therapy in the recent guidelines. In the United States, it is the only FDA approved therapeutic agent for MAC. It is not recommended or FDA approved for initial Mac therapy, but again, we'll come back to that. The most significant change in NTM therapy recommendations between the 2007 and 2020 guidelines is this recommendation, this strong recommendation for use of Alice in treatment refractory Mac disease. Now, uh, intravenous ammocation is recommended as part of initial therapy for cavity or severe nodular bronchiectatic disease that is not a change from prior guidelines. Now, the FDA approval of Alice in refractory ma lung disease, uh, in my opinion, um, It is, is very wrong. Uh, in the sense that I can think of no other mycobacterial disease where you wait for your best drug, in this case macrolide to fail before adding your second best drug, which is Alice. It is a recipe for acquired mutational resistance to both drugs. In my opinion, the optimal use of Alice is including it in the initial MAC treatment regimen. So there is a difference in use of Alice in Europe and in the United States. As I mentioned, the US Food and Drug Administration or FDA. Allows patients with pulmonary disease who have failed therapy after at least 6 months of guideline-based therapy to add Alice to the treatment regimen rather than continue the standard oral regimen. As mentioned a couple of times, it is a strong recommendation. Now, the European Medicines Agency or EMA. has recommended Alice for use in the European Union to treat NTM mycobacterial lung infections caused by MAC in adults with limited treatment options. There is no limitation based on treatment response or treatment failure. Uh, under these uh uh guidelines, uh, Alice in Europe can be used as part of initial treatment. So now we come to a follow-up study, the Arise study with Alice, which was a randomized double blind placebo controlled active comparator multicenter study to validate patient reported outcome instruments in adult subjects with newly diagnosed NTM lung infection caused by Mac. In the AI study, adults with nodular brachiectatic or non-cavitary mack lung disease were randomized 1 to 1. To receive Alice plus azithromycin and hambutal versus patients who received azithromycin and hambutal without Alice. Now it's important to keep in mind the primary objective of this study was to try to validate a patient reported outcome instrument for use in patients with back lung disease. The backstory on that is when Alice was initially approved by the FDA for refractory disease, they made it clear that they would not. Allow further approvals based on microbiology alone. Uh, they had to show that patients improved, uh, symptomatically or uh in their life function. The secondary objectives were safety and, uh, culture conversion. This slide illustrates the correlation between culture conversion and uh QOLB respiratory domain scores, uh, the changes in those scores uh between Alice and the non-AI arm. The QOLB is a validated instrument for bronchiectasis but not yet for Mac. But what it shows uh is that for patients who are culture converted by month 6. Uh, versus not culture converted by month 6, there was a significant improvement in the QOLB respiratory domain scores. Similarly, patients who culture converted by month 7 versus not culture converted by month 7 had significant improvement in the QOLB respiratory domain scores. So this met the FDA requirement for showing in a Patient reported outcome instrument improvement uh in patient symptoms. Um, also, uh, culture conversion by month 6 and by month 7, was significantly better in the Alice arm at month 7. it was greater at month 6, With Alice, uh, but not significantly so. But by month 7, microbiologically, there was a significant difference in culture conversion favoring the Alice group. Additionally, if you looked at how rapidly people converted their sputum, uh, the patients who received Alice had significantly more rapid sputum conversion than those patients in the comparator arm. So in summary, the AI study was aimed to establish that the QOLB respiratory domain is reliable to measure respiratory symptoms in patients with Mack lung disease. Now, this tool, even though there were positive results in the study, has not yet been validated until it is determined to be validated by the FDA. Secondary objectives included assessment of culture conversion and change in patient reported outcomes. As mentioned, there was higher culture conversion in the Alice arm at month 7. Culture conversion was achieved earlier in the Alice arm. There was greater improvement in the QOLB respiratory domain scores within the Alice arm versus the comparator arm, greater improvement in QOLB respiratory domain scores observed in Alice converters compared to Alice non-converters. So a pretty successful trial all around and probably the most important outcome was what we hope will provide validation for this patient reported outcome too. Additionally, uh, there were no new safety events observed in the AliceA, uh, and a 15 month confirmatory study, the Encore trial will be closing soon. So hopefully, uh, we'll have information on a larger study with this patient reported outcome instrument and with more microbiologic data. I'm sure everyone is aware that the FDA has recently approved a new drug for bronchiectasis called renzoatti. It is the first and only treatment for non-cystic fibrosis brachiectasis. The results of the pivotal Aspen trial for Brenzy Adam, uh are are show shown here on the left, but they are summarized on the right. Among patients with bronchiectasis, once daily treatment with renzoate either 10 mg or 25 mg led to a lower annualized rate of pulmonary exacerbation versus placebo. Probably more important, the decline in FEV1 was less with the 25 mg dose of benzoca than with placebo. In essence, what this study showed was that renzocaib helped preserve lung function in this population of ronchiectasis patients. Sorensacade was studied in non-cystic fibrosis, bronchiectasis, and what was labeled the Aspen trial. These are the baseline characteristics of patients who participated in the trial. Uh, you can see it was an international study with many, many sites. Uh, it involved almost 1700 patients who had to experience at least 2 exacerbations per year to enter the study. They received either renzat of 10 mg or 25 mg, or they received placebo. They were randomized to one of those three treatment regimens. And if you look, they were equally matched, uh, pretty much between the three groups. The purpose of the Aspen trial was to evaluate the efficacy of benzocadib, which is a selective DPP1 inhibitor in reducing pulmonary exacerbations and bronchiectasis. DPP1 inhibitors decrease the release of serine proteases by neutrophils. The primary outcome was significant reduction in annualized exacerbation rates with both the 10 mg and the 25 mg doses, the treatment benefits were observed across all subgroups, um, and Adverse event incidents was similar across all subgroups. Generally, the adverse events were infrequent and mild. The conclusion was forensicca have consistently reduced exacerbations across nearly all subgroups. In the Aspen trial, patients also underwent a sequential pulmonary function testing and in the group, the placebo group, uh there was a decline in FEV1 over the 52 weeks of the study. In the renicca group, the decline was much less severe, and in fact, the difference between placebo and rinicat was highly significant. Now, the effect was more in the 25 mg per day than the 10 mg per day, uh, renzicat groups. There's one other study I want to highlight, uh, and it is a study I, I showed last year. It's the impact of time between diagnosis and treatment for anti pulmonary disease, on culture conversion and all cause mortality. This is over 700 patients, uh, and the median waiting period without antibiotics among all patients was about 5 months, which actually is not too bad. After treatment initiation, 2/3 of the patients achieved culture conversion within 6 months. Now, there was no association between that 5 month waiting period and a 6 month culture conversion on treatment or with mortality. But, um, the 6 month culture conversion did demonstrate a significant negative correlation with death, meaning those patients who converted within 6 months were less likely to die than the ones who took more than 6 months. There was a subgroup treated for more than 12 months, and 12 month culture conversion was also associated with decreased mortality. Now reading between the lines, this study suggests that for patients who are treatment refractory at 6 months, that an intervention resulting in sputum culture conversion could reduce NTM disease mortality, and we know Alice significantly improves sputum culture conversion for treatment refractory patients. And the preliminary data also suggests that Alice improves sputum culture conversion if given as part of initial treatment. So at least theoretically it's possible that using Alice as upfront therapy or for refractory disease could have a beneficial effect on overall Mac disease mortality. Published Created by Related Presenters Professor Christoph Lange, MD - Program Chair Medical Director/Clinical DirectorResearch Center BorstelBorstel, Germany
