Good morning, and welcome to the Mereo BioPharma R&D update. At this time, all attendees are in a listen-only mode. A question-and-answer session will follow the formal presentations. If you'd like to submit a question, you may do so by using the Q&A text box at the bottom of the webcast player or by emailing your questions to questions@lifesciadvisors.com. As a reminder, this call is being recorded and a replay will be made available on the Mereo website following the conclusion of the event. I'd now like to turn the call over to Dr. Denise Scots-Knight, Chief Executive Officer of Mereo BioPharma. Please go ahead, Denise. Thank you, Tara, and good morning, everyone, and welcome to today's R&D update call on Mereo's alvelestat program for Alpha-1 Antitrypsin Deficiency and specifically the lung disease. I'm Denise Scots-Knight, CEO of Mereo. Before we begin, on this slide you'll see our standard disclaimer language statements in this presentation. Statements on this call may be forward-looking, including our plans, objectives, and expectations for our programs. These matters involve risks and uncertainties, and the company's actual results may differ significantly due to a variety of factors. Moving on to the next slide. Today, I'm delighted to be joined by three speakers. Professor Stockley from the University of Birmingham, who is the chief investigator for ASTRAEUS. Professor Sandhaus, Clinical Director of the Alpha-1 Foundation, and Dr. Jacqueline Parkin, who runs the alvelestat program at Mereo. Both Professor Stockley and Professor Sandhaus have decades of experience in AATD. The next slide shows the agenda. Professor Stockley will provide an update on the biomarker data from the ASTRAEUS trial. Dr. Jacqueline Parkin will then review the ASTRAEUS data, associating changes in the biomarkers with clinical benefit. Finally, Professor Sandhaus will share his perspective on the phase II ASTRAEUS results and the unmet need in AATD. Following Professor Sandhaus, I'll provide a few remarks on next steps before we open for general Q&A. The next slide is a reminder of A lpha-1 Antitrypsin Deficiency and the lung disease. The role of Alpha-1 is to inhibit neutrophil elastase, and alvelestat is an oral neutrophil elastase inhibitor. AATD typically results in early onset emphysema with symptoms which present when patients are 20-50 years old. It's a large patient population in both the US and in Europe. Current standard of care is IV augmentation therapy, which is given once a week. It's actually thought that higher doses may be needed of augmentation therapy, and the efficacy is not recognized uniformly, especially across payers. In fact, in many countries in Europe, augmentation is not reimbursed. In 2021, U.S. augmentation revenues reached $1.2 billion, and they're forecast to be over $3 billion by 2031. Alvelestat has the potential to be the first oral therapy. The next slide is a summary of what we're going to discuss today. On the primary endpoint, we'll present data on those patients who completed their 12 weeks treatment. This was a pre-planned analysis, and as a reminder, the study was conducted during the pandemic and over three lockdowns in Europe. It was very challenging to enroll in this vulnerable patient population. This was a pre-planned analysis that we'll be showing here today. With these 12-week completers at the high dose at 12 weeks, we see statistically significant reductions in all three biomarkers that we measured. On the secondary endpoints, we reduced neutrophil elastase to below the limit of quantitation, and this was statistically significant at the high dose. Moving on now to biomarker associations with clinical response. The most critical feedback from our Type C meeting with the FDA in March this year was the need to demonstrate that the biomarkers are linked to clinical benefits in patients treated with alvelestat. This is needed to provide us with the opportunity to further discuss the accelerated approval pathway with the FDA. What you'll see today is a significant association between decreases in two of the biomarkers, desmosine and Aα-Val360, with the activity component of the St. George's Respiratory Questionnaire at 12 weeks. This association was only observed in the alvelestat-treated patients. The St. George's Respiratory Questionnaire is a validated PRO instrument, and it's well known that the activity component is the most impacted in AATD patients. What's impressive with this association is that we observe this after only 12 weeks treatment, and we expect this response to broaden and deeper with longer therapy. As we expected for a 12-week study where patients have their COPD medication optimized, there was no change in FEV1. There were also no new safety findings. Following on from the Fast Track designation, which we recently received, we believe the data now supports moving into phase III with a single dose and that we have the potential opportunity for an accelerated approval pathway. Before we go into the data, I'd just like to remind everybody that our intention for this program is to seek non-dilutive capital to fund the phase III, and this includes exploring potential partnerships. I'd now like to hand over to Dr. Jacqueline Parkin. Thank you very much. Now we'll move into the further planned analysis of the biomarker endpoints. Just to remind people, the two key disease activity biomarkers that were measured in the Astraeus study were Aα-Val360 and desmosine. The features of both of those are written there and the known clinical associations. Aα-Val360 is a specific footprint of NE activity elevated in Alpha-1, and desmosine is a marker of elastin breakdown. In this disease, the key component that we're interested in is can we inhibit the elastin breakdown, which is a key part of the lung tissue. There have been cross-sectional associations of both of these biomarkers with disease severity and activity in Alpha-1 Antitrypsin lung disease. For desmosine, a relationship over time with the change in lung tissue as measured by CT densitometry. However, as Denise mentioned, when discussing these with the FDA Type C meeting earlier this year, although these data cross-sectionally are important, it is also important to see a relationship change in these biomarkers to the use of a specific therapy and a relationship to a clinically recognized benefit. Both of these biomarkers have been shown to decrease on augmentation therapy, and we'll show you some benchmark data around that. Before I hand over to Professor Stockley to go through the 12-week completed data, I wanted to show the difference between the data that presented in terms of population that we presented back with top line in May and the data that we're presenting today. As Denise has alluded to, we did have a number of patients who had to drop out early. The key sort of reason for that, the single most common reason, was due to COVID and patients not completing their course of therapy. Other causes of patients dropping out early was the second most common cause, due to headache. This occurred early. Some patients dropped out. We now know that headache is related to susceptibility factor of a history of migraine and also that with dose escalation and also with maintaining patients on therapy, this tends to resolve over time. We do not think that these features are going to be those which will be taken into consideration for the phase III trial. Therefore, we wanted to look at more detail in those patients who actually completed the full course of 12 weeks therapy. With that, I will hand over now to Professor Stockley to go through the biomarker data. Thank you, Jackie. For those of you who are not au fait with dealing with biomarkers, there is a major advantage if you're studying chronic diseases that progress slowly. Important thing is that if you have an agent that is effective on the process that you're studying, it should do what it says on the bottle. In other words, even short course treatment should alter the biomarkers that are implicit in the disease progression. You've heard Jackie already mention neutrophil elastase, and the first bit of data that I'm going to show you is measurements of elastase actually in the blood, in the blood plasma. Now, the concentrations of blood plasma have to be, by nature, incredibly low, because otherwise it would be particularly dangerous to the human being. These data are generated by a very specific and sensitive test for identifying some neutrophil elastase activity. There's three sections to this slide. The vertical axis is the measurement of the neutrophil elastase activity as its median and interquartile range. On the first panel of four histograms, this is the data for the 120 mg dose with baseline and measurements made at week four, week eight, and week 12. As you see from that, the levels actually on treatment are much, much lower. The middle panel is for the 240 mg dose, and again, showing the same sort of trend. The third panel, the open histograms, are the patients who received placebo. Statistically, the p-values you can see on the right-hand side of your slide are highly statistically significant in this small number of patients. Of course, that in its own right is also very important. Sometimes you need a massive number of patients before you find statistical significance. If you're looking at a drug which is wiping out something you think is important, you should be able to see it very quickly, and you should be able to see it very easily, even in a small number of patients. The 120 mg dosage for four, eight, and 12 weeks is shown, the p- values there, and the similar data is shown for the 240 mg over those same time courses. We also analyze that data by saying, "Well, if we can measure neutrophil elastase in the plasma, does it disappear? Does it come down below the lower limit of detection of the assay?" As I said, it's a highly sensitive assay because the levels are very low. Here the histogram is divided into baseline, week four, week eight, and week 12, which are shown for patients on placebo. Those are the open histograms. Patients on the 120 mg, that's the gray ones. Patients on 240 mg, which are the dark blue ones. More of the patients are actually having their levels suppressed below the lower limit of detection over the 12-week period, particularly in the 240 mg dosage. Now, Aα-Val360 is a much more relevant marker in that this is generated within the lung as the neutrophils migrate and release elastase, causing lung damage. This can be measured in the plasma because it circulates from the lung into interstitium, through the lymph system, and back into the blood. The first slide here is the percentage of individuals with their 95% confidence intervals that has changed from baseline. The open histograms again are the placebo group. The gray histogram, which is just above the baseline value, is for well, the 120 mg dose. Then the dark histogram, which is now well below that baseline value, is the reduction seen in the 240 mg dosage. You can follow this a bit more carefully if you actually look at the absolute levels of this marker of elastase activity. Here again at baseline, week four, week eight, week 12, and this is the mean data with its standard error of the mean showing this progressive drop that occurs during the treatment phase with the higher dose of alvelestat. For those of you who are not all familiar with A lpha-1 Antitrypsin Deficiency in health, we've put in the kind of levels that we would expect to see in healthy individuals at the bottom there. This is around about four to five micromolar. For the Alpha-1 Antitrypsin Deficient patients who are heterozygous, just to point out that although those patients have one abnormal gene, unless they smoke heavily, they are actually not susceptible to developing emphysema. Of course, the values for the ZZ individuals are at the top. This has come down from the ZZ levels to levels just below what we would expect for an MZ individual who should not be at potential risk. Desmosine is a marker of the destruction and turnover of elastin, and that's a very key element in the lung. You can measure this breakdown product of elastin in the blood as well, and that's been measured by many people. Next slide. This again shows the percentage of individuals compared to where the baseline data is for placebo, 120 mg and 240 mg. At 240 mg, you can see once again the data is now dropping below baseline, so there's a reduction over this 12-week period. Again, you see the same trend with time, but desmosine is not quite so impressive. Desmosine has a lot of sources. This drop in desmosine with the trend is showing a significant change. The upper limit of normal again for healthy individuals is indicated. You can see in the main these individuals with A lpha-1 Antitrypsin Deficiency have really quite high levels of elastin turnover. This just then summarizes the data in a table form. This compares what we've seen in the alvelestat study with the kind of data that we would see in people who've gone through a proper augmentation study with a statistical change in their progression of emphysema. On the top you can see desmosine here now taken from the RAPID study at month three and month 20 and month 12 of that study. RAPID, a placebo-controlled study of augmentation therapy showing a slight drop in desmosine from the baseline. That is apparent at month three and particularly apparent at month 12. With continued treatment, it becomes more and more reduced. For the alvelestat study, the study duration you can see now is much shorter, and it also shows even a greater change in the desmosine average level during that 12-week period. Alvelestat on the bottom was never tested against augmentation over three months. In the original EXACTLE study, which was performed over a 12 to 24-month period, we found a 16% reduction in Aα-Val360 at the six-month point. Six-month point was chosen in that study because that's when we had most people sending their samples back because it was a multi-center study. If you then look at what's happening over the 12-week period with alvelestat, we've got a much greater drop in this Aα-Val360 marker of disease activity. Thank you. Thank you very much, Rob, for going through that. I now take back on from Rob to go through. First of all, just wanted to show the effect of looking at those patients who took the drug throughout the 12-week period, rather than those who didn't take the drug throughout the 12-week period. This is comparing what was presented on the left-hand table at the top line data in May, and then what we're presenting today in terms of the primary endpoint, which was the percentage change from baseline. The neutrophil elastase was not affected in any way. Of course, as you would imagine, that including 12-week completers, the data got stronger in terms of a greater effect, and also greater statistical significance, with that progressive change out to week 12. From the placebo perspective, there was no change. Placebo remained non-significant change from baseline throughout the study. This is really just to show the difference which are in line with what we'd expect for a 12-week completed population. Moving on now, having the further analyses that we've done since those top-line data. First we're looking at the pharmacokinetics of alvelestat. Going to 120 and 240 are higher doses that have been used previously. In this population, we showed that there was linear PK between those two doses. That's important to know that we can therefore we've got a predictable PK in this population. Alvelestat has been measured in induced sputum in a number of studies, and it's known to be well-distributed, and the levels in the sputum are directly related to the levels in the plasma. With these two pieces of information, we're able to calculate what is the level of alvelestat expected in the sputum in these patients with A lpha-1 Antitrypsin Deficiency. And to say that the calculated concentrations of alvelestat in sputum are well within what our target for neutrophil elastase inhibition at the 240 dose. I think this is important to raise because we see that in the blood we have suppression of neutrophil elastase in the blood at the 120 dose. When you look at those lung sort of lung-released biomarkers of desmosine and Aα-Val360, then the effect is clearly in the 240 dose. An explanation of this is the concentration of alvelestat in the sputum with EXACTLE in line with that observation that we're getting the levels reached. Also to remember that our target for alvelestat is not just to suppress elastase, it's to suppress elastase based on what we know about fully stimulated neutrophil elastase release levels. Inhibiting elastase during the times of activation, for example, considering episodes of acute exacerbations. We move on from that to then look at the further data analysis looking to associate the clinical changes, any clinical changes with the biomarkers and focusing particularly on the St. George's Respiratory Questionnaire. Now, to put all of this into context, we had a Type C meeting with the FDA in March this year. The aim of that meeting, which was before we had our data, was to discuss with the FDA the potential for an accelerated approval pathway to really understand, get a better understanding of their approach to this and their thoughts around the biomarkers that we were investigating. We've had feedback from the FDA around exploring more than one biomarker. They were very keen to look not just at one, but to look at more along the pathogenic pathway. The key sort of pieces that came through in the discussion in March, which we hope our data will now help us to go back and further discuss with the FDA, was that for an accelerated approval endpoint, they're using a reasonably likely biomarker. that they, the data which had the cross-sectional association with clinical parameters, but what they really wanted to see was some change over time with the drug, and change over time with a clinical marker as well. The data that were available were good, but they needed more to be able to fully consider whether desmosine Aα-Val360 could form that reasonably likely surrogate for an accelerated endpoint. This is one piece that we have looked at and will describe to you. They encouraged us, as I mentioned, to look at more than one biomarker because they're very keen on the specificity of biomarkers and showing that that you're affecting more than one biomarker along the pathogenic pathway. Therefore, when we have assessed our biomarkers, we've looked at in that context relationship to clinical benefit and also looking at dual biomarker responses in light of the feedback they gave us. The other key component of the discussion earlier this year was if for an accelerated approval pathway, there also has to be post-approval delivery of a confirmatory clinical endpoint. The discussion had with the FDA, which I think is consistent with what they've told with others, is that for them, the CT densitometry is not an acceptable post-approval clinical endpoint. I know that your experts will disagree with this, but the FDA has been very, very consistent, I think with all sponsors around this, and they weren't for moving. They asked us to consider what a clinical post-approval confirmatory endpoint would be. This feeds back into the relationship between what we've seen in terms of these 12-week data with biomarkers in St. George's, with that being our potential clinical confirmatory endpoint for discussion with the FDA. Now I'm going to talk, just put a context slide here. St. George's Respiratory Questionnaire is not something that it has been perhaps familiar to everybody, and we have Sandy, who will talk with us a bit more about the sort of experience of using this. It is a validated patient-reported outcome, quality of life health status outcome. There is guidance for industry for its use in obstructive airways disease, including COPD, produced by the FDA in 2018. In fact, at the moment, it's the only piece of guidance, industry guidance, that is available for COPD from the FDA. It's recognized in that context. It has been applied in development of drugs for COPD, and also it has been adapted for use in IPF and used for approvals in that disease as well. It's a recognized way of evaluating efficacy for approval purposes from the FDA's perspective. For the St. George's Respiratory Questionnaire, on the right-hand side, I've shown you the profile from the ASTRAEUS study of the total score, and of the different components within that. It's shown in other studies with Alpha-1 that the activity domain is the one that's most impacted within the St. George's questionnaire. For the St. George's, the current situation in terms of validation is a clinically meaningful difference is four points in the total St. George's questionnaire. There is no clinically meaningful work being done on the activity component, but you'll see from our interest in this area, this is something that we would intend to do. In terms of Alpha-1, the activity domain is the most impacted, and it shows a relationship in terms of associations with both our two biomarkers, with Aα-Val360 and with desmosine, including the desmosine in the ASTRAEUS study at baseline. There is a correlation at baseline disease activity severity biomarkers, and the activity domain, particularly. I think that in terms of looking at this further, just to mention that within the guidance, the FDA guidance, they do talk about the potential to discuss using individual domains of St. George's for efficacy evaluation in discussion with the review division. Moving on to go through the data, the analysis of the data. As per the feedback from the FDA, we did show there was a relationship between desmosine and St. George's activity decrease, and also with Aα-Val360 and the decrease in St. George's activity domain. In light of the feedback, we have looked at dual biomarker responses. Looking at those patients who get a reduction in both of their biomarkers at, you know, at week 12. That's the way we've done it, in light of the feedback we have. To orientate you to this first slide, the graph on the left-hand side is looking at alvelestat-treated patients, and we put all of the patients together because the importance is to show the relationship between the change in biomarkers, and the drugs. We put both doses together, 120 and 240 together. We looked at the effect, the change, a reduction in St. George's is improvement, looked at the reduction in St. George's and a sort of responder analysis to those patients who showed no overall reduction in their Aα-Val360 and desmosine and those who showed a reduction of any reduction, greater than 0% decrease or putting more stringency on it, those who had both biomarkers, at least a 5% decrease, and many had much more than that. What we've shown on that graph is that there is a relationship between the extent of response in terms of the depth of the reduction in the biomarkers with the improvement in St. George's Respiratory Questionnaire. Also over time you can see that there is an increasing improvement, if you will, in the St. George's Respiratory Questionnaire. Although the four points hasn't been yet validated, I just put the four points difference in those dotted lines just to give context to the results. As you can see, comparing those whose biomarker decreased compared to those who showed no decrease or an increase, then we were seeing this relationship and a statistically significant relationship. This is key to what the FDA had asked us to do, not just as cross-sectional relationships, but can you show a relationship with a specific marker which they recognize as elastase activity and in relationship to the effects of your drug on the biomarker. On the right-hand side, again, just for context, this is looking at week 12 with the alvelestat-treated patients, looking to see what sort of change we have in the total St. George's, and then just a 1.8 decrease in the St. George's. So, o bviously our expectations seeing the biomarkers improving over time, decreasing over time, is that with further duration of therapy, we'll start to deepen and broaden that, you know, that response and that relationship will continue into the longer-term treatment that we'd plan for a phase III trial. Next slide is just looking at, you know, comparing what we saw with alvelestat with what we saw within the placebo group. What you can see here is the alvelestat group on the left-hand side, the same data that's shown in the previous slide, and then the placebo, you know, comparing like for like. What we saw in the alvelestat was this responder and response with more improvement over time, deepening response. We didn't see that in placebo. As you can see, there were very few placebo responders. There are big error bars on the right-hand side because it was just three responders. We didn't see the relationship with the biomarkers. We didn't see improvement over time with placebo. In the box at the bottom beneath the two charts, you can see that for alvelestat, the greatest responder rate was in, as you might expect, in the active group. In the high dose 240 group. If we move on to sort of our conclusions from this is that, having had that initial discussion in March, we now feel in a good position to go back to the FDA to further discuss the opportunity for accelerated approval pathway, given we have addressed the questions that were asked of us at that initial discussion. To summarize, decrease in biomarkers was significantly associated with improvement in St. George's activity, which we believe is a relevant clinical parameter for this population. In active, not in placebo, as you'd imagine, with the very few actually showing that biomarker, dual biomarker response in placebo. From the regulators, as I mentioned, I think that there's importance of this for the accelerated approval pathway based on a biomarker. That's what we hope to be able to discuss with them, is to use the biomarkers now that we've shown some further associations that they've asked us to deliver. It helps us with that initial accelerated approval discussions, but also potentially now it helps with that discussion about, well, what would the confirmatory post-approval clinical endpoints look like? Of course, you know, we would be then working with the St. George's activity domain total score as our confirmatory endpoint for the discussions we're having with the FDA. I think this helps us on the two fronts that were raised by the division in our initial discussions. Moving on now, into the summary and then going to the Q&A with Professor Sandhaus. Bringing it all together, there's a lot about alvelestat we've not talked about it up to now in terms of today's presentation, but just as a reminder. There are some you know biochemical sort of benefits of it in terms of its resistance to the sorts of oxidative inactivation that happens during inflammation in the lung and its ability to inhibit cell bound neutrophil elastase. I've mentioned that, you know, with a small molecule, it gets into the lung as you would expect, and we're able to reach levels which are expected to inhibit elastase even during the greater levels of the neutrophil elastase in the lung during, for example, new episodes of acute exacerbations of COPD. Some of the key features are that, by dosing, you know, daily, twice-daily dosing, we're able to provide a sort of stable, you know, inhibition of elastase. The data that we've shown is always taken at the lowest trough levels of the drugs. We know that we are able to, you know, suppress that throughout the dosing cycle reliably. Also of course, it's an oral therapy which which leads in terms of convenience, and cost, and complexity, improvements for the patient. To move on to where we go next, we believe that we are now in a good position with these clinical data, to support our next move, which will be a progression into phase III. We are intending our discussions for an end of phase II meeting with the FDA. Meaningful impact of the biomarkers, linking that to what's been seen with augmentation, the association with a clinical outcome, and the potential to address accelerated approval pathway through those pieces of data. We have a dose that we believe is supportive to take a single dose into phase III. Not to forget that, you know, this drug has been used in over sort of 1,200 individuals, mainly patients, and with a range of respiratory diseases and over 90 with A lpha-1 Antitrypsin Deficiency. Extensive experience with the drug in terms of delivering a safety database to move forward. We've had our final review of that study IDMC, who endorse us, endorse our approach to move this into a large population phase III. Great. Thank you, Jackie. Next steps for the program. Following on from the Fast Track designation, we expect to have our end of phase II meeting with the FDA and the scientific advice from the EMA, and to report a regulatory update in Q1 next year. Just as a reminder, you know, augmentation is not reimbursed in many countries in Europe. We feel that the scientific advice back from the EMA is going to be very important as well, in terms of progressing the program. Secondly, in mid-n ext year, we expect to have the phase II data from the ATALANTa study. This will have enrolled over 50 patients. It's looking at the low dose that we use in ASTRAEUS, it's a 120 mg alvelestat dose versus placebo. This is in most patients in that study on top of stable augmentation. We'll be looking at the impact of that combination. Finally, the open-label study in Subhankar Bhattacharya' s investigator-led study in Bronchiolitis Obliterans Syndrome. The phase II has now started with this program. He's looking to enroll 24 patients again at the 240 mg dose. This was actually initiated at the end of Q3 this year. We look forward to seeing data from that. With the next steps, tracks now. I'd like to hand over to Jackie, who is going to have a Q&A with Professor Sandhaus. Thank you very much indeed. Welcome to Sandy Sandhaus. We've got some questions that we would like to ask of you, Sandy. If I kick off with those. Sandy, first of all, just, you know, you've got a lot of experience with drug development and the patient population. Be interested to hear your reaction to the data and your relevance for patients with A lpha-1 Antitrypsin Deficiency. Thanks very much, and thanks for inviting me to come and share my experiences. I'm a principal investigator in the ATALANTa study that was just referred to. Obviously, that's still blinded, but it's been fun to work with an oral medication for Alpha-1. The treatment of Alpha-1 in the United States depends on augmentation therapy, most clinicians who see many patients with Alpha-1 believe is effective, but not perfectly so. Patients continue to advance their lung disease, and it's also a therapy that has to be given by weekly intravenous infusion. The prospect of an orally bioavailable product, and one that perhaps could be either a supplement to existing therapy or replace augmentation therapy by intravenous infusion with a plasma-derived product, is promising. We have a lot of experience looking at St. George's Respiratory Questionnaire and have found it to be very responsive and track very well with other more clinical endpoints that are more usually viewed by the general physician community and by regulatory authorities. It really has gained traction for its ability to detect changes often much more quickly than other types of measurements that have been used in the clinical trials of COPD and Alpha-1. My general feeling is that this shows some promise that has many of us that treat Alpha-1 patients very excited. Sandy, I want to ask your sort of thoughts on the, you know, in Alpha-1 it seems that the activity domain particularly is elevated, which is a little bit different from the sort of regular COPD. What do you think is behind that? Personally, I think it has to do with the fact that patients with A lpha-1 Antitrypsin Deficienc y develop significant lung disease at an earlier age than the usual COPD patient. Often, Alpha-1 patients will develop a significant lung disease in the prime of their lives when they're still working. I think that they notice. Remember, this is not a measurement of someone's activity, it's a measurement of how they perceive their activity. When someone has to cut back on their work, stop working, not attend every single event that their children or grandchildren might go to, things along those lines, that has an effect on their quality of life, especially the activity component, that is magnified because of their young age and the rapidity, compared to COPD, of the progression of that disease. Just one final question. You mentioned that we're, you know, looking at this as a potential longer-term confirmatory endpoint for phase III. Just you've had some experience in the studies that you've been comparing between U.K. and the U.S. in terms of the using this as a longer-term measure of efficacy. Just like perhaps you could talk a little bit about that. Sure. Hi, Rob. It's good to hear your voice. Robert Stockley's group in the U.K. and our group at the Alpha-1 Foundation compared matched patients on therapy in the U.S. and not receiving therapy in the U.K., where a reimbursement is not widely available for augmentation therapy. We found with respect to the St. George's Respiratory Questionnaire that it was actually. We followed patients for as long as 16 years, comparing over 600 patients per group matched on the basis of their age, sex, smoking history, and in some analyses, lung function. And the difference in St. George's Respiratory Questionnaire components and total in the case of a long study like ours was actually the most sensitive test that differentiated those two groups. We went on to show that over that long time period, we saw major effects in much more obvious clinical endpoints, including mortality. The test that became so meaningful quickest was the St. George's Respiratory Questionnaire. Thank you. Great. All right. I think, operator, we're gonna move on to Q&A, a more general Q&A. Great. Thank you, Jackie. At this time, we'll be conducting a question and answer session with our speakers. As a reminder, if you'd like to submit a question, you may do so by using the Q&A text box at the bottom of the webcast player, or by emailing your questions to questions@lifesciadvisors.com. Our first question comes from Kristen Kluska from Cantor Fitzgerald. Please go ahead, Kristen. Hi, good morning and good afternoon, everybody. Thanks for hosting this event and taking my questions. I know that the St. George's Respiratory Questionnaire is pretty extensive at 50 items, and of course, you're reporting that activities are normally more impacted than other items. Could you perhaps provide some anecdotes or context on the activity scale, perhaps where you saw some of these changes in the trial, and were they consistent amongst the patients? Yes. I think here within the components, when you sort of looked into, as you say, within the activity component, it's got several different questions. I think where I was noticing, 'cause we did have some younger patients there as well, was around the breathlessness on exertion, those kind of sort of things, you know, sort of to do with day-to-day activities. It seemed to be, to me, particularly around the sort of breathlessness piece of this. Which we know from, you know, sort of from work that's been done by the European Registry that breathlessness is one of the things that the patients with AATD find the most disruptive, and probably that ability as Sandy was speaking to in terms of performing day-to-day activities, more so for example than cough or sputum, which is more predominant for the usual COPD, where that comes up. I think that that's the piece that we're sort of pulling out. It's in small numbers, I have to say, but when you look through the individual patients, that seemed to be the more sort of regular feature. Okay, thank you for that. I noticed that the target population estimates have gone up a little bit in the U.S. and Europe from previous citations. Can you help understand the work that's going on to understand the true size of these markets? Of course, I understand the struggles that come with rare diseases, but this one, you know, is perhaps one of the larger rare diseases out there. Yeah. I mean, I think, Kristen, look, we're updating the data as you know, the market data, the publications come along. I think what's recognized in you know, AATD is that there are a lot of patients who are undiagnosed. In fact, I was just you know, as an example, contacted by someone who was recently being diagnosed who's in their fifties. You know, that goes with that, the lack of diagnosis and just I think you know, the target patient population. We're really just taking the published information and updating it as we go along. Great. Thank you so much. Thank you, Kristen. Our next question comes from Joe Schwartz from SVB Securities. Please go ahead, Joe. Hi. Great. Thanks so much for the presentation. I was wondering if you could talk some more about phase III in terms of the power I think we've obviously, you know, look at the phase III. I mean, just to say that we're looking at, you know, a study which will be say less than sort of 200 patients. Obviously, you know, we need to see, have the regulatory feedback, but from the data we have, that's the sort of, you know, trial size we're thinking about. We're looking at something, you know, sort of up to 12 months. Could be as short as six, but maybe as long as 12 months, Joe. I think, Jackie, the specific question was around the power. I mean, I think what we're sort of looking to be, so to be powering on the biomarker, digital biomarker response, and that gives us those sorts of numbers I mentioned. Great. Thanks. Sorry, I was cut off there a bit, but I gathered the feedback on the primary endpoint. That's super helpful. Given the longer duration of phase III, will you be looking to see if you can improve other things like CT density, FEV, and exacerbations? Yeah, I think there was the FDA workshop in 2019, where they looked at what those confirmatory endpoints would need to be from their perspective. They put several things out there, but it was quite helpful. What they said, and it's in their sort of slide, is that for the confirmatory it would be showing improvement in one or more clinical endpoints. So they seem to be with a p-value of 0.1. So they've been quite sort of flexible on that. But I think, yes, we would be looking at a number of things. You know, CT densitometry, you know, even if the, you know, FDA isn't interested, others are, including those who reimburse. So the study that we have, we believe we designed from a confirmatory endpoint to deliver on all of those things. We'd be looking to deliver on all of those things in terms of the study size. Obviously in discussions with regulators, they're going to want to know some specifics about what one they're going to be interested in, which is where we're going with St. George's. Great. Just one more quick one, if I could. On the safety and tolerability side, will you be titrating in phase III to manage things like headache? Yeah. I think we've got a lot better understanding of how to manage the headache. We know it's particularly those who've got a history of migraine who seem to be susceptible. We've got more experience, including from the BOS study about how we dose, escalate to be able to get you know people sort of through that period. What it does seem is that if people get through the period of headache, it goes away over time. It doesn't stay there, so it is a tolerance induction which we now feel you know comfortable that we can manage. Excellent. Thank you for taking my questions. Thanks, Joe. Our next question comes from Yun Zhong from BTIG. Please go ahead, Yun. Hi. Thank you very much for taking the questions. I have three questions. The first one is to clarify the selection of efficacy endpoint for the confirmatory study. You talked about the difference between the questionnaire and the FEV, this challenge of long-term evaluation for the FEV. My understanding is that for a confirmatory study, the timeline doesn't seem to be an issue as long as the company is actively engaged in initiating the study. What was the reason that you... Maybe I can ask in another way. In your discussion with the FDA, do you have to use the same efficacy endpoint both for the confirmatory study and to establish this correlation with biomarker? No, not at all. They were interested in any clinically relevant associations. They recognized the problems with FEV1. They really did. That this is not appropriate instrument for this disease. No. FEV1 doesn't have to be measured. There's a, you know, for example, in COPD, fluticasone was approved based on St. George's without an improvement in FEV1. No, there's not a- But- Yeah. There's as Jackie said, there's not an absolute requirement. I mean, obviously the key here is that the FEV1, you know, takes a long time to see those changes in this patient population. I think, you know, Jackie was saying that's why, you know, we're potentially looking at alternatives here for the confirmatory study. Okay. The activity domain, does it capture the lung function better than other domains like six-minute walk test? It's a bit different. I mean, the activity is a patient-reported symptoms, signs, quality of life instrument. There is a relationship. Rob has shown a correlation between the shuttle test and also VO2 max and the activity domain in the Alpha-1 population. There is a relationship between the two, but they are measuring rather different things. Okay. The second question is on the correlation that you showed between biomarkers and the questionnaire. You did mention the neutrophil elastase. Is there not a significant correlation between elastase inhibition and the questionnaire, please? Perhaps as you might imagine, the correlation is much, is there for the disease activity biomarkers, you know, released from the lung. Sort of so I think it's much more reflective of what's happening in the, you know, in the patient. I think the other thing you'll sort of notice is that, the, you know, the error bars on the activity biomarkers desmosine and Aα-Val360 are much tighter than for the blood desmosine. So I think, you know, what these two biomarkers, the Aα-Val360 and desmosine are measuring, is really a reflection of what's happening in the lung. I think that's why we're getting that tighter relationship. I see. Okay. Last question. I think, on one of the slides you showed that in placebo treatment group, some patient, they do, have a decrease in neutrophil elastase, down below the detectable level. What about the clinical symptoms of those patients? Do they improve as well? I think, I mean, I would say that some of those patients they sort of go if we're looking below the limit of quantification, some of them are just above and they go just below, and it's not such a big difference. But I think to link, we haven't been able to sort of look at linking neutrophil elastase near to clinical symptoms, particularly in the blood. I mean, I don't know. Do you want to start, Robert? I think it's very difficult, firstly, in a smaller study, but in any placebo-controlled studies because patients have a real want to get better. I will give you an anecdote. The first patient I ever put on augmentation therapy for a biomarker study. Patient came back after three weeks, told me never been better. He was now able to run upstairs, which he could never do before, and he was on placebo. The issues are the interpretations, and this, they're not sensitive to an individual. A biomarker can be quite sensitive to an individual. If you're looking at these other things that are very variable in how people interpret them, the numbers needed to actually be convinced that you're seeing a change are more than if you just want to look at a single biomarker. Okay, great. Thank you very much. Right. Thank you for the questions. Our next question comes from Gil Blum from Needham. Please go ahead, Gil. Good afternoon. Good morning, everyone, and thanks for the presentation. Now just one question from us, and this is on the matched study that was discussed earlier. Can you please remind us what was the powering of that study and how long it took to see an effect between the augmentation-treated patients and the ones who were not? Thank you. Yeah. For the EXACTLE, it was a six-month augmentation study, and there was no measurements prior to that. We just had to look at three months in alvelestat and six months in augmentation. For the desmosine in the RAPID study, they looked at three months and then at 12 months. There was a reduction seen at three months. I think it was a. They showed some statistical significance. They showed progressive reductions. Yes, it was three months and 12 months for the desmosine in that augmentation study. Those are really the only two proper placebo-controlled trials where these biomarkers have been measured using the same, yes, sort of techniques where we can make that comparison fairly. Great. Thank you. Thank you. Thank you, Gil. This concludes our question and answer session. I'll now turn it back over to Denise for closing remarks. Great. Thank you, Tara. As there are no further questions, I'd just like to thank everyone for their time today and for the questions. I especially want to thank Professor Stockley and Professor Sandhaus for their insights today and to Jackie and all the alvelestat at Mereo for the continued work on this program. We're looking forward to bringing you further updates on the progress of both alvelestat and also setrusumab, our other rare disease program. If you have any further questions, please don't hesitate to reach out and contact one of us. Thank you very much.