So good morning, everyone. Uh and uh uh welcome uh welcome uh uh in Milan uh which is my city. My name is uh Stefana Liberte. I'm a full professor of Respiratory Medicine at um University here in Melan and uh the chief of the PM Department at the Humanitas Research Hospital in Milan. I'm really happy to share a couple of um a couple of data with you about non tuberculous mycobacteria and especially mac lung disease. Thank you, Professor Griffith for his excellent talk. Uh I will get some of his point uh in my presentation. Uh But um I would like to uh have a specific focus on the microbiological monitoring in patients with lung disease and especially how to recognize uh outcomes uh once uh treatment uh has been initiated. So as we discuss the diagnosis of uh NT MP D is mainly based so far on three pillars. The clinical domain, uh the patient is supposed to have pulmonary or systemic symptoms consistent with known tuberculoma, bacterial and disease. The radiological domain, either the nodular bronch or the fibro cavitary appearance uh on merely CT scan or even chest x-ray. And finally, the microbiological domain these are daily uh as the first author uh guidelines published in 2020 a big effort from four international societies to ID Infection Disease Society and to Pulmonary Society that actually uh as the 2007 guidelines highlighted the importance of having at least two sputum positive for the same species, species or one bl positive or uh biopsy and culture to have the microbiological domain reached in order to have the diagnosis of NT MP D. Actually, the coexistence of a clinical radiological and the microbiological domain is a way to define the disease activity in people with NTM. So, in patients with a suspicion of NT MP D guidelines are suggesting uh uh an approach which is mainly based on expert opinion and very few data. So let's take a look at uh at those recommendations starting from the 2007 A T SI DS A guidelines. Uh at that time, three early morning specimens on different days were suggested in patients with a suspicion of NT MP D. And for those unable to produce bum induced bum was recognized as a possible uh uh procedure uh for those uh uh able to produce neither spontaneous nor induced, but maybe a bronchoscopy was the right thing to do. The BT S 2017 guidelines are reading as the, these three kind of recommendations. A minimum of two sputum samples on separate days. Uh bronchoscopy if patients uh is unable to expect the rate, uh maybe sputum induction may avoid a bronchoscopy. And finally, ac T directed bronchoscopy if sputum is negative. But still there is a high suspicion of NT MP D and the 2020 A TS er sx me, the I DS A guidelines are suggesting at least three respiratory samples over an interval of at least a week while for those who are able to produce neither spontaneous nor in the sputum bronchoscopy might be suggested. So you see that uh there are different uh different suggestions. But at the end of the story, uh what the three guidelines are telling us is that uh we need to be sure that the pathogen is there uh repeatedly. So two or three respiratory specimens are important over an interval of uh at least a week. And uh the induced sputum, the induced sputum from one hand and bronchoscopy from the other hand, are two very important procedures that we might want to suggest to our patients to reach the microbiological diagnosis of NT MP D. Then once we have defined the NT MP D, then treatment decision should be individualized. So the presence of these three domains does not implied treatment in 100% of the cases. But first of all, if the three domains are there, treatment might be suggested instead of a watchful weighting, especially if smear is positive and especially if uh there is a a cavitation on the CT scan and or if sign symptoms are severe. In this case, in this case, is treatment uh uh should be strongly considered uh instead of watchful waiting on the other end, watchful waiting might be suggested instead of treatment in case of mild symptoms, mild radiological appearance, and a species isolated on two sputum cultures or even on BL, but that is not considered a pathogenetic species. So there are several other factors that we daily uh consider in order to decide treatment or watch, we're waiting in our patients. I mentioned the pathogenicity of the organisms. I mentioned patient symptoms, but also the underlying immunosuppression is important. Uh pro treatment. Uh The uh spec the presence of specific factors associated with a poor prognosis. I mentioned cavitation but very important is also a low BM I. And finally, we need always to mention uh and to discuss with the patient, potential risks and benefits of therapy. Uh We should always discuss patients priorities and have an agreement on what are goals of therapy. Now, usually I take time to do this, not at the first visit. Uh I I take at least two or maybe three visits to go over the different aspect of the disease, the disease activity, the need of treatment, uh treatment options, uh treatment outcomes, uh safety. Uh Usually I'm based uh I ba I base my discussion on available data. Um And uh I try to make the patients uh feeling to be part of, of a of a family. You know, uh we're a multidisciplinary team is around her or him. And this multidisciplinary team made by respiratory physiotherapists, psychologists, um nutritionist uh will take care of her or him during this long journey. Uh I usually present a very clear program um I always discuss also on possible exit strategies. Uh I give contact about patient associations and I try to identify the family uh a care uh because um in the next uh at least one year and a half, uh there might be some issues, some problems. So having a caregiver checking for patient psychological status, patients compliance is very, very important to me. Treatment of MAC PD uh suggested by the 2020 guidelines. Uh uh uh is stratified according to disease severity. Uh not only clinical but also radiological severity. So, in nodular bronch static disease, uh ayin revamp and a three times uh weekly is the suggested regimen while in people with a more severe disease or uh or a cavitary appearance or in cities can usually uh the uh frequency uh is increased to a daily treatment with the three drugs plus. Um A IV mainly uh I mean, ideally for three months uh but sometimes uh uh sometimes uh there might be some issues with patient uh tolerance uh treatment should uh uh should be uh conducted for at least 12 months after cultural conversion. This is what guidelines are uh telling us. So what happens usually uh once treatment is initiated. So I prepare a very simple cartoon usually uh as as it happens in several other infection diseases or other respiratory infections. The result uh So the outcome is mainly based on the interaction of three factors, right, the host, um immunosuppression or a patient with immunocompetence, the mycobacteria uh mac uh or abscessus for example. And the drugs we are using and there are plenty of factors that uh are involved in these interactions. I'm talking about PKPD, toxicity, resistances, violence, immune deficiency. And uh all these interaction usually determines our patients outcome. If we think how to the disease uh might evolve. Once treatment is initiated, I'm thinking about a microbio microbiological resolution or suppression of the mycobacteria. So, the bacterial count in the Alvira space goes down. After that, we might have an new resolution uh followed by a clinical resolution. So there is a decrease in, in the intensity and severity of sin and symptoms. And finally, there might be a radiological resolution for NT MP D for Mac PD. Actually, it's very difficult to define exactly the timing of this four part of physiological aspects, right. So what we know is that usually radiological uh uh improvement uh followed uh a clinical improvement and that we might not have very, very clear and uh uh and uh good uh biomarkers uh for disease activity and for response to treatment in NT MP D. So, the microbiological resolution still is one of the most important endpoints uh in Mac PD when we start treatment. So in order to assess response in NT MP D patients undergoing treatment, the three previously mentioned guidelines are suggesting as sputum smears and culture obtained monthly during treatment. These were the 2007 guidelines recommendations. Uh The BT S 2017 are suggesting to have sputum samples every 4, 12 weeks during treatment and 4, 12 months after completing treatment. Uh CT directed uh BL or bronchial wash is important uh if I have a negative sputum, but the suspicion of a persisting NTM infection is there. And the CT directed the bronchial wash after six and 12 months is suggested uh um with AC T scan. If the patient is not able to expect for it, the 2020 guidelines are suggesting that the sputum culture should be done uh should be performed every either one or two months during treatment in the sp if patient is unable, enabled, unable to have spontaneous sputum, uh while bronchoscopy might be used in very exceptional circumstances. So there is a rule in microbiology, there might be different uh suggestions across guidelines in terms of timing of sputum culture. But still it's very important to check sputum culture because eradication is the most important early endpoint when we start treatment in these patients. So another cartoon that can help us in better understand uh what's going on. Uh If, if the patient is doing well, we have a negative sputum culture, sinus symptoms are improving and later on also, the imaging is getting better. We might also have a situation why. Uh while the, the, the the the microbiological domain uh still is positive for the isolation of the same species sinus symptoms uh do not, they do not improve but they do not get worse. And also the radiological imaging is almost the same. So this is a situation where the patient is neither improving nor worsening while we can recognize a worsening of the patient. If the pathogen is still there, sudden symptoms are getting worse and the imaging is getting worse. So six months is a time point once treatment is initiated, that is very, very important to understand if our patient is in one of these three situations. The six month time point has been also recognized by the 2020 guidelines uh in defining refractory market as a patient with a sputum culture positive for the same species after six months of guideline based therapy. So the definition of refectory PD is detailed in the guidelines and the guidelines are suggesting in these patients to add a first drug which is Alice according to randomized control trials that proved the efficacy in this population of Alice versus standard of care. I'm talking about the convert data. So the convert was um uh a study enrolling adults with treatment refractory Mac PD screened and enrolled in a two by one fashion uh enrolled uh randomized to guidelines based therapy alone or guideline based therapy plus Alice uh during a 12 month uh of treatment phase and uh 12 months of treatment phase. Primary endpoint uh was the percentage of patients with a cultural conversion by six months. While among the other secondary endpoints, the durability of cultural conversion, three months of treatment was one of those. So the data of the convert study clearly show uh that between patients who achieved cultural conversion on Alice plus or LGBT. Uh there was uh a statistically significant difference in comparison to patients uh on the oral G BT alone arm. So 29% of the patient in the ali plus G BT reached cultural conversion uh versus 8.9% of those in the guidelines based therapy alone. So there was a threefold increase if Alice enriching cultural conversion, if Alice was added to guidelines based therapy, and 63% of Alice treated patients who converted, remained converted after treatment. So at month 12, there was a statistically significant difference between patients who reach cultural conversion in the uh guidelines based therapy plus Alice drop 18% versus 2.7% of those in the guidelines based therapy alone. And then there was also a durability because cultural conversion was a durable uh after uh discontinuation of Alice. So you can see uh of after treatment uh uh discontinuation at three months and 12 months, there was uh 16% of patients in the ally plus guideline based therapy arm, uh rich culture conversion versus zero in the guidelines based therapy alone. And the same was this, this statistically significant difference was also proved uh at month 12 of treatment, 13% of patients reached card conversion in Alice group versus zero in the guideline based therapy group. So, uh this is another paper that uh the Griffith published in just uh recently uh that evaluate uh the different cultural negative uh and culture, cultural negative. Before and after 12 months of treatment reinfection and relapse among the uh convert patients. Uh 80% of the patient had a, a negative sputum culture. Uh And only 7.7% had a relapse and 4.6% had a reinfection in terms of safety data. Uh treatment. A vig adverse events uh occurred in the same way in the Alice group and in the oral G BT alone group. So any treatment emergence adverse events was 98% in the Alice group and 91 in the or LGBT alone group. While the serious uh treatment emergence adverse events uh uh prevalence was 20% in the Alice and 18% in the G BT alone group. Uh And the um rate of adverse events was consistent uh up to the end of the study at month 28. So let's take a look at the uh Alice uh adverse events. So, uh this is a uh a study uh if we, if we, this is the, the convert study published in the blue journal in 2018, uh showing all the different uh adverse events related to ally treatment, mainly dysphonia cough dip. Uh so mainly respiratory uh driven uh adverse events. And uh um if you take a look at the 12 month open label extension, uh clinical trial data published by Kevin Winthrop, uh you can see that uh in the Alice naive Court, uh dysphonia cough dias uh were there together with fatigue and uh and in the prior Alice court, also opis was there. So at the end of the story, this is what we are expecting, right? Uh If we give an inal antibiotic to uh patients with uh with, with a, with a lung disease, so we can anticipate these adverse events and we can manage these adverse events. So, for example, uh if our patients have as dysphonia, we might want to use some anti toys uh agents. Uh We want to suggest the patient to Ryan's mouth after the after the nebulization. Uh If my patient has a dias for example, we we we tend to give bronchodilators before giving the inal antibiotic. We might also think about an adjustment uh a temporary adjustment of the dose if my patient has an increased cough or increased put, uh we want to be sure that every clearance and pulmonary gene are optimized in the pa on, on that specific patient because we want to have uh the out uh of the lung in order for the in an antibiotic to go in. Right. So all these management strategies that we know since many, many years for us who are working in the cystic fibrosis uh community, for example, where inal antibiotics have been used since uh several decades. Uh All these management strategies are um are crucial in order to optimize Alice and other inal antibiotic use. So if we take a look at the um label given by the FDA for Alice, uh so the um the the FDA uh recognize Alice uh uh to be given in adults um uh for the treatment of Mack lung disease as a part of a combination antibacterial drug regimen in patients who do not achieve negative sputum culture after at least six consecutive months of a multi drug background regimen therapy. So, an indication in line with the convert data, right, for us who are practicing in Europe, actually, the European Medicine Agency uh gave a different label of is so is is indicated for the treatment of NTM lung disease due to mac in adults with limited treatment options who do not have cystic fibrosis, right? So my question is what limited treatment options mean. So this is a very important question because uh the treatment uh uh might be under used or overused according to a different interpretation of the Mabel. So this is the reason why in order to clarify a among experts. What limited treatment options are in Mac Pulmonary Disease, the MAC PTO consensus uh uh methodology and Delphi process have been developed. So we developed a board of independent European experts uh that are treating and managing, managing people with MP D in order to define what limited treatment option means actually. And after a systematic review of the literature, after a strong and long discussion of real case scenarios, after a face to face meeting uh where we run a Delphi process, we were able to identify different limited treatment options in Mac PD. First of all, a patients with Mac PD and with a macrolite resistant strain should be considered a limited treatment option. Uh This was a very clear situation of LTO for all the 14 experts. So there was a massive agreement in defining a macrolite resistance situation as a limited treatment options. And in case there was a newly diagnosed non cavitary Mac PD due to a male resistant and amica sensitive uh both um not bro and cavitary or a muca intermediate strain. Uh The majority of the expert, I would say all the expert, 100% of them suggested the as part of the treatment. While in newly diagnosed Mac to a macrolite resistant a case in resistance, only 50% of the experts suggested Alice as a part of treatment. And a lot of discussion has been conducted about uh uh the the position of the drug in the lung, uh the ability to oversee um some, some resistance data and so on. Another, uh the other uh important limited treatment option situation is when the patient is not able to take or to tolerate drugs. Mali for whatever reasons, a thol for whatever reasons or IV Amy, when indicated for whatever reasons, there was uh an 100% agreement in identified this as a limited treatment option situation. And uh uh in case of Mali's inability, inability to take or to tolerate Mali or IVM Alice was suggested to be part of the treatment while in case of a thrombo, um the majority of experts have suggested uh uh to consider another oral drug uh or other suitable options like and finally relapse. So according to the NTM net definition in patient underwent a guideline based therapy. Um assuming that that was not a reinfection, relapse was considered by all the experts as a limited treatment option situation where Alice uh was suggested to be part of the treatment. So this is uh um an effort by independent European expert to help physicians in better understanding the indication. The other very interesting point uh is about um a phase three trial uh which is called a rise. Uh The arise trial is a randomized double blind placebo controlled multi center study in patients with muck pulmonary disease, newly diagnosed in order to validate uh uh two different treatment regimen ayin plus plus S versus aroy plus A tham plus um an liposome control with the primary end point composed by different P OS patient reported outcomes. So we are now talking about patience, uh naive, never, they never underwent treatment for MP D and we are testing plus ayin and buol versus two drugs ayin. And, and I would like to talk to you a little bit at the end of my presentation about the phase three rice trial because very, very recently September 5th uh uh press release have been published uh on the on the social media and on the web by Inmet with positive topline results about the phase three rice trial. So the study met its primary uh its primary objective of uh demonstrating that the quality of life measured by the quality of life bronch domain actually works effectively as a patient reported outcome in people uh affected by mat lung disease. As I mentioned, this was a randomized trial enrolling 99 patients. And among those 43.8 patients uh achieve an improvement in the quality of life bronchitis, respiratory score if they were treated with Ali Ayin and the thrombo. In comparison to 33.3% of patients treated with AROY AOL and placebo. And this core difference was 14.8 from a microbiological point of view. As I I mentioned previously in my presentation, patient enrolled in the Alice arm achieved a statistically significant higher cultural conversion rates at month seven in comparison to control group. So 78.8% in the two drugs plus Alice group versus 47.1% in the two drugs plus placebo group. And the culture conversion was faster and more likely to persist through months seven in the ali arm. Another uh interesting point is about the proportion of patients in the Alice arm who actually achieved a cultural conversion by month six. compared to patient in in Comparator arm. Uh We are talking about 80.6% versus 63.9%. Although this was not statistically significant. Um The press release also informed us about uh uh a group of patients who achieved cultural conversion by month six, more patient in the arm achieved the first of their two required monthly negative culture for clinical conversion at month 1 74 versus 46%. And finally, a patient in the Alice arm who achieved the cultural conversion by both month six and month seven attempt. A statistically significantly greater improvements in quality of life bronch respiratory domain scores at month seven compared to patient in the ali arm who did not achieve cultural conversion in terms of safety data. No new safety uh events were observed in the ALIS arm and the safety profile in general was as expected to be. So these are very interesting data in the population of patients with M CPD or should start uh a treatment. The last slide is about the Encore trial, the encore trial is a randomized double blind placebo controlled phase three P study uh that has been designed uh to uh enroll um roughly 250 patients uh and to evaluate the efficacy and safety of analyst based regimen in patients with a newly diagnosed or a current MP D who have not started antibiotics. So there will be one by one randomization ali plus background regimen versus placebo plus background regimen. Uh once daily for one year and patient will tell will, will then uh discontinued uh discontinue all the study treatments. They will remain in the trial for three months. And the reason why is because they want to assess the durability of the cultural conversion. Primary end point of the Encore study is the change from baseline to month 13 in respiratory symptom score and there are several other end points. So you can take a look at the Encor uh Encore Protocol in Clinical trial dot gov. So in conclusion, there, there is a lot of uh new data in the field of uh NTM and especially in the field of pulmonary disease, as I mentioned at the end of my presentation also in patients with Mac PD that are supposed to start at new treatment but also inpatient uh with a refractory Mac PD. These are data published from the convert study that have been uh taken uh from the guidelines and uh regulators both in the States the FD A&E I A make a recommendation about the use of Alice. We should always think that treatment of refectory and PD uh is long and tough to the patients. Some, some of my patients are telling me that this is sometimes harder than disease by, by itself. Uh We need to uh anticipate and manage adverse events and uh uh try to stay uh to stand by the patient to complete the treatment, not only physicians and health care professionals, but also caregivers, family members and patient association. And finally, to know that we might want to discuss or to send the patient to referral center where a multidisciplinary team can take care of, of the, of the patient, not only from an antibiotic perspective, but also from a comorbidity perspective, from a nutritional point of view, from a psychological point of view. So with this, I would like to thank you for your attention and thank the organizers and the sponsor to organize this uh meeting and the webinar. Thank you so much.
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