Good afternoon, and welcome to the Quince Therapeutics Virtual KOL event. At this time, all attendees are in a listen-only mode. Live question and answer sessions will follow the formal presentations. As a reminder, this call is being recorded, and a replay will be available on the company website following the conclusion of the event. I will now turn the call over to Dr. Brigette Roberts, Chief Corporate Affairs Officer and board member at Quince Therapeutics. Please go ahead, Brigette. Thank you, Wilson. Good afternoon, everyone, and thank you for joining Quince's KOL event. For those of you who are not yet familiar with this story, we turn to slide three please. Our company is focused on LAM-001 that we're studying across three pulmonary conditions. The first is PH in the setting of interstitial lung disease, estimated to affect about 200,000 patients between the U.S. and Europe. Based on promising phase II-A data that Dr. Paul Yu presented at ATS this year, we have moved forward into a phase II-B study, in PH-ILD with expected data in the first quarter of 2028. The second indication is Bronchiolitis Obliterans Syndrome post-lung transplant, estimated to affect about 30,000 patients between the U.S. and Europe by the early 2030s. This is a very severe complication, post-lung transplant. Unfortunately, the leading cause of death in the majority of patients. We are currently in an investigator-sponsored study being run at UCSF by Dr. Steve Hays, and that data is expected in the first quarter of 2027. Finally, we're also studying the drug in a third indication, sarcoidosis-associated pulmonary hypertension, estimated to affect about 60,000 patients between the U.S. and Europe. Another very severe disease, complicating about 15% of patients with underlying pulmonary sarcoidosis, and we'll be starting a phase II study toward the end of this year with a readout expected approximately two years thereafter. Next slide. The entire premise behind this drug was the goal was to try to find a safe and well-tolerated means of delivering rapamycin to patients' lungs in disease settings where the mTOR pathway was known to be truly implicated. What we created here is a product where we are delivering one-twentieth of that standard oral dose, 100 mcg is being delivered daily via this DPI, delivered directly to the pulmonary tissues. That is one-twentieth of the typical oral dose. Because of that, what we are seeing in humans is a less than one nanogram per mL systemic level, which is less than one-fifth to one-fifteenth the systemic level seen with oral delivery. Thus far, that has translated into a very benign profile in patients, and importantly, at least so far in our initial studies, efficacy as well. Next slide, please. Next slide. Oh, sorry. On that prior slide, it just highlighted our upcoming timelines for datasets. We, as mentioned, will have that PH-ILD data in Q1 2028. We'll be delivering this BOS data in the first quarter of 2027 and that SAPH data toward the end of 2028. It's now my pleasure to introduce our three KOLs who are going to be presenting today. For the PH-ILD discussion, we're joined by Dr. Aaron Waxman and Dr. Paul Yu. Dr. Waxman is the Director of Pulmonary Vascular Disease Program at the Brigham and Women's Hospital, and he's Professor of Medicine at Harvard Medical School. Notably, he's been the lead PI on numerous PH clinical studies, including the phase II SPECTRA study for sotatercept and the phase III INCREASE study for TYVASO, which led to the first approved agent to treat patients with PH-ILD. He holds an M.D. from Yale University, a Ph.D. in anatomy and neuroscience from Albany Medical College. He completed his residency in internal medicine at Yale and his fellowship in pulmonary and critical care medicine at Yale. He's board certified in pulmonary disease, critical care medicine, and internal medicine. Dr. Waxman was the lead PI for our phase II-A study of LAM that was just presented at ATS, and he's the lead investigator for our ongoing phase II-B study in PH-ILD. Turning to Dr. Paul Yu, he is the Director of Cardiovascular Research Center at the Massachusetts General Hospital and an Associate Professor of Medicine at Harvard Medical School. He holds an M.D. from Duke University and a Ph.D. in immunology from Duke. He completed his residency in internal medicine at UCSF, a clinical and research fellowship in cardiovascular disease at MGH, and a postdoctoral fellowship in cardiovascular biology with Dr. Kenneth Bloch at MGH. He's board certified in cardiovascular medicine. Dr. Yu has made a significant impact in pulmonary hypertension through his translational work, including the study of BMP and TGF-beta signaling and cardiovascular homeostasis, repair, and disease. Among his many contributions to the field, his work helped to elucidate the vascular remodeling activity of sotatercept, the first agent approved for PAH with a disease-modifying mechanism of action. Turning third to Dr. Steve Hays, who will be leading our BOS discussion. Dr. Hays is the Medical Director of the UCSF Advanced Lung Disease and Lung Transplant Program and a Professor of Medicine at UCSF. He holds an M.D. from the University of Kansas and completed his residency there in internal medicine. He completed his fellowship in pulmonary and critical care medicine at UCSF and in lung transplant at Stanford University. Dr. Hays is board certified in critical care medicine and pulmonary disease. His clinical focus is the treatment of advanced lung diseases, and his research focus includes lung transplant immunology and airway remodeling, chronic lung allograft dysfunction, infectious disease, and transplant digital health. Dr. Hays is the principal investigator for the ongoing investigator-sponsored phase II study of LAM-001 in BOS patients. Before starting, just to note, we are going to be breaking today's presentation into two sessions. The first will be on PH-ILD, the second one will cover BOS, and at the end of each session, we'll be opening it up for a 10- 15 minute Q&A, and questions will be taken in the order in which they're received. With that, I'll turn it over to Dr. Waxman and Dr. Yu to discuss pulmonary hypertension. Okay. Thank you, Brigette, and hello, everyone. We can go to the next slide. I always like to start out with a general statement of the problem and really just pointing out, which probably isn’t that necessary anymore, that Group 3 PH is something we encounter increasingly as people recognize the disease state and now that we actually have a treatment for it. I like to show the histopathologic slides that are on the right of this slide just to illustrate, for so long, we kind of ignored the idea of PH in the setting of Group 3 disease, and especially in Group 3 ILD, but these are all from patients with Group 3 except one. If I were to challenge doing that, the point is that vascular remodeling is a big deal when it comes to advanced lung disease and something we shouldn’t have ignored for the many years that we did. Next slide, please. This is just a summary of the prevalence and epidemiology of the disease state. I actually think that we underestimate how much is out there. I think part of the problem has been that because we had no treatments until recently, people didn’t get right heart cath, they didn’t get a diagnosis, and were pretty much ignored. But I think there’s no question that when we do have pulmonary hypertension in the setting of interstitial lung disease, we see a significant decline in the pulmonary function itself. We can go to the next slide. This is, again, restating some of the prevalence of the disease and showing what happens as far as mortality when we add pulmonary hypertension onto interstitial lung disease. Generally, there’s about a threefold increase in mortality once patients develop pulmonary hypertension. It’s always been kind of siloed into ILD clinics, but more and more as people recognize that pulmonary hypertension is a significant component, it’s overlapping with the pulmonary vascular clinic. But in spite of that, I think there’s still very significant delays in diagnosis, and as more treatments are coming to clinical trial, I think we’ll get better at finding the disease earlier in the disease process. You can go to the next slide. This is just the algorithm for diagnosis of PH-ILD because it is now putting two bad diseases into one patient. I think the things we start looking for and what we’re preaching out to the audience of pulmonologists, cardiologists, rheumatologists is that as patients start to become increasingly short of breath out of proportion to any changes in their pulmonary function or maybe their CT scan, it’s time to start thinking about pulmonary hypertension. There are some subtle findings on other tests like EKG. Echo is still an important screen, but echo becomes much less reliable when patients have advanced lung disease, so we start to look for other clues in the pulmonary function testing realm. If that DLCO, the diffusing capacity, which for those not familiar, is a measure of the surface area of the lung involved in gas exchange, as that starts to fall out of proportion to the forced vital capacity, that’s a time to be thinking about pulmonary hypertension. Certainly, if the patient’s exercise tolerance is on the decline, but lung function is not, then we start thinking about it. Echo still remains the important screening tool, but a low bar to take a patient to right heart cath is key, and I think that is starting to change as treatments become available. This is the general algorithm. You can go on to that next slide. This is just looking at the track record, and I think this raises a couple of important questions. I think we know endothelin receptor antagonists have now got themselves a black box warning, which I think is unfortunate because it’s probably related to clinical trial design more than any harmful effect of the drug itself. But so far to date, trials have not shown any consistent benefit and do raise the question of harm. The data right now does not support their use in PH associated with ILD. If we think about the PDE5 inhibitors, sildenafil and tadalafil, some studies have shown improved hemodynamics. Some have shown some improved quality of life or preserved exercise capacity. But the functional benefits to date have been inconsistent. There is always concern that these drugs can worsen gas exchange in patients, especially with COPD, but also ILD. The prostacyclins have been studied to some limited approach. They may improve some pulmonary hemodynamics and right heart function, but have also been found to worsen ventilation perfusion matching and worsen hypoxemia. The inhaled prostacyclins preferentially treat those well-ventilated lung regions. Although iloprost, which is not used in the U.S. much anymore, has shown mixed effects on exercise tolerance and oxygenation, and the recent PERFECT trial, which is PH-COPD, also raised some concerns with the drug. But I think that too gets to the importance of phenotyping our patients. Overall, the data suggest uncertain benefits of PAH-specific therapies in Group 3, with no clear improvement in mortality or clinical worsening and need for larger long-term trials. You can go to the next slide. I think there are a number of reasons as we analyze these, and it really comes down to phenotyping these patients properly. There's been biologic mismatch, such as with the STEP-IPF and simtuzumab studies that really didn't look to engage the dominant driver of progressive fibrotic disease. So the clinical readouts remained poor in spite of what seemed good clinical rationale. There are some harmful hemodynamic physiologic aspects, as I mentioned, with the ERAs and now also with riociguat. Really suggested that systemic vasodilator strategies can worsen gas exchange and worsen outcomes in fibrotic lung disease, especially when the lung is trying its very best to redistribute from poorly ventilated regions to better ventilated and make those better perfused. There's also some late heterogeneous populations. I think what PERFECT showed us is that patients with advanced PAH-COPD have a higher comorbidity burden. And one thing we also learned with the PERFECT trial is that patients who have a diffusing capacity that is too low, which was the real fundamental finding in that study, there just may not be enough vasculature to target. And endpoint dilution has also been a big problem with a lot of these clinical trials. Most of the programs were judged by broad functional decline in diffuse fibrotic disease rather than by a vascular endpoint linked to any treatment mechanism. You can go to the next slide. I think one of the big things that changed with INCREASE was the use of the inhaled route. Treprostinil, by giving it as an inhaled drug, was delivered to those ventilated lung units which were preserved and likely improved vascular tone while minimizing ventilation perfusion mismatch with what we saw with systemic vasodilators. Also, importantly, the right phenotype might have been stumbled upon, if you will. Patients had established PAH-ILD, and the treatment was targeting the pulmonary vascular problem rather than assuming an anti-fibrotic benefit alone. Although as it turned out, there was also an anti-fibrotic component there. We also designed it around the right endpoint at the time, where INCREASE showed a 31-meter placebo-corrected improvement in that six minute walk distance, also saw improvement in NT-proBNP and also fewer clinical worsening events. All of these would be consistent with a true vascular efficacy. Next slide, please. I think what we've learned from treprostinil and maybe from PDE5s is that we have one positive trial in this area, in PAH-ILD, a lot of cautionary history. I think the real clinical reality is that we're balancing symptom burden, oxygenation, RV function, and uncertainty. I think INCREASE was a landmark trial, but it certainly did not solve PAH-ILD. I think what it taught us was that treating the label helps some patients, but not all, and that it has allowed us to continue, I think, with a better approach overall. We can go to the next. This is just showing you the recent data from the TETON studies, which were the subsequent studies after we did INCREASE, where we saw a preservation of the FVC percent in ILD, suggesting that treprostinil truly does have an anti-fibrotic effect. I think importantly, it, like all the other anti-fibrotics, simply slowed progression. They did not reverse anything. I think the one positive here is that treprostinil not only had a little better preservation than what's out there but also was better tolerated. Next slide. I think the real rationale, it came down to the inhaled therapy, excuse me. Treatment with systemic pulmonary vasodilators, as I've already suggested, often results in worsening VQ, or ventilation-perfusion imbalance, and that leads to worsening oxygenation and can certainly make patients feel worse. Using an inhaled targeted therapy really optimizes ventilation perfusion and allows for drug delivery where it's needed the most and may have the best efficacy. I think inhaled approaches really have the most potential for increased efficacy and decreased systemic side effects. Next slide, please. Now, kind of switching gears to the mTOR pathway, and this is some of the preclinical data. On the left of this slide is a paper that was published by Goncharov and colleagues looking at "mTORC2 derives abnormal vascular smooth muscle growth and survival in PAH." This was a study looking at pulmonary artery smooth muscle cells that were obtained from patients with idiopathic pulmonary arterial hypertension, and also complemented by a study of chronic hypoxia in a rat model. The key findings here are that both mTORC1 and 2 promoted proliferation, and mTORC2 additionally supported glycolytic energy production and resistance to apoptosis. The treatment effects of an inhibitor were that the dual mTOR12 inhibitor, here they used PP242, induced smooth muscle cell apoptosis and reversed pulmonary vascular remodeling in rats. This study had supported targeting the mTORC2 pathway to address vascular remodeling. Obviously, clinical efficacy was not evaluated in this study. The middle panel is a paper by Hussaini et al., entitled "The rapamycin suppresses abnormal smooth muscle proliferation in experimental PH." In this study, oral rapamycin at 5 mg per kilo per day was evaluated in the monocrotaline model of pulmonary hypertension, and they looked at both prevention and treatment in this study. The key findings were that reduced pulmonary arterial pressure, improved right ventricular hypertrophy, and pulmonary vascular muscularization were all noted. The mechanistic findings, there was a normalized exaggerated smooth muscle cell growth associated with suppression of mTORC1 and mTORC2 signaling. Selective mTORC1 inhibition at low concentrations, though, was not sufficient, so I think that's also suggesting a limitation of systemic delivery. The implication here was that preclinical evidence for treating established pulmonary vascular disease with effects dependent on dose and pathway inhibition were the final findings. The last study on this slide on the right is by Kato et al., and looked at rapamycin enhancing endothelial autophagy and attenuation of severe experimental PH. Here they used the SuHx hypoxia model. Rats were given rapamycin at 5 mg per kilogram via intraperitoneal injection. This was given three times weekly over weeks three to eight, which allows for establishment of pulmonary hypertension after the treatment of the model. The key findings here were that they saw reduced right ventricular systolic pressure and improved increased endothelial autophagy markers of reduced proliferation, and increased apoptosis, accompanied by fewer endothelial cells with DNA damage. All a result of blocking the mTOR pathway. This study, I think, also supports endothelial autophagy as a potential therapeutic target, and benefits remain preclinical in this study. We can go to the next slide, please. This is the last preclinical study that I'll show. This is a study by Yoshizaki et al., looking at rapamycin attenuating fibrosis in two mouse models of systemic sclerosis. Here, rapamycin was given at 1.5 mg per kilo per day for 28 days in these two models, one a skin tightening model and the other a bleomycin induced model. The reduced hypodermal thickness and skin collagen content with the mTOR inhibition was about 38% in those skin tightening model mice, and the reduced skin and lung fibrosis in the bleomycin-treated mice was also noted. They also saw that a lot of the pro-fibrotic cytokines and inflammatory infiltration was suppressed, as well as fibroblast migration and proliferation. This study really also supports mTOR inhibition as an anti-fibrotic strategy. But again, this is all animal data, not human. We can go to the next slide, please. So I think to summarize what I've shown you so far is to ask the question, why should inhaled sirolimus work? I think, one, we have a lot of preclinical data that targeting the mTOR pathway makes sense mechanistically, and it's above and beyond any vasodilating approaches. mTOR is upstream of remodeling, and sirolimus can suppress proliferative, inflammatory, and pro-fibrotic signaling, which is all relevant to the pulmonary vascular bed and pulmonary vascular smooth muscle and endothelial dysfunction, as well as fibrotic mechanisms involving fibroblast activation and migration. I think the compartment targeting matters. I think as we've seen with pulmonary vasodilators, it makes sense to target drug into the lung at the disease site, so that inhaled delivery is really designed to maximize drug delivery to epithelial, interstitial, and vascular elements of the disease while reducing systemic immunosuppression and any off-target toxicity. I think the potential also of differentiation from pure vasodilators, sirolimus could modify the remodeling biology so that this could provide us with a second disease-modifying drug, potentially with even less side effect potential. I think the most defensible development path is you replicate the INCREASE playbook by targeting PH-ILD patients. It preserved the inhaled lung selectivity, and we use the same endpoints of exercise tolerance, biomarkers, hemodynamics, and disease progression. I will hand it over to Paul at that point. Thanks, Aaron, for presenting the rationale for our first study. I am going to provide top-line results from an open-label phase II-A study of dry powdered inhaled, or DPI, formulation of rapamycin called LAM-001. This was tested in Group 1 PAH and Group 3 PH-ILD patients with the goal of enrolling 10 of either patient category. All of these patients were on maximal background therapy for pulmonary arterial hypertension or PH-ILD, or anti-fibrotic therapy for ILD at the time of enrollment, and all of them had functional Class 3 disease. This was an invasive cardiopulmonary exercise testing study with the primary endpoint of peak oxygen uptake, or VO2 max, at 24 weeks versus baseline, as well as safety and tolerability endpoints. The secondary endpoints included hemodynamics based on pulmonary vascular resistance, also exercise function, and NT-proBNP was an exploratory endpoint. Next slide, please. There were five Group 1 PAH patients and five PH-ILD patients enrolled in the study. The demographics were very similar to other contemporary PAH or PH-ILD trials. All Group 1 PAH patients were on stable regimens of two or more standard of care PAH drugs at the time of enrollment and throughout the study. Importantly, all the PH-ILD patients received treprostinil therapy in some form at baseline, and also anti-fibrotic therapy if appropriate, and this was consistent with maximal medical therapy. Next slide. All of our patients who completed the study were seen to improve across several functional hemodynamic and biomarker endpoints. There were four early terminations that were not attributable to study drug, but due to unrelated hospitalizations and complications, including acute coronary syndrome in one subject and a classic vaping-induced lung injury in another subject. The six patients, most, if not all, of the primary and secondary endpoints shown on the table on the left and by forest plot on the right. What we saw was a highly consistent effect in directionality for each of the endpoints. Six minute walk distance, VO2 max, percentage change of forced vital capacity, pulmonary vascular resistance measured both under exercise loading conditions and under supine static conditions, as well as NT-proBNP. These improvements were seen whether we looked at the population as a whole or with PAH or PH-ILD. You can see that there was a median increase in six minute walk distance of 60.1 meters. That was true among the overall population in the PH-ILD group. There was an improvement in VO2 max of 5% predicted among the overall group, slightly higher in the PH-ILD group. There was a reduction in the PH-ILD group in the pulmonary vascular resistance of 38.6% under exercise and -43.7 under supine conditions, and approximately a 28% drop in NT-proBNP. The forced vital capacity improved across the whole cohort, 3.5% as a whole and 1% within the PH-ILD group. With the caveat of this being a very small cohort, the magnitude of these changes compares favorably with other modern phase II and phase III studies in PAH and PH-ILD. These include the INCREASE study that Aaron Waxman just told you about, as well as PAH studies such as PULSAR and STELLAR for sotatercept. Next slide, please. Consistent with those objective endpoints, the functional classes were also seen to improve, with 100% of completers improving from their baseline functional Class 3 to at least functional Class 2 by week 24. In fact, two of the patients improved to functional Class 1. Next slide. In this trial, LAM-001 was well-tolerated with few Grade 1 or 2 adverse events involving either cough, productive cough, or gingivitis. There were no dose interruptions or discontinuations due to drug, and there were no drug-related serious adverse events. To summarize, this open-label study, LAM-001, demonstrated favorable tolerability, improvement or stabilization in multiple cardiopulmonary exercise capacity, hemodynamic and functional status endpoints, suggesting physiologic benefit, and these provide our rationale for the new randomized control study, this phase II-B study of LAM-001 in PH-ILD. This will involve two doses of LAM-001, the dose that was tested in the open label, as well as a higher dose to explore whether there's greater efficacy and the similar endpoints, except that the primary endpoint for this phase II-B trial will be pulmonary vascular resistance. In looking at the therapeutic landscape, mTOR is known to be a master integrator of metabolic state, environmental stress and lies at sort of the intersection of many growth factor cytokine and hypoxic stress signals. This results in the ability to influence a lot of downstream processes important to PH and ILD, including cell growth, cell fate, and metabolic adaptation. While many of the other investigational approved drugs in this space can, in theory, affect these processes, including pulmonary arterial smooth muscle cell proliferation, fibrosis, and inflammatory cell recruitment, mTOR lies really in a central position in many of these pathways. By virtue of its longstanding clinical experience as an anti-vascular proliferative drug in cardiovascular indications, as well as being an established immunosuppressive agent in transplant medicine, it has really a clinically known ability to target many of these drivers of obstructive vasculopathy and fibrosis in PH and ILD. I think it makes a lot of sense based on both the mechanistic understanding of how mTOR inhibition works, as well as the clinical track record of this particular agent and its potency. With that, we can open this up to questions. Thank you, Dr. Waxman and Dr. Yu. At this time, we will begin our first live Q&A session. To our covering analysts, please use the raise hand feature to be added to the queue. Kindly hold for a brief moment while we pull for questions. Our first question comes from Mazi Alimohamed at Oppenheimer. Please go ahead. Thank you, and thank you for taking our question. As we think about the BOS trial, and maybe this is one for Dr. Hays mostly, how are we thinking about the potential for advancement as we think about a phase III and as we think about best determines the potential registrational path forward for a phase III, and what endpoints do you think would be most useful here in thinking through with the FDA as we align on a phase III? That is specific to the BOS study? I think Yes, specific to the BOS study. Because I think Dr. Hays is going to be talking about the BOS data, and that would probably be a better time. Oh, I see. Oh, I didn't realize. Right. Okay. I can flip that for this one as we think about PH-ILD. Maybe I'll switch to thinking about as the readout. As we think about even the BOS readout coming up, as we digest that and we think about the PH-ILD moving forward in, I think the two things that I was thinking about for the PH-ILD is how should we think about target engagement and safety profile in the upcoming readout, and how does that de-risk or add risk to the possible future in PH-ILD? I guess the issue of risk, are we talking about the potential adverse effects of the drug? Yes. How we should think about the safety profile as it relates to PH-ILD in that landscape. I think as we've seen and as Brigette pointed out in the very beginning, the dosing of this drug is orders of magnitude less than what we would do normally with this drug as a systemic drug. At least our limited experience would suggest that it's extremely well-tolerated and the benefits that we're seeing, again, in small numbers, but are impressive, especially in comparison to other drugs that are out there since not much else has worked in this target space. Paul, do you want to? Yeah. I think what we want to see in our phase II-B RCT is continued evidence of that same really promising open-label experience. There's no substitute for an RCT, as we all have learned in this area. But I think with more patient exposure, especially in that population, we'll get an even stronger sense of the tolerability. We know that the approved medications are limited in their tolerability due to the frequency of cough, and hopefully, that advantage that we think might be present with this in terms of tolerability and lack of cough, which is specific to different agents, even with the inhaled modality, will bear out, and that we'll hopefully see a similarly low frequency of adverse events, I think afforded by that therapeutic index of having really good tissue delivery without exposing systemically our patients to this drug. Great. Thank you so much. Thank you for your questions, Mazi. Our next question comes from Joe Schwartz at Leerink. Please go ahead, Joe. Great. Thanks for hosting this great event and taking my questions. One for Dr. Waxman and one for Dr. Yu. Dr. Waxman, you ran SPECTRA and the LAM-001 phase II-A used a similar open-label CPET design. I guess having seen how SPECTRA carried into controlled trials, how does this signal that you are seeing here compare at the same stage and for sotatercept, and what part of it do you expect to hold up under blinding? I think great question. Obviously, comparing two different or very different populations of patients. I think the important things that we saw with these patients on LAM, the improvement in the VO2 max was really impressive. That says that exercise tolerance is clearly improving on a physiologic basis purely because of the drug, because these patients did not exercise. They did not go into physical therapy or really have any other training exercises. Even though those numbers seem small, I think when you do a lot of exercise physiology, and this was actually a little bit better than what we saw with SPECTRA, that percentage improvement is impressive. I also think the 6-minute walk distance goes along with that. I think I would probably characterize it, and again, stressing that these are very different patient populations, pretty comparable positive findings that we saw with this approach. Thank you. If I could just ask Dr. Yu, given we saw the patients improved a functional class, in some cases really early, I was just wondering, based on the mechanism here, what could explain that speed, and how does it influence your view of how the drug works, be it through inflammation, blood vessel lining, or right heart unloading? What do you think drove some of the impressive early responses we saw in functional class? That is a great question. It always has surprised us when we have looked at recent trials, such as with sotatercept, how quickly we are starting to see symptomatic benefit with drugs that are trying to correct a situation we think that developed over years, if not decades. The answer might lie in what is causing a lot of that chronic disease state physiology. We now know that sotatercept has probably some very early hemodynamic effects when people look very closely using. That possibility could exist here. We would have to look. There may be more rapid improvements in symptoms and functional class due to acute effects on smooth muscle cell function is what I would predict, but I could not rule out anti-inflammatory effects. We would expect that anti-fibrotic effects would probably take more time for the extracellular matrix to remodel and change. My best bet is that there is a very potent effect on smooth muscle cell biology. Thank you. Thank you, Joe. Our next question comes from Sam Slutsky at LifeSci Capital. Please go ahead, Sam. Hey, thanks for taking the questions. I guess as we think about PH-ILD and the potential future treatment approaches, how do you envision combo therapy advancing here? Do you see potential synergy with LAM-001 and inhaled treprostinil standard of care? Then just any thoughts on how Roivant's mosliciguat could have an impact on development paths, if any? No, great question. I think there's no question that combination therapy in this disease state will be standard of care. Just right now, we don't have that option. I think that last slide that Paul showed really suggests some of the potential overlap and synergy that one could expect with combination therapy. I think importantly, mosliciguat, even though the data was really good in regards to six minute walk and time to clinical worsening in NT-proBNP, it is a pure pulmonary vasodilator. It is not an anti-fibrotic. I think where one could envision combination therapy working really well, also I think really importantly simplifying the patient's daily need for drug is combination of this LAM-001 with something like TPIP, if it should get approved, or even treprostinil, even though it's four times a day. Sotatercept and the TGF-beta signaling pathway could also make sense, but I'm not aware of anyone who's going to study that yet. But one could really simplify our patients' care by adding something like treprostinil plus LAM-001. The other drugs on that list, I think as pure pulmonary vasodilators, it's hard to say. Combination with nerandomilast could even be synergistic there as well. I would just add real quick to what Aaron said, is that the combination therapy is the opportunity. Yes, a once-a-day therapy based on treprostinil, like the prodrug TPIP, could be a great match for this agent, LAM-001. But we're in an era now where we have to demonstrate efficacy on top of inhaled treprostinil. In this open label experience and in our randomized control trial, I think we're going to make every effort to maintain that as we did in the open label. So it's very hard to understand how mosliciguat being primarily a vasodilator would compound or build efficacy on top of that if they're. In the current trial, the rate of inhaled treprostinil was a bit lower, closer to 25%, I believe. Not only is it an opportunity, but it is a new high bar that I think all these drugs will have to meet. Super helpful. Thanks. Thank you for your question, Sam. Our next question comes from Olivia Brayer at Cantor. Please go ahead, Olivia. Olivia, you may be on mute. Okay. I am going to take the next question. Please hold. All right. Thank you for your questions to our analysts and speakers. This is all we have time for in this first Q&A session. As a reminder, there will be a second Q&A session after Dr. Hays' presentation. I will now turn it over to Dr. Hays. Please go ahead. Dr. Hays, you may be on mute. Thank you so much. Thanks, Wilson. Next slide, please. Today I am going to talk to you about the use of LAM-001 for a syndrome that many of you may not be familiar with, but it is one of the leading causes of death after transplant, and that is known as Bronchiolitis Obliterans Syndrome. It falls into a disease entity which we call Chronic Lung Allograft Dysfunction. That is what we used to refer to as chronic rejection. Bronchiolitis Obliterans Syndrome is the most common phenotype or endotype of that syndrome. It occurs in 50% of patients by five years, and it is, while rare in the first year, it may affect 40%-80% of people in the first five years, and it is a leading cause of death by 10 years. 90% of patients either have Bronchiolitis Obliterans Syndrome or have died from their transplant. Ultimately, this is the final common pathway of a dysregulated repair and fibrosis of the small airways, the bronchioles in the lung. You can see by the histology here, the bronchial tube, which normally might look like this, then becomes fibrotic and essentially occluded by this fibroproliferative tissue. In this more cartoon illustration, you can also demonstrate this. You could imagine this would cause severe airflow limitation in these patients. Next slide. How do we define BOS? Bronchiolitis obliterans syndrome, unfortunately, is very difficult to diagnose by pathology. It's a clinical diagnosis of exclusion, and it is identified when someone's lung function declines and it's persistent over the course of three weeks. By lung function decline, specifically, I mean the forced expiratory volume in one second. The amount of air someone can blow out in one second. When that's sustained over the course of three months by 20%, that's considered bronchiolitis obliterans syndrome if you've ruled out other reversible causes such as infection. FEV1, which is the measurement of lung function, really is the primary surveillance tool. It's important that we're measuring this on a regular basis because oftentimes in the early stages of bronchiolitis obliterans syndrome, patients are asymptomatic. They may not pick up on it. Unfortunately, it carries a very grim prognosis, three to five year is the median survival after the diagnosis of BOS. The clinical progression is variable. There are patients that progress relatively rapidly, whereas other patients may progress a bit more slowly or medium-term. Next slide. There are a lot of risk factors. We don't completely understand the pathophysiology around what causes bronchiolitis obliterans syndrome. Other than that, we know it's an aberrant healing response to an injury to the bronchial tubes, and the injury could be an alloimmune injury, such as acute rejection or an antibody-mediated rejection, but it also may be a more blunt, or activation of the innate immune system as which occurs during infections or gastroesophageal reflux disease with microaspiration. There's numerous risk factors for development of this entity. Next slide. Currently, we don't have any accepted FDA-cleared treatments for BOS, but we have many strategies which we try to employ with limited efficacy. One of the most common is to intensify immunosuppression by increasing corticosteroids and/or cell cycle inhibitors. That has not been shown to be effective in most patients. One entity I will point out is that there is a group of patients who develop bronchiolitis obliterans syndrome that is responsive to macrolide therapy. This is an entity now known as neutrophil responsive airway disease. These patients do tend to improve with macrolide therapy, at least initially, and they may, at some point in the future, develop progression. Treating chronic or recurrent infections is an important mainstay of treatment, and then some treatments which have been shown to have some efficacy in some patients, but unfortunately have not undergone rigorous trials include extracorporeal photopheresis, which is an interesting therapy. Quite arduous, similar to a dialysis where patient's blood is removed, exposed to psoralen, which makes the blood and the white blood cells sensitive to UV light, and that induces apoptosis of leukocytes and stimulates Treg production. Then finally, retransplantation is an option for some patients who have progressive BOS and respiratory failure. Next slide. There is an evolving experimental landscape in bronchiolitis obliterans syndrome. Most of these therapies are still in phase I and II, including LAM-001, which I'm going to talk to you a bit more about the design. JAK inhibitors and ROCK2 inhibitors are also being trialed currently as a treatment. Most of the foundation of those trials comes out of hematopoietic stem cell transplant-related bronchiolitis obliterans, which has some similarities, but obviously the underlying disease and cause is different. In terms of phase III, there is a RENAAL trial, which is basically like an antioxidant therapy that's nebulized, and liposomal cyclosporine A, which is again an inhaled therapy which did not meet the primary endpoint. Then finally, as I mentioned, extracorporeal photopheresis is considered to be rescue therapy for BOS. It has not undergone rigorous double-blind placebo-controlled trials and therefore is not approved by CMS Medicare. Antifibrotics are also used as salvage therapy, and there are large European-based phase III studies ongoing. However, I think initially the readout is that these may not be shown to be effective. Next slide. What's the rationale for mTOR inhibition in BOS? Similar to what Dr. Waxman pointed out, there are multiple different pathways of potential efficacy in lung transplant recipients. Immunomodulation may be one, where there's decreased proliferation of T cells as well as increased upregulation of Tregs. These drugs are also thought to be renal protective, so they allow us to reduce the amount of calcineurin inhibitor therapy to salvage kidney function. There are antiviral effects of mTOR inhibitors, including suppression of particularly herpes virus, namely CMV, and antifibrotic effects, which I think we are capitalizing with the treatment in bronchiolitis obliterans syndrome, where there's decreased fibroblast activation and decrease in extracellular matrix deposition. Finally, anti-oncogenic effects. This is another use case in lung transplantation. In patients who have unrelenting skin cancer, we use mTOR inhibitors to decrease the calcineurin inhibitor use, which is the most potent pro-cancer drug. Then there are cardioprotective effects in heart transplantation. For example, mTORs are considered essential therapy for graft vasculopathy, which is the form of chronic rejection in heart transplant. Next slide. Preclinical studies that I'll review briefly, but there's really been no significant randomized controlled trial in lung transplantation with oral mTOR inhibitors. There is a biologic foundation, though, similar to in pulmonary hypertension. There have been some tracheal transplant models in mice. For example, this study exposed tracheal transplant is considered to be a sort of a biologic correlate of bronchiolitis obliterans syndrome, though clearly there's some differences in that this occurs relatively rapidly after transplantation as opposed to in the actual human transplant. But exposure to rapamycin in mice that have had the tracheal transplant show two interesting findings. One, there is a marked reduction in the fibroblastic proliferation in the trachea in those patients who are treated with rapamycin, comparable to those rats who had an iso-transplant. The other finding that was interesting was that there was an upregulation by 28 days of both Treg and Breg and anti-inflammatory cytokines. So rapamycin in the tracheal transplant model appears to not only reduce the amount of fibroblastic proliferation in the airway, but also upregulate both Treg and Breg. Next slide. In the humans, there's several case series, retrospective studies. These both come out of Spain. The graph on the left shows 57 patients who were treated with everolimus after the diagnosis of Bronchiolitis Obliterans Syndrome. You can see that the rate of decline pre-everolimus significantly reduced in the post everolimus group. The challenge of looking at these data, there is no control group. There is kind of a natural sort of decrease in the rate of decline in Bronchiolitis Obliterans Syndrome, but it is still a very impressive flattening of this curve. The challenge in both of these trials, the second trial being in rapamycin, a much smaller trial of 11 patients, which also showed a pretty dramatic decrease in the rate of decline of FEV1. The main challenge with both of these trials is they had a very high rate of dropout, meaning about 30%-35% of patients who were treated with oral everolimus and oral rapamycin ended up stopping it a median of 12 months after initiation due to side effects. Next slide. This has really been one of the big limitations in mTOR inhibitors, at least in lung transplantation, has been the incidence of side effects. This is why the inhaled preparation of sirolimus is so exciting to our field. As we have already heard, oral ulcerations or mucositis, hyperlipidemia, specifically hypertriglyceridemia, some GI side effects, and hematologic side effects such as leukopenia and thrombocytopenia are relatively common. The other side effect we oftentimes see in our patients is edema, peripheral edema, lymphedema, occurring in up to 12% of patients. Next slide. There are many potential advantages of using inhaled sirolimus in lung. Similar to what Dr. Waxman had described, we are really delivering the drug to the site of disease activity, which is the small airways of the lungs, and it provides this potent immunosuppressive and antifibrotic and anti-proliferative effects. By achieving these high concentrations in the lung without having high concentrations in the serum, which are associated with most of the side effects. It is easy to use as a once-a-day dry powder inhaler. As I mentioned, it reduces the systemic exposure versus oral therapy, which we anticipate would lead to fewer systemic side effects, such as bone marrow suppression, nephrotoxicity, which includes proteinuria and the edema and GI side effects. Next slide. We have designed and are fully enrolled in a phase II randomized placebo-controlled trial, looking at 100 mcg of LAM-001 versus placebo in a group of patients who have been diagnosed with Bronchiolitis Obliterans Syndrome. The trial extends for 48 weeks, and then patients are able to transition over into an open label extension. We are including all adult patients over the ages of 18 who have newly diagnosed Bronchiolitis Obliterans Syndrome, which is study defined as a persistent drop in lung function from baseline of greater than 15%-50%. The primary endpoint at 48 weeks is a change in the percent of FEV1 across the 48 weeks of the trial. We have numerous secondary endpoints, which include the absolute change in FEV1 at 48 weeks, as well as a change in the rate of progression in FEV1 at 48 weeks versus pre-enrollment. Progression-free survival level one, which is basically a 10% drop in FEV1 after enrollment, is considered progression. We have exploratory endpoints, which include some patient-reported outcomes and six minute walk distance, in addition to some biologic studies looking at the UCSF CLAD gene signature profile, as well as activation of the mTOR pathway. As I mentioned, the study is currently fully enrolled December with readout of top line in the first quarter of 2027. Next slide. What we're hoping to find in this phase II trial is that the safety and tolerability are equivalent to placebo. I think if we see that there's a 5%-10% difference between the drug and placebo arms in the change in FEV1 over 48 weeks, that would be clinically meaningful, as well as a decrease in the slope of decline and a trend toward progression-free survival. Next slide. Where do I see this falling into the BOS therapeutic landscape? As I mentioned at the very beginning, we currently have zero FDA-cleared treatments for Bronchiolitis Obliterans Syndrome in transplant. In fact, we've had no randomized placebo-controlled trials that have shown a therapy to be significantly beneficial. I think this would become the standard of care for patients who have Bronchiolitis Obliterans Syndrome in lung transplantation, if this passes through our phase II with significant top line and we get through phase III. I think that's the last slide. I'm happy to open it up to questions. Thank you, Dr. Hays. At this time, we will begin our second live Q&A session. To our covering analysts, please use the raise hand feature to be added to the queue. Kindly hold for a brief moment while we pull for questions. Our first question comes from Olivia Brayer at Cantor. Please go ahead, Olivia. Hi. Hopefully, you guys can hear me okay now. Dr. Hays, given that FEV1 trajectories in BOS patients can be pretty variable, what were the main things that you actually looked for when you were selecting patients, just to make sure that you enrolled patients with truly progressive disease? I've also got a quick follow-up on drug delivery. Sure. This is tricky. I think that inherent in this disease, and I think most diseases, there is quite a bit of heterogeneity in terms of disease progression. Because we are using this physiologic metric, we did want to make sure that we were enrolling patients that had evidence of new BOS with progression. We have a screening protocol at our institution where we are looking at every FEV1 that is generated by patients. When patients enter into this point where they have had a more than a 10% drop in FEV1, they appear onto our watchlist so we can follow them more closely over the ensuing months. When the patients do drop into the inclusion criteria, which means a persistent drop in FEV1 of greater than 15%, we are able to screen those patients. How we are ensuring that we are really identifying patients who we think would benefit are one, we are really trying to identify those patients who have a new decline, so new BOS. We think that enrolling patients early gives us the best chance of making a meaningful impact, and then we are making sure that they have a sustained drop. It is not a one-off drop, but they have to have repeated measurements that meet criteria that are at least 30 days apart. By the time they come in for screening and enrollment, they have had at least three FEV1 measurements that meet criteria. That is the method that we have used. I think that there are other trial designs which include looking at the rate of decline as a potential inclusion criteria, and I think that is something that we may consider for larger trials. But for a single center trial where we have pretty good control over the patients that we are enrolling, our methods worked really well. Okay. Very helpful. On the drug delivery question, BOS, obviously a small airway disease. What is your view on whether inhaled LAM-001 is actually getting into the affected bronchioles? Could that get more difficult as the disease progresses and the obstruction potentially gets worse? Great question. I think that the preclinical data shows that with both the and again, maybe Keith Fandrick, who is on the call, would like to jump in on this, but I know that the preclinical data suggests that the design of the drug was that it would make it all the way to the alveolar spaces of the lung. I recognize that as the small airways do start to become more narrow, that might theoretically decrease the deposition of the drug in those airways. But again, I think we do not anticipate it necessarily being blocked from the small airways of the lung, even in those patients who have some obstruction. But it is certainly something that we will learn over time. Keith, do you want to dive in any more detail about that? Yeah, I think you said it very well. Our drug has been well-formulated in a classic DPI configuration. Our particle size, which is actually measured with an impactor, which mimics a lung, clearly shows that the drug is deposited effectively everywhere where the lung will be aerated. I think at the end of the day, it is going to be your efficacy study from these trials that are going to eventually prove that it gets to the right place at the right amounts to perform and as expected. Thank you both very much. Sure. Thank you for your questions, Olivia. Our next question comes from Gavin Clark-Gartner at Evercore. Please go ahead, Gavin. Hey. Thanks for all the insights here. This is super helpful. The five of 19 blinded FEV1 decliners is a really interesting data point here, especially since the study is on top of triplet background therapy and given what happened in Zambon's previous studies. Maybe you could help us contextualize that data point. I guess more specifically, based on the patient selection criteria that you just walked through, how are you expecting the placebo arm to perform on FEV1 in this study? Thank you. Thanks, Gavin. Great question. I think you're referring to some safety data, looking at just ensuring that we had a sort of expected number of patients who've had what we call progression. Progression was defined in the trial as a drop in FEV1 of 10% from the enrollment baseline. In our pre-study planning, we'd looked at a cohort of patients with Bronchiolitis Obliterans Syndrome over the course of three years at UCSF, and we showed that about 50% of patients have a 10% decline, or what we would define as progression, over the ensuing year following the diagnosis of Bronchiolitis Obliterans Syndrome. That kind of helped us power our study and also understand what to expect. I guess my developed that endpoint of progression, because it fell in line with what we were estimating from our preclinical data from our cohort. That's helpful. This may be a slightly more technical question, but for the patients that did have that over 10% FEV1 decline, was this based on multiple visits, or was it just at a single point in time they had that drop? Yeah, good question. For both enrollment as well as the diagnosis of the progression endpoint, they had to have repeated measures that met the criteria separated by 30 days, or separated by greater than three weeks, I'm sorry. Typically, when patients have what we diagnose as progression, we bring them back at three weeks to document that they have continued progression. Then those patients are obviously offered other alternative treatments, such as extracorporeal photopheresis, that is all directed by the clinical team. Great. Sorry, just last quick question. Sure. Have you said anything about the discontinuations or drop-off rates throughout the course of the study? Have I done what? Have you disclosed anything about the discontinuations or dropout rates on a blinded basis over the course of the study? No, we have not published that. I think I would say in general, our data aligns pretty well with Dr. Waxman's in that we've had very high tolerability. Of course, we're still completely blinded with very limited dropout due to drug intolerance. Great. That's really helpful. Thanks, Dr. Hays. Thank you for your questions, Gavin. Our next question comes from Michael King at Rodman & Renshaw. Please go ahead, Mike. Thanks for taking the question. I'm stepping in for my colleague, Seema Sheoran. I guess, Dr. Hays, the magnitude of improvement and decline that you mentioned, how clinically relevant is that? It seems like with the heterogeneity of decline, how meaningful is a 5%-10% improvement in the rate of decline to your patients? Good question. I think that it's sometimes easier to put this. Well, there's I guess a couple of answers to that question. One is that from a physiologic perspective, many. I mean, many of these patients start off with an FEV1 of, say, 2 L. This is essentially a difference of 200 ml, which again, is well outside the expected change that you'd see with day-to-day variability. It's considered a clinically significant difference. But the other factor is that it is this kind of 10% change that predicts whether someone's going to have a really poor prognosis after the diagnosis of bronchiolitis obliterans. By that I mean, in population studies or registry studies looking at the progression of bronchiolitis obliterans syndrome, those patients that have had a 10% decline in FEV1 after diagnosis have a much poorer prognosis overall than those patients who did not meet that progression threshold. That's another reason why I think that from a clinical perspective, that is meaningful. Thanks. Thank you for your questions, Michael. Our next question comes from Mazi Alimohamed at Oppenheimer. Please go ahead, Mazi. Thank you. Thanks for taking our questions again. I think one, again, around the heterogeneity of the disease. With that, do you expect LAM-001 to only work in obstructive BOS? How early in the disease course does it need to be given to matter? Maybe as a follow-up to that, as we think about steroid use, is this something that you would use alongside existing systemic immunosuppression or something you think could be swapped in? With that, I'm also thinking with the calcineurin inhibitor and mTOR interactions, how could that complicate the use of concurrent therapies at the same time? Okay. I should have started writing these questions down. Okay, I think the first question was, with the heterogeneity, how important do I think that it's going to be to enroll these patients early? I think we don't know for sure. Again, this is a fairly small study. I think it's going to be a meaningful trial, but it's a fairly small trial. I think based on just prior experiences at other studies and even looking at potentially some subgroup or at post hoc analysis of some of the earlier trials, it does suggest that patients who are started on treatment and diagnosed and start on treatment early in the disease process have a much better likelihood of having a response. We believe that. I think that as we gain more experience, and I'm sure as we develop the phase III and start enrolling in the phase III trial, there is going to be the potential for some increased heterogeneity in the enrollment. We'll probably have some experience in how patients do who are enrolled later in their BOS journey. I certainly hope that this therapy would be available and make a meaningful difference in that group, too. In terms of the other question, at least at the current time, we consider that this treatment would be an add-on treatment to the standard immunosuppressive therapy that patients are on. In fact, it's a requirement of the trial that patients are on three-drug immunosuppression prior to enrollment, because we didn't want to introduce another potential variable that might impact outcomes. I think that'll be the way we design the phase III trial as well, I presume. Though I do think in the future, I could see this potentially replacing or allowing us to limit other maybe non-effective immunosuppression in the setting of BOS because of its both local immunosuppressive effects as well as these anti-proliferative effects. Noted. I guess maybe to further on the first question, so because of FEV1, what I guess I was getting at, is it something you think will only work in patients like obstructive Oh, sorry. Yeah. Or can it be generalized? I missed that part of your question. I actually don't have any reason to think it wouldn't necessarily be effective in the RAS phenotype or endotype. The restrictive alveolar syndrome, which is a much more of a fibrotic disease that does impact both more the alveolar space and the subpleural space. I think for the purposes of a clinical trial, I think we want to try to make the group as homogeneous as possible. So I think as we move forward, it may be a different subgroup that we look at, because I don't see a reason why it wouldn't necessarily be effective in that group given its kind of anti-fibrotic, anti-proliferative effects, which ultimately is the I think just the commercialization aspect of this, as we think about the patients, how concentrated is the care of these patients across sites in the U.S., and how do you think about that as you think about if this were to be approved in the future, about how fast uptake would be amongst the providers and transplant surgeons who are caring for these patients? Yeah, I think similar to a lot of these orphan diseases, including PH-ILD, these patients do tend to be cared for by very specialized transplant centers. So there's a little more than 50 in the United States, and I think that, in the end, does increase and speed the uptake of these treatments for these patients because it's a very focused and well-versed group of physicians who are specialized physicians who are taking care of these patients. I think the uptake and the distribution would be pretty rapid if these phase III trials are positive. Oh, great. Thanks for taking our questions. Sure. Thank you, Mazi. Our next question comes from Sam Slutsky at LifeSci Capital. Please go ahead, Sam. Okay, thanks for taking the questions. Two for me. On concomitant medications, are they able to be changed after enrollment in the ongoing study in a way that could alter FEV1 independent of LAM-001? That is the first question. Then second, you touched on it a bit, but how is baseline FEV1 defined? Is it a single study visit, kind of an average of repeated measurements, et cetera? How much variability could we expect between a screening and baseline measurement? Yeah. In terms of the con meds, patients, they are required to be on three-drug immunosuppression at enrollment. After enrollment, their medications can be adjusted by the clinical team. However, essentially, the patients, they are not prescribed or given other types of, say, experimental treatments, unless they have the defined progression, which is an FEV1 decline of 10% or greater. That, again, is something that is a bit easier to do in an IT that is at the center. We have very engaged lung transplant pulmonologists who are in our group who understand the trial and the mechanisms of the trial. We do not think that there is going to be any medications that interact with the primary outcomes of the trial. Just so you know, the one treatment that I think could potentially have the most impact would be the extracorporeal photopheresis, which again, in some patients does seem to allow for some stabilization. Again, that treatment is not rolled out to patients unless they have hit the endpoint of progression of 10% decline. In terms of the baseline FEV1, that is standard calculation of the average of the two highest FEV1s after lung transplantation that are separated by greater than three weeks, and that is what is considered a standard post-transplant baseline FEV1. I do not know if that is the baseline that you are speaking of, or you are speaking about the enrollment baseline. Enrollment baseline. Okay, got it. The enrollment baseline is the baseline at the enrollment visit. It is not the average of multiple measurements, and ultimately, we can expect anywhere from a 1% - 3% variability in FEV1, which is why we have the bar of a significant progression at 10%. Okay, thanks. Sure. Thank you for your question, Sam. Our next question comes from Joe Schwartz at Leerink. Please go ahead, Joe. Thanks. I guess, Dr. Hays, how much weight do you put on the registry data showing better survival on sirolimus-containing regimens? Obviously, those are retrospective analyses. But just knowing what you know about the patients that are captured in those different data sets relative to those that you are enrolling now, how much weight do you put on those studies? Yeah. Good question. I think there's been a couple of registry studies that have shown that if we're looking at all the different immunosuppressive regimens, patients who are on an mTOR-based immunosuppressive regimen tend to have the best long-term outcomes. I think that in terms of how much weight I put on those, they're more hypothesis-generating. I think they should definitely make everyone interested in knowing more about why this signal might be there. I would say that there are some challenges in over-interpreting that data because certainly, patients who have certain kinds of medical complications such as cardiac issues or lipid issues or things like that may not do well in mTORs. There may be a patient selection bias there. But having been in this field for 25 years and our center has been fairly avid users of mTOR inhibitors for specific reasons, which include varying causes, I do think that there may be something to that registry data, and this is why we're diving into this. Makes sense. Thanks. Given the trial includes bronchoscopy with BAL, I was just wondering, what are you hoping to see there? What you'll be looking for there? Yeah. A couple of exploratory things. UCSF has developed a kind of an epithelial cell gene profile, which has been validated to demonstrate patients who are high risk for progression of CLAD. We're looking at that gene profile and seeing whether or not that is valid in this trial and/or if there's any other signals that could be interesting using that brushing sample. We're also in the BAL sample. We're looking for evidence that there is inhibition of the mTOR pathway, as well as looking at sirolimus levels in the alveolar space. That's not really been measured or identified yet in clinical trials is what concentration of sirolimus is in the alveolar space at three months post-dosing. So those are some of the general scientific questions that we're answering. Thank you. Sure. Thank you for your questions, Joe. Our next question comes from Jon Wolleben at Citizens. Please go ahead, Jon. Hey, thanks for the session today and taking the questions. Wondering if you could recall how long it took to enroll the trial and what the primary reasons for folks screening out of it. Then looking ahead, what would you expect or hope from FDA in terms of a regulatory endpoint here? It seems like given the severity of the disease, that outcomes may not take too long to accrue. But what would you hope and what do you expect from FDA in terms of a registrational endpoint? Yeah, good question. In terms of the speed of enrollment, we estimated, just based on our patient population, our experience enrolling in Boston, that we would be able to enroll about a patient per month. And we were pretty close to that target with this particular trial, again, enrolling 20 patients over the course of, I think, around maybe 30 months. There were a couple of reasons for the delay that were more logistical than based on the design of the trial or the patient population. In terms of those patients that screened out, I would say that for patients who underwent screening, I don't have this number exact, but my estimation is around three-fourths of patients passed the screen to enrollment. The quarter that screened out ended up usually not meeting criteria from an FEV1 perspective. Their FEV1 either didn't continue to progress or didn't make the enrollment criteria. There were few other esoteric reasons, but that was the main cause or the main reason patients screened out. In terms of what I hope to see, I'm not sure. I think that this is still something that's being developed within the lung transplant community are what are the most meaningful outcome metrics. I would say that we are right on target with these current outcome metrics that we're looking at, which are primarily lung function based. So either a stabilization or a decrease in the progression of lung function decline in the patients who are treated, I think is going to be probably the primary endpoint that the FDA is going to be looking at. Obviously, other endpoints, which include patient-reported outcomes and possibly an outcome metric related to functional status, could be something that we would want to incorporate into the phase. Well, we have incorporated into the phase II, but incorporate into the phase III. I think the primary outcome metric is going to be physiologic and related to FEV1 decline. One more, if I may. What would an untreated annual FEV1 decline look like in this enrolled population? Yeah, good question. I think that, again, we know that 50% of patients in our hands, 50% of patients have a 10% decline, which is again, a clinically significant decline over the first year. If we put that into real numbers, that would be an average of around 200 ml- 300 ml of lung function over the course of a year. So again, between a quarter and a half a liter of loss of lung function. Thanks, Dr. Hays. Sure. Thank you for your questions, Jon. Our final question comes from Albert Lowe at Craig-Hallum. Please go ahead, Albert. Hi. I was wondering, going back to stabilization, do you know if any of the patients in those studies of oral mTOR inhibitors have shown any improvement in FEV1? How often have you observed patients improve in FEV1, and how surprising would this be in this ongoing study? Yeah, good question. I cannot say that in these larger kind of more retrospective studies, I do not have the individual patient FEV1 data to know if there were patients in those groups that had improvement of their FEV1. I think most lung transplant pulmonologists may be surprised if there were an increase in FEV1 in the trial, just because I think in most diseases that involve fibrosis, which this disease does, we have not seen an agent that has been able to reverse fibrosis per se. I think there may be other potential modeling that occurs that may be directly related to mTOR inhibitors. There is certainly potential for that. So I am, of course, hoping that patients have an improvement in lung function, but it is not something that we initially expected or would expect based on the design of the trial. I think we're going to know more, hopefully, in the next few months of whether that is at all feasible. I would say that the other thing I would note is that when we look at the pathology of patients with Bronchiolitis Obliterans Syndrome, I guess what I would say is that there's a potential that there may be some, not just fibrosis, but inflammation, edema, swelling of the airways that are contributing to the lung function decline. And certainly, that has the potential to get better with certain types of treatment. It's not completely out of the question. Great. Thank you very much. Sure. Thank you, Albert, and to all of our analysts for your questions. I will now turn the call over to Brigette for closing remarks. Yeah. I just wanted to thank everybody for joining today and spending the past hour and a half with us. And importantly, I want to thank our KOLs for all the time they've dedicated on this call and frankly, throughout the years, really helping to move LAM-001 forward. Thanks, Wilson.