Good morning, and welcome to the Mereo BioPharma Conference. My name is Brandon, and I'll be your operator for today. At this time, all participants are in a listen only mode. Later, we will conduct a question and answer session during which you may dial zero one if you have a question. Please note it is zero one, not star one. Please note this conference is being recorded. I will now turn it over to Dr. Denise Scots-Knight. You may begin. Thank you, operator, and good morning, and welcome to Mereo BioPharma's conference call to discuss the top-line results from the ASTRAEUS phase II study of alvelestat in severe alpha-1 antitrypsin deficiency associated emphysema. We're very excited to share these data with you, as well as to discuss the next steps for the alvelestat program. With me on the call today are Dr. Jackie Parkin, who runs our alvelestat program, and Dr. John Lewicki, our CSO. Before we begin, I'd like you to flip the slides to the next slide, and remind you that we may make certain forward-looking statements as outlined on slide two. Following the prepared remarks, we'd be happy to take any questions that you have. Moving on to slide three, which describes alvelestat. This is the first time an oral therapy has been demonstrated to have an effect on neutrophil elastase activity in patients with AATD and to also have a consistent impact on the downstream biomarkers for lung disease, which are known to correlate with clinical outcomes in patients with AATD. Jackie and John will walk you through those relationships. I'd like to, first of all, thank all the patients, their carers, and all the medical staff for their participation in this study, which was conducted at the height of the pandemic and through the numerous lockdowns. Alvelestat. Alvelestat has the potential to be the first in-class oral therapy for AATD. It's a potent reversible inhibitor of neutrophil elastase, which we in-licensed from AstraZeneca in 2017. AstraZeneca had previously established the safety of the molecule in over 1,000 subjects and demonstrated efficacy in phase II studies in cystic fibrosis and bronchiectasis. ASTRAEUS is one of two phase II studies in AATD, with the second being ATALANTa, which is investigating a broader patient population. There is also an ongoing phase I-B/II investigator study in bronchiolitis obliterans, and we previously reported a positive proof of concept study in COVID-19 infected patients. Moving on to the next slide, which describes AATD lung disease. At Mereo, we're focused on the lung disease that occurs as a result of AATD. The role of alpha-1 antitrypsin is to inhibit neutrophil elastase. Individuals who lack alpha-1 antitrypsin or produce misfolded inactive alpha-1 may have progressive lung damage resulting in early emphysema. This may happen to patients as early as in their 20s, and unfortunately, some of the patients go on to require lung transplants. It is estimated that there are over 100,000 people with AATD in the U.S. and Europe, although it is broadly undiagnosed. Currently, patients are treated with replacement AAT, which is a weekly intravenous therapy. This therapy is currently not reimbursed in many European countries, and as you will see from ASTRAEUS, around 90% of the patients enrolled in our study had not previously been treated with augmentation therapy. I'd now like to hand over to Jackie, who's going to go through the study design and with John going through the data that we announced this morning. Thank you, Jackie. Thank you. As we're now on slide five, and this is a reminder of the trial design for the ASTRAEUS study. It's a 12-week study investigating patients who have severe alpha-1 antitrypsin deficiency, so levels below 11 micromolar and with CT evidence of emphysema as entry criteria. The study design had an initial dose escalation cohort in terms of starting at the low dose. This dose, which we've disclosed previously, was 120 mg twice daily, which is a higher dose than had previously been used in many of the AstraZeneca studies. Once we had safely got through the IDMC review of the safety data, we then escalated to the highest dose. Again, after that cohort, the initial cohort, had been enrolled, there was review by the IDMC, which then allowed an open enrollment at that high dose cohort. The IDMC continued to intermittently about every quarter of the year, review our safety monitoring adverse event data and never raised any concerns with the study. During the COVID-19 pandemic, we took the opportunity which was within the protocol to prioritize randomization to the high dose group once we had adequate safety information in order we could come to a decision in the appropriate timeframe once we knew we had enrolled enough patients at that high dose. That is why you see in the final numbers there is an imbalance between the high and the low dose compared to each other. We enrolled 99 patients into the study. Of those, 98 were dosed. One withdrew consent before being entered into the study. If we now go on to the baseline data of this target population, the biomarkers. Now skipping over to slide seven. Thank you. First of all, I wanted to go through as to give context to the biomarkers that we measured in the study, and to where they fit in our strategy for development for alvelestat, and also, within the disease itself. Now, as you may be aware that, as Denise has said, alpha-1 antitrypsin lung disease is an aggressive and progressive lung disease. In terms of clinical endpoints such as CT densitometry or FEV1, it takes a number of years for those to progress in terms of what you can detect in a clinical trial. Therefore, a phase II trial, the focus was on biomarkers that were relevant to the pathogenic pathway as listed in here. Also, choice of biomarkers where previous investigations in studies had shown a link with alpha-1 disease severity in terms of the degree of lung damage, also had shown response to replacement of alpha-1. That's behind the choice, not only of the neutrophil elastase, which of course is the key target for alvelestat, but also for Aα-Val, which we'll discuss a little bit in more detail further on, and desmosine, which is a breakdown product of elastin. The discussions that we had in the dialogue with the FDA in the Type C meeting recently really focusing upon the potential to use a biomarker strategy for development in this disease. The FDA recognizing the challenges of use of the clinical biomarkers in this disease. Although we believe that of course, you know, you're going to need to show some evidence down the line of clinical efficacy in terms of these standard markers. In terms of these first steps, this is what we have been discussing in terms of strategy with the regulators. You'll be aware that we asked for consideration about the potential for a biomarker strategy for accelerated approval pathway. We amended our protocol to include these three biomarkers on the causal pathway because that is of particular importance in terms of regulatory interactions and their thoughts about showing evidence of effect. If we now move on from that to the study itself. Here is the study endpoints. Today we are reporting out on the data that we have in hand, which is the top-line data, which covers the primary efficacy endpoints. Those biomarkers that were in the previous slide. Also, you know, the safety and tolerability. If we focus now onto the patient population that was recruited into the study. Now we're onto slide nine. The patient's medical history is shown here. As you can see, they fulfilled the requirements for the study in that they had severe alpha-1 in terms of the levels, the low levels of alpha-1 protein in their blood. The normal range being 20-60. The eligibility criteria being less than 11, which characterizes severe deficiency, and our patients all having levels well below that at entry. All of the patients were ZZ patients, as expected of those categories who have the most severe deficiency. As Denise mentioned, your previous augmentation that was in about just in 11% of the patients, and we ensured there was a long washout before they went on to the trial. The number of days since the diagnosis of alpha-1 is shown there. As you can see, there was quite a range there, which was not different between the populations. We had a broad range of disease severity in terms of the lung function in terms of the predicted percent predicted FEV1. A broad range of patients in terms of disease severity was enrolled in the study as per protocol. Moving on to the next slide now, looking at the demographics of the patients and on slide 10. Again, nothing out of the ordinary of what you'd expect for an alpha-1 antitrypsin disease population in terms of the age of the patients. The racial characteristics go along with the genetic nature of the condition, and in terms of BMI. Smoking history was reported there. You know, between the different groups, there is some difference in that the high dose had a slightly higher proportion of smokers. But none of the patients were smoking at entry to the study. As we were thinking about the data and the analysis of the data ahead of seeing any results, we defined a per protocol set. What this included was patients who had gone into the trial, had the eligibility criteria as expected and did not fail to meet any of the required criteria for the assessment of efficacy. Because of the known effects of acute exacerbations on COPD on two of the biomarkers in particular, on the Aα-Val and on the desmosine, we knew that this may cause some noise in the analysis in this short-term study, and therefore we predefined a group of patients, which was 10 in total, who had acute events that may cause some variability in the data. We go on to the actual results themselves. We can move straight to slide 12. The baseline levels of these three biomarkers is shown in this slide. I think we're going to talk a little bit about the neutrophil elastase assay. This is something that we've been working hard with partners in the industry in terms of developing an assay which could be used to detect levels of elastase activity, not just in their chemical levels within patients. Again, if those who attended the R&D day, you'll know that we have achieved success in working with commercial partners in developing an assay which has the relevant sensitivity to detect elastase in the blood. The other markers are shown there in terms of the baseline values with no significant differences across the patient groups. To say that you- With those normal controls there, you can see that all the endpoints were elevated at baseline as would be expected, and in line with other placebo-controlled trials in this disease population, if anything, slightly higher, so perhaps a slightly more active group in terms of these biomarkers. In terms of the analysis then, the baseline levels of biomarkers, along with other factors that may contribute to outcomes such as smoking history, and FEV1, were included within the modeling to account for those factors. Then we're going to now walk through the biomarkers, three primary endpoint biomarkers one by one. I'm gonna hand over to John Lewicki just to talk about the neutrophil elastase assay itself, because this is something that is new to the field that we've worked hard to develop, and I think to help the understanding of it and how it differentiates from other neutrophil elastase or anti-elastase assay, it will be helpful to walk through that. John, if you'd like to take this next slide for you. Yeah. Yes. Thank Yes. Thank you, Jackie. I just wanted to make a few comments here on this novel neutrophil elastase assay that we developed for this study. To enable the determination of the neutrophil elastase activity in blood of the treated patients, we worked with external partners to develop a new and highly specific assay for this target of the alvelestat. This assay uses a specific ProteaseTag technology to enable specific determination of neutrophil elastase activity. The important points I wanted to make here is that this actually contrasts with functional PK assays that have been reported by others, and I think you've seen some of that data, in that these assays basically enable quantification of neutrophil elastase inhibitors in blood versus an isolated preparation of neutrophil elastase. As such, they do not quantify neutrophil elastase activity directly in blood. It also contrasts with historic assays that have been used in this field, which measure neutrophil elastase in substrates such as sputum. As such, the data we're showing today actually represents suppression of authentic neutrophil elastase activity in blood, and it's inhibition by alvelestat. I wanted to make sure to highlight this distinction, and I think you'll see in the next several data slides that we pretty much achieved the target neutrophil elastase inhibition level in blood that we targeted when we initiated this study. Next slide, and I'll pass it back to Jackie. Thank you. Next slide, please. Yeah. Looking through the data from the trial itself. As John mentioned, we got absolutely the degree of suppression inhibition of neutrophil elastase activity in the patients that we were targeting. As you can see there, in the high dose, an effect at 4 weeks, lasting out to 12 weeks, and just tipping over the 90% at week 8. The results are very important, and we are really pleased to see that we've hit the target. If you look at the low dose, again, there is inhibition of activity in the low dose, not quite at the level of the high dose, as you can see, in the point estimates of effect shown there, and also the p- values being slightly less significant than for the high dose. This here is shown as the FAS analysis, exactly the same in the per protocol analysis, all with p- values, you know, of great significance. That we are doing what we expect to do with our alvelestat, and in terms of the dose rationale that we took forward in these two higher doses than previously taken by AstraZeneca, again, we hit those targets that we were hoping and predicting to hit with the PopPK models that we had. I think that we're really pleased with that. It gives us a very good way for the future of monitoring the effect of the elastase inhibition. If we then go on to the next slide, just trying to put that into context of, you know, where this is taking us in the patients. This is just showing the high-dose data. This is in the FAS dataset on slide 16. You can see that we've shown before that our patient population had detectable, significantly higher levels in their blood, than a healthy control population, which is shown in blue, healthy volunteers on the right-hand side. That's 39 subjects in that healthy volunteer study that we did as part of this development that John mentioned. By week 12, in terms of the alvelestat treatment, we are bringing the level of activity down really nicely. It's coming close in terms of median, and lean towards that seen, healthy volunteers. I think that's a really good sort of benchmark to say that we are doing exactly what we wanted to do with the elastase and even in this group of patients, with high levels of activity, at baseline. If we now move on to the next biomarker, which is the Aα-Val360. This is a biomarker which is looking really at the effects of the neutrophil elastase on a fibrinogen cleavage product. This is a biomarker that has been investigated in alpha-1 previously, both in disease but also in a response to augmentation treatment. This is a very specific breakdown product of neutrophil elastase. From that perspective, again, very important that we can see some effect of alvelestat. We know it inhibits neutrophil elastase. Does it affect the breakdown of relevant proteins in patients with this disease? Just to show there in terms of the importance to thinking about these biomarkers of how these link with disease activity, clinical disease activity in the target population. It is known to be elevated in alpha-1 antitrypsin deficiency and correlated with physiological parameters of disease severity, including FEV1, transfer factor, lung density and symptom scores. It's importantly been shown to have a treatment response. There was a 6-month trial of augmentation versus placebo AAT replacement. In that study, there was a response of the Aα-Val footprint to treatment. If we sort of look at that graph on the right here showing the relationship between the Aα-Val and the FEV1% predicted in patients with severe alpha-1 deficiency, it was also important that in terms of even with sort of less severe individuals who have alpha-1 deficiency that they may be a predictive factor for future progression of disease. That's something of interest to us, which we sort of are thinking about how we can use these biomarkers in response to the biomarkers used to help at various stages of the disease. Looking at what we saw in the study, in the augmentation trial that I mentioned, which is referenced there, Carter et al, the change from baseline, the percentage change was around about 15% or 16% change from baseline, after 6 months of augmentation. That's to give you a context of what might be seen with the currently approved therapies, you know, around about a 16% reduction from baseline. Of course, we are really pleased to see that we are in a different study but another placebo-controlled study, a similar population showing similar levels of reduction and in comparison to placebo, showing those changes from baseline, comparison to placebo, highly significant changes and of an effect size which is meaningful in comparison to what is seen with the current benchmark therapy of augmentation. You know, really important data. Again, to say that as we present here, the per protocol set, and that's because we had determined in our stats that that would be the population we'd look at because of the potential of interference or of acute exacerbations or other acute events on the patients. Just to say that if you were to look at the protocol set, the p- values for weeks 8 and 12 are no different to what you're seeing in the per protocol set. Again, an effect which is shown in both datasets and at a level which is very comparable to what is happening with augmentation, which is really what we're trying to sort of benchmark ourselves to be able to explain the levels of these effect sizes. Finally, going on to desmosine. Desmosine is a breakdown of mature elastin. In alpha-1 antitrypsin deficiency, it's been shown that there are elevated levels in the blood, but also importantly, there are elevated levels in the lung, suggesting or supporting that the breakdown of elastin that is occurring in these patients with accelerated breakdown of elastin is occurring in the lung tissue. Monitoring this marker is a way to look at the downstream effects beyond elastase onto the elastin of the lung. Increase and a progressive increase is shown in patients with severe alpha-1 antitrypsin deficiency. If you look at some of the larger placebo-controlled trials, in particular the RAPID study, which is the largest to date, you can see that progressive increase in desmosine over time occurring in that study starting at 3 months, which is the first time point they looked at. This is a marker of progressive lung destruction. It has been correlated again, like Aα-Val, with measures of more clinical lung disease in terms of FEV1, transfer factor, and also CT densitometry. I think that again, this is another marker which helps us in terms of its relationship and correlation with clinical markers down the line. Also with desmosine, there was a therapeutic response, as was seen with Aα-Val, to augmentation replacement therapy and an association of reduction in desmosine with a slower lung density decline. In that study, this was following patients out for 2 years, which is what needs to be done in terms of looking at lung density, but that relationship was certainly shown. We go on to slide 22 and looking at for our trial, the change, percentage change from baseline, which was our primary biomarker endpoint for desmosine. What we showed there, again, a similar sort of pattern to the Aα-Val of increase or as an improving effect on reduction in desmosine over time, over the 12 weeks. Placebo actually is showing an increase in desmosine over the time frame. For both and for all of these biomarkers, what we saw in terms of the active was this consistency of response in terms of reduction across time points across the biomarkers, and in placebo, either no change or an increase over time. It's a really consistent data which reflected in the statistical analysis that, you know, every time point it was showing the same effect which I think again is very encouraging when you're looking across, you know, a range of relevant biomarkers that there is that consistency there. In terms of the data set, for the desmosine, what we're showing here is again the per protocol set. In the FAS, then we did show the changes were not so marked in the FAS. It did not reach statistical significance, although directionally the same. I think that what we're seeing here is that desmosine, because it is not a less specific biomarker which comes from other tissues like, you know, elastin in the blood vessels, that may be more affected by, for example, these acute exacerbations. I think also in terms of the change from baseline. We have here the within-group analysis change from baseline. We also saw statistical changes in terms of compared to placebo. We mentioned there about, you know, how does this compare again with other trials. We always benchmark ourselves, you know, to the RAPID study because that's a study which is probably, I would say, the largest and most controlled placebo-blinded study available to us. We showed there we're measuring something different. We're looking at percent change from baseline. If we look at the effect size in the RAPID study from baseline, they showed an absolute reduction as shown there, quite a small reduction. They showed an increase in placebo. We calculate that the delta, the difference in active and placebo in the RAPID study was around 5.5%-6.5%. Again, we are very, very comfortable and pleased to see the percentage reductions from placebo and from baseline that we have seen with our trial to give some comparison to what's happening with augmentation. That's the efficacy data that we have in hand at the moment to share. We now move on to the safety and tolerability. I think from that perspective we are delighted with alvelestat in terms of its ongoing consistent safety profile. We've obviously, as Denise has said, you know, over 1,000 patients treated in total. We have gone at higher doses in COVID, in bronchiolitis obliterans, and now in this study, and also in the ongoing ATALANTa alpha-1 study. We've not seen any signals emerging of any concern in any of these safety parameters that have been monitored, and neither of the independent unblinded DMCs for either ATALANTa or ASTRAEUS haven't saw any signals of concern. We're really comfortable with the safety. We have here the two adverse events of special interest that were identified in the study. The adverse events of special interest were infections because although no signal of infection had been seen previously with alvelestat in COPD or other diseases, we want to make sure that we're not seeing anything in this new disease population. We do not expect to see anything because we're targeting a very specific part of host defense, and leaving the majority of host defense intact. Indeed, that was the case. The infections in the AESI-reported group were not different in active or placebo, and would be the same as you'd expect in this population of patients, and the response to treatments for infectious diseases were as expected. We had one case of an elevated alanine transaminase in a single patient. This was without any changes in bilirubin or other obstructive pathways in the liver, such as alkaline phosphatase and gamma glutamyl transferase, and resolved on cessation of the drug. This was not considered to be of importance. It resolved, and it's just a single case. This has not caused any concerns, as mentioned, with the DMC. I think for those who've done a lot of clinical trials, this is not unusual in active and placebo to have one-off cases like this, and it raised no concerns, and supported by the lack of any signal in the regular liver function monitoring that is done in these patients. We also had a case of prolonged QTc in another individual on active. As we've listed here, that was an individual who had a history of prolonged QTc and was on QTc-prolonging medications at entry to the trial. The event resolved, and it was considered to be, from our perspective, related to the other ongoing treatments that they were having. In terms of toleration, headache has been identified previously as an adverse event that is more frequent in alvelestat treated individuals, and it showed itself to be more frequent in this study. The way that we are addressing this is through instigating a dose escalation, a within-patient dose escalation to manage the headache. That's something we feel that we're on top of. Very comfortable with all of that perspective. Where do we sit now in terms of development? From our perspective, those results are really encouraging. Effect sizes on key biomarkers of relevance that are well within what we might have expected to see with augmentation or even better than that. We're really pleased with that. We're really pleased with the safety. We have an ongoing study, the ATALANTa study that was mentioned, which is continuing to enroll, you know, really nicely. A slightly broader population, including SZs as well as ZZ patients, and also including patients who are on stable augmentation, to assess the effects of alvelestat on top of augmentation. That study is ongoing and will yield some additional complementary data to that we have achieved from alvelestat in ASTRAEUS study. Now let's hand over to the slides, the summary slides to Denise. Thank you, Jackie and John. To summarize, the ASTRAEUS study has delivered on what we set out to do, and we're very pleased with the data. We've demonstrated statistical significance in all of these three key biomarkers of lung disease, and also importantly, shown a difference between the two doses of alvelestat, which should support a single dose going forward into phase III. We're also very happy with the changes that we're seeing, and the fact that these are comparable to the changes seen with augmentation therapy at longer time points. We'll have data from the ATALANTa in the first half of 2023, and that'll be very helpful as we look at going forward into the pivotal study. As Jackie said, we've got a very clean safety profile with alvelestat in all of the studies to date, including in liver, and so we're very, very comfortable taking this program forward in AATD. We plan to engage with the FDA and the EMA. Once we've got all the data together and the package, we'll have an end-of-phase II meeting, and this obviously will follow on from the Type C meeting that we held in March, which we have previously discussed. Alvelestat has potential in other indications, and we're particularly interested in the phase II investigator-led study in bronchiolitis obliterans, which is expected to enter phase II in the second half of this year. Moving on now, briefly before we move to Q&A, I'd just like to remind everyone of the other catalysts that we have coming up for the rest of the year. If you move to the next slide just to review the milestones. In June, we'll have an update on our etigilimab program, the phase I-B / II ACTIVATE study, which is a combination study with nivolumab. We expect an update on that in June, and then an additional update on ACTIVATE in Q4. On alvelestat, we'll be providing another update in late Q3. As I mentioned, the BOS study is expected to enter the phase II part in the second half of this year. Finally, with setrusumab, we're expecting our partner, Ultragenyx, to provide an update on the dose-ranging part of the phase II-B/III study of setrusumab in osteogenesis imperfecta patients before the end of the year. Just as a reminder, our cash runway, as we've just reported, continues to be into 2024. I'd now like to turn this back to the operator for the Q&A. Thank you. Thank you. We will now begin the question and answer session. If you have a question, please dial zero one on your phone keypad. If you'd like to be removed from the queue, please dial zero two. If you're on a speakerphone, please pick up your handset first before dialing. Once again, if you have a question, please dial zero one on your phone keypad. From SVB Securities, we have Joseph Schwartz. Please go ahead. Hi. Congratulations on all the progress. I was wondering if you could give us any insight into what the high and low doses were that were used in the ASTRAEUS study. Was there any titration used? Can you describe that? I have a follow-up. Okay. I can answer the first question, and then I'll lead over to Jackie. We've previously disclosed that the low dose is 120 mg. We haven't disclosed the high dose, Joe. Jackie, do you wanna talk about the second one? I think those two doses were chosen based on population PK to have a differential effect on the neutrophil elastase suppression. We've achieved that, which is why we think that we're in a good place to take forward with some dose modeling or a single dose into phase III. Do you want me to start with the second question? Thank you. I guess how do these results from ASTRAEUS now fit into the construct of potential accelerated approval that you discussed with the FDA previously, and what are your next steps on the regulatory front? You talk about that, Jackie? Yeah. Yeah, absolutely. I think the discussions with the FDA were very much around the They're very keen to see the data in terms of biomarkers. They were pleased to see that we're measuring a number of biomarkers along the causal pathway, which seems to be of importance to them. Our next steps going back to them would be to discuss that further. What we had been talking through was the potential for a biomarker primary endpoint and then some a secondary endpoint, which would be a clinical endpoint, which would not necessarily, that could be the confirmatory in this accelerated approval pathway. Now, of course, that was what we discussed. They said, "You need to come and bring your data to us and we can discuss further." Certainly that door was open from them and they didn't define. They, you know, it's up to us to go back with what a clinical secondary endpoint or confirmatory endpoint should be. They weren't dictating what it was, what it should be. I think also, Joe, you know, we mentioned on the call that augmentation, you know, is not reimbursed in many countries in Europe. We're also very keen, as you can imagine, to go and talk to the EMA as well and the MHRA. Great. Thanks. I'll jump back in the queue. Thank you for your question, Joe. From Needham & Company, we have Gil Blum. Please go ahead. Hey, good afternoon, everyone, and thanks for taking our questions. It might be just a clarification. It seems you still have a discussion with the FDA the second half of the year. So the path for accelerated approval remains open. Is that a correct assumption? Yes. Yes. We had the Type C in Q1, which was before, obviously we had the data. We came out of that meeting, you know, feeling that the door was open for the accelerated approval approach. But clearly, you know, one of the key comments from the FDA is you need to come back with your data. That's, you know, clearly what we intend to do and go for an end-of-phase II meeting. Okay. Excellent. Maybe a question a little bit around desmosine, isodesmosine being you know the more established biomarker in this indication. How important would you, if you had to guess, put desmosine, isodesmosine versus the other two newer biomarkers? I mean, I think that it's the consistency that's going to be really important when we go to the FDA. I think that's the important piece. I think that we have shown before that there is some correlation between Aα-Val and desmosine, which you would expect. They're on the same pathway. I think that we're thinking about, you know, what could be a really good response biomarker, you know, for us. I think Aα-Val is looking really nice from that perspective. Yeah. On our R&D day, you may have heard, Professor Stockley who is our chief investigator on the ASTRAEUS study is actually, you know, I would say arguably a bigger believer in the Aα-Val than in the desmosine because of the specificity. We believe this having the multiple biomarkers and showing, as Jackie said, the consistency across those biomarkers is going to be really important when we go to talk to the FDA. Okay. Thank you. That's very helpful. Maybe a last one. It seemed like there was a bit of a change in activity over time. Is there? Do you guys have any comments on that? I don't think it is different, that it's sort of, you know, it's quite, you know, the variability is there. It is a relatively small study, and I don't think you would really see any difference, you know, over time. Apart from, I think, the week 4 to week 8, I think that's an uptick happening for Aα-Val and for the desmosine. Outside of that, I don't think we're seeing something different at, actually between the weeks. I think what we're of course interested in is we've studied very intensively over, you know, over a 12-week period. Our position would be that you'd expect, you know, eventually those to improve over longer treatment durations, as you've seen with augmentation. We're yet, you know, obviously what we've got is short-term data. It looks pretty stable to me. All right. Maybe just a final one. As with regards to timelines and updates, I guess the next thing to look for is your update from your end-of-phase II. Yes. We may have, Gil, probably another data update before the end of phase II update in that order. Okay. That's it for me. Thank you very much for taking our questions. Thanks. Thanks for your questions, Gil. From BTIG, we have Yun Zhong. Please go ahead. Hi, thank you very much for taking questions. Is there a disconnect between the two biomarkers of neutrophil elastase inhibition or reduction in Aα-Val and also desmosine? So you talked about the possibility of other tissues of desmosine turnover affecting data readout. But aren't those blood levels of neutrophil elastase inhibition and, sorry, Aα-Val also measuring? Were samples from all tissues? Yes. Perhaps I didn't explain that so well. The Aα-Val is a specific neutrophil elastase breakdown product. It's you know is detected in blood. It's not tissue specific. It is neutrophil elastase specific, so that cleavage fraction, the 360, is specific to neutrophil elastase. Desmosine is a breakdown product of elastin. Elastin you know is broken down by neutrophil elastase, and that's what we think is happening in the lung, that neutrophil elastase is driving that breakdown in the lung. In other tissues then there are other you know proteases, which are involved, which are not neutrophil proteases. I think that, you know, in terms of the extent of reduction we saw, that was, as I showed, you know, very, very comparable to what has been seen previously with augmentation. I think the noise is more, you know, around desmosine, because, you know, various other factors that may affect it. We know that, for example, an acute exacerbation can elevate desmosine for between 4 and 6 weeks, which is why we need to take that into consideration. Okay. Also I think you had to reduce the number of patients enrolled in the study because of COVID. Looking at, for example, slide number 12, the baseline, there seems to be a really big inter-patient variability as compared to healthy volunteers. If I remember correctly, the previous study by AstraZeneca in cystic fibrosis patients, they also kind of blamed the inter-patient variability. How do you think that there may be a reduced powering of the study impacted the data readout? I mean, I think we were looking at, you know, within each the change from baseline for individuals rather than across the groups. That was the way that we addressed this, so the different starting levels. Yes, there were different starting levels for the biomarkers, but we were looking at the change within an individual. That was how we approached it. Okay. Last question on the dose, a follow-up question on the dose. If I see it correctly, the ATALANTa study is using the lower dose of the current phase II study. Given that the lower dose cohort data doesn't seem to be so positive, do you expect data from the ATALANTa study to add a meaningful contribution to the entire data package? Yes, I do. I think that there was some effects, you know, just lower effects and the sample size was small because we preferred recruitment to the high dose. I think it adds. I think particularly understanding what happens on top of augmentation is going to be, you know, really interesting. Discussions to date, you know, with the investigators, you know, for the trial is, I think, you know, to complete this. Yeah. I think that, you know, we probably would have a different perspective if it weren't on top of augmentation. Most of the patients in that study are on augmentation, Yun. I think it will add to the data package. Do we think the 120 is the dose? No. We believe, you know, from our data and all the modeling that Jackie commented on previously, that, you know, the high dose is our dose. You know, it will add to the data package on that low dose. Okay, great. Thank you very much. Thank you. We have a follow-up from Joseph Schwartz with SVB. Please go ahead. Great. Thanks so much. Welcome back, Joe. Thanks for having me back. I was wondering if you could talk a little bit about the difference between the full analysis set and the per-protocol analysis that you performed? Mm-hmm. I guess I'm just curious how many patients were excluded from each of the arms and whether the conclusions from the trial change at all when looking at the full analysis set versus the per protocol. Yes. Great question, Joe. I'll take that. The per-protocol set excluded those who had failed eligibility criteria that could've affected the assessment of efficacy. In fact, there was none of that type of patient. It also excluded patients who'd had an acute exacerbation or acute respiratory event which required systemic corticosteroids and antibiotics during the study conduct. That was specified in the SAP to enable us because we felt it would affect the assessment of efficacy on the biomarkers. There were 10 patients who excluded from the FAS for that reason. The per-protocol set was set with 10 less, and it redistributed. It wasn't a difference across the groups. Oh, great. That's very helpful. Can you give a- In terms of Jackie, just to answer the follow-on question that Joe asked, in terms of whether that would have affected our presentation of the data with the filings. Oh, I see. I think it would have, as I mentioned, it was the FAS. I think, you know, the Aα-Val in neutrophil elastase, the results are, you know, the same. Directionally, they're the same for desmosine. Very helpful. Thank you. Could you give us any insight into the exploratory endpoints, like exacerbations and spirometry? Is there any extension phase to this study where you might be able to track these things over a longer period of time? We haven't seen the exploratory data yet. Those that will come in, so we don't have to have sites for that. We can't comment on that at the moment. Then we don't have an extension phase, so we will be- As Jackie said, Joe, you know, and I think as we've discussed before, in terms of the FEV1, for example, that's in the exploratory endpoints, you know, with this shorter study, you wouldn't expect to see changes in FEV1, nor do they with augmentation at 3 months. It takes much longer time to see changes in FEV1. I mean, we'll see what we have in there. Makes sense. Thanks for all the clarity. Thank you, Joe. Thank you. We'll now turn it back to Dr. Scots-Knight for closing remarks. Great. Well, thank you, everybody, for joining the call today. We very much look forward to updating you further on our progress with alvelestat for AATD. As I said, we're very excited now to go to the regulators to discuss the outline design for a pivotal study for this. We very much look forward to moving it forward. Thank you. Thank you. Ladies and gentlemen, this concludes today's conference. Thank you for joining. You may now disconnect.