Thank you for standing by, and welcome to Krystal Biotech's Interim Clinical Update Call on rare respiratory disease programs KB408 and KB407. At this time, all participants are on a listen-only mode. After the speakers' presentations, there will be a question-and-answer session. During the question-and-answer session, there will be a limit of two questions per participant. As a reminder, today's call is being recorded. I would now like to hand the conference over to your host, Stéphane Paquette, Vice President of Corporate Development. Good morning, and thank you all for joining today's call. Earlier today, we announced positive interim safety and gene delivery results for Krystal Biotech's rare respiratory disease programs KB408 and KB407. The press release and today's presentation are available on our website at www.krystalbio.com. Both the press release and today's presentation have also been filed as an 8-K with the SEC. Joining me today will be: Krish Krishnan, Chairman and Chief Executive Officer; Suma Krishnan, President of Research and Development; and Trevor Perry, Vice President of Research and Scientific Affairs. This presentation will, in our responses to questions, may contain forward-looking statements. You are cautioned not to rely on these forward-looking statements, which are based on current expectations using the information available as of the date of this webcast and are subject to certain risks and uncertainties that may cause the company's actual results to differ materially from those projected. A description of these risks, uncertainties, and other factors can be found in our SEC filings. With that, I will turn the call over to Suma. Thank you, Stéphane. Good morning, everyone, and thank you for joining us. We are excited to be sharing today an initial clinical update on our rare respiratory disease programs, KB408 and KB407. The lung has historically been a very difficult tissue to target with gene delivery. Delivery via inhalation has been explored for decades with little success. Although the challenges have varied by delivery technology, consistent themes have been difficulties in achieving efficient delivery, toxicity, product instability, and cargo limitations. For these reasons and others, there's still no platform available to safely and repeatedly deliver genetic material to the lung. Our clinically validated vector already shown to be safe, effective, and reusable for the treatment of dystrophic epidermolysis bullosa, and FDA product approved for this indication, has many attributes which we have long believed made it particularly well-suited for gene delivery to the lung. These include broad tropism for epithelial cells, large cargo capacity, reusability, and comparability within off-the-shelf nebulization devices. With today's update on KB408 and KB407, we now have our first direct evidence in humans of efficient HSV1-based gene delivery to the airways, demonstrating that our vectors can be safely administered to the lung via inhalation and that, once administered, are able to effectively deliver and express the genetic cargo. We are excited about the implications of this data for our long-term ambitions in the lung, as well as our exciting programs, KB408, KB407, and inhaled KB707. We will start with updates on KB408, a program which is driven by the clear unmet need that exists for safe and effective therapies to address the progressive lung decline associated Alpha-1 Antitrypsin deficiency, AATD. AATD is a monogenic autosomal codominant genetic disease where the mutations in the SERPINA1 gene encoding Alpha-1 Antitrypsin prevent efficient secretion from the liver. This leaves the lung exposed to unchecked proteolytic activity, primarily from neutrophil elastase, which eventually leads to functional decline. While a subset of AATD patients suffer from severe complications in the liver, it is the lung manifestations that most commonly present in patients. Critically, there are few treatment options for AATD, and none that have shown clear clinical benefit in protecting the airways. Current standard of care is weekly IV infusion of AAT, referred to as augmentation therapy. This regimen is burdensome on patients, and impact on lung disease is poorly defined. KB408 is an inhaled genetic medicine designed to deliver two copies of full-length AAT genes to the lung in order to achieve sustained local AAT expression. The program is supported by a robust preclinical data package in which we have shown across a variety of models that KB408 efficiently transduces clinically relevant cell populations. KB408-encoded AAT is functional and binds its target neutrophil elastase. KB408 lung administration is well tolerated and effectively delivers genetic cargo to epithelial cells of the airways. And based on NHP studies conducted with KB407, our vectors are amenable to nebulization, broadly distributed in the airways, and payload expression persists for at least 28 days. Based on these data and our clean GLP toxicology results, we progressed KB408 into the clinic earlier this year. KB408 is currently under evaluation in our first-in-human phase I SERPENTINE-1 study. SERPENTINE-1 is an open-label, single-dose escalation study in adult patients with AATD, with a PIZZ or a PI*ZZ-null genotype. SERPENTINE-1 is designed to include up to three-dose escalation cohorts, evaluating single administration of 10E9, 10E10, and 10E11 PFU of KB408 via inhalation. The primary focus of SERPENTINE-1 is evaluation of safety and tolerability of inhaled KB408, as well as initial molecular assessment of gene delivery, functional AAT expression, and molecular correction in a subset of patients that received pre- and post-dose bronchoscopies. Originally, bronchoscopies were scheduled for the top-dose cohort three, but we were fortunate enough to have the opportunity to add bronchoscopies to a subset of cohort two patients as well. Key inclusion and exclusion criteria are shown on the slide. As of December 6, 2024, data cut off, a total of seven patients had been enrolled in SERPENTINE-1, including three patients in cohort one who received the 10E9 PFU KB408 dose and four patients in cohort two who received the 10E10 PFU KB408 dose. Two patients in cohort two also received bronchoscopies to assess the SERPINA1 gene delivery and AAT protein levels in the lung. The timing of the bronchoscopies relative to dosing is shown on the slide. Today's data update includes safety data on all seven and 11 subjects and initial molecular data for the two patients from cohort two who received bronchoscopies. Please note that the safety follow-up is ongoing for both cohort two patients that had received bronchoscopies. As of data cut off, at least two weeks of follow-up data was available for each patient. Demographics and background augmentation status of the patients included in today's interim update are shown here. In line with expectations, our study population skewed older, and all were in the PIZZ genotype. Two of the seven patients were on some form of background augmentation therapy, including one of the two patients that received bronchoscopies. Safety findings are briefly summarized here. We have found KB408 to be well tolerated in all patients dosed to date across both dose levels. No serious adverse events or dose-limiting toxicities have been observed. Any KB408-related or possibly related adverse events have been mild to moderate in nature and transient. We have also seen no evidence of meaningful neutralizing antibody response, a positive leading indicator for potential long-term efficacy and safety, and consistent with expectations given prior clinical experience with the FDA-approved VXJUVEK. I will now hand it off to Trevor to walk through the initial molecular data we have collected from our two cohort two bronchoscopy patients. Thank you, Suma. Baseline and post-dose bronchoscopies from participating cohort two patients were conducted for molecular analyses of vector transduction and associated functional AAT expression in the airways. Specifically, endobronchial biopsies were collected at multiple sites throughout the lungs from each patient, both pre-dose and at 24 to 48 hours after KB408 nebulization, to demonstrate transduction of the air-exposed epithelium of the conducting airways and associated expression of human AAT by immunofluorescence detection. Additionally, a bronchoalveolar lavage was performed to quantitate the levels of AAT in the epithelial lining fluid, as well as to determine the proportion of unbound and assumed active neutrophil elastase present before and after dosing. Finally, bronchial brushings were collected to measure genome deposition and code and optimize human SERPINA1 transcript expression of the airway surface by qPCR and qRT-PCR, respectively. Starting with the patient that was not receiving background augmentation, key findings from the endobronchial biopsies are shown here. The biopsies were assessed by a hematoxylin and eosin staining to determine the location in the airways from which each biopsy was harvested. The conducting airway surface is marked in each image, established by the typical cell morphology observed for columnar ciliated cells and mucus-rich secretory cells. These biopsies were then stained for human AAT protein and imaged by indirect immunofluorescence. Included on this slide is a representative pre-dose sample, as well as biopsies from two unique locations post-dose. Clear evidence of vector delivery and associated transgene expression was demonstrated by the presence of AAT in the air-exposed cells exclusive to the post-treatment period, consistent across multiple locations within the lung. Quantification of the proportion of AAT-positive cells was conducted manually by counting the number of DAPI-positive and DAPI-AAT-co-positive cells at the airway surface. A clinically meaningful proportion of the cells were observed to be transduced by the vector, as shown by 39% of all air-exposed cells being AAT-positive post-dose versus 0% positivity at baseline for this subject. We were very excited to achieve such high rates of transduction with a single dose of KB408, in particular given the positive read-through implications to our KB407 program for cystic fibrosis. Shown here is a summary of the epithelial lining fluid analyses from this same patient who, as a reminder, was not on concurrent IV augmentation therapy. Consistent with the robust airway transduction we detected by immunofluorescence, we also saw increased AAT levels in the KB408-treated lung, with a greater than eight-fold change in free AAT being detected in epithelial lining fluid after dosing, increasing from 85 nanomolar at baseline to nearly 730 nanomolar 48 hours after KB408 nebulization. Not only were clinically meaningful levels of AAT achieved in this patient, but clear functionality of the vector-expressed transgene was seen, as the percentage of active neutrophil elastase dropped by more than 50% after receiving a single dose of the vector. Turning to our second patient and starting with the endobronchial biopsy data, we again saw robust transduction of the epithelial cells of the conducting airways, with 35% of cells positive for AAT post-dose versus 3% at baseline. The post-dose bronchoscopy was conducted 24 hours after KB408 administration for this subject. Of note, this patient was on augmentation therapy, which may at least partially explain the differences in AAT background staining patterns versus a patient not on augmentation as shown previously. In spite of this, we are encouraged to see unambiguous evidence of transduction and AAT expression in the conducting airways of this patient as well. Unfortunately, protein characterization of the lung lining fluid in this second patient was not possible due to sample collection challenges, including unacceptably low return volumes in the lavage samples. However, bronchial brushings harvested from this patient revealed quantifiable vector genomes and associated codon-optimized SERPINA1 transcripts across the airways, in agreement with the imaging analysis. These qPCR assays are specific to the KB408-encoded SERPINA1 payload, as demonstrated by no signal being detected in baseline samples. Consistent detection of DNA and RNA across multiple independent lung samples provides further evidence of successful gene delivery following KB408 administration, and together with our other molecular findings, demonstrates the capacity for Krystal's platform to effectively deliver genetic cargo to the conducting airways. I will now hand the call back to Suma. Thanks, Trevor. Although we only have molecular data from a few patients so far, we are extremely encouraged by our findings to date. Not only have KB408 proven to be well tolerated in a study population of advanced age with underlying lung disease, we have demonstrated SERPINA1 delivery, AAT expression, and function across multiple independent assays. High transduction rates in the conducting airways, as evidenced by bronchoscopy, validate the potential of our platform for gene delivery to the lung and a high nanomolar level of AAT with corresponding measurable impact on residual neutrophil elastase activity indicate we are already in clinically relevant range after a single dose. With this positive data, we have the intent to accelerate our work on KB408 and simultaneously enroll confirmatory patients in cohort two and open cohort three to explore safety and gene delivery at the top dose. In addition to KB408, we are also happy to share an initial safety update on our second rare respiratory disease program, KB407. Cystic fibrosis is a devastating, lifespan-shortening, monogenic rare disease caused by a mutation in the CFTR gene, which led to mucus accumulation, lung clearance defect, and progressive lung disease. Despite great advances with the development of small molecule modulators in recent years, a significant subset of patients are either ineligible or otherwise unable to benefit from these therapies. KB407, encoding two full-length copies of the CFTR gene, is designed as mutation-agnostic therapy with our principal focus of providing benefit to patients underserved by modulators, including the 10%-15% of patients with mutations for which modulators are unable to provide any benefit. As with KB408, KB407 is supported by a robust preclinical package that collectively demonstrates efficient transduction with KB407 and subsequent expression of functional full-length CFTR. NHP data also indicate that repeat dosing via inhalation is well tolerated and results in broad dissemination and CFTR expression in the lung, which is sustained out to at least 28 days after last dose. As further validation of our preclinical data package, we are also happy to report that we recently received conditional sanctioning from the Cystic Fibrosis Foundation Therapeutic Development Network on our clinical study protocol, with the only remaining item being review of our Data Monitoring Committee charter to ensure alignment with TDN guidelines. No additional preclinical data is required. Based on this data package, we are excited to progress KB407 into the clinic. KB407 is currently under evaluation in our first-in-human phase 1 CORAL-1 study. CORAL-1 is an open-label dose escalation study in adult patients with CF. CORAL-1 is designed to include up to three dose escalation cohorts evaluating either one, two, or four daily administrations of 29 PFU of KB407 via inhalation. As with SERPENTINE-1, the primary focus of CORAL-1 is evaluation of safety and tolerability of inhaled KB407 administration. CORAL-1 is also designed to include bronchoscopies in cohort three to evaluate CFTR delivery and expression. Key enrollment criteria are listed here. Cohort three includes minimum enrollment requirements for modulator-ineligible patients. Patients in the safety cohort could be on concurrent modulator therapy. As of December 6, 2024, data cut-off, a total of five patients have been enrolled in CORAL-1. Three patients received a single 29 PFU KB407 dose in cohort one, and three patients, including one rollover patient from cohort one, received two daily 29 PFU KB407 doses in cohort two. All are included in today's safety data update. Demographics and modulator status of the patients are shown here. All but one patient was on background modulator therapy, and all but one were homozygous for the F508del genotype. In line with our findings with KB408, KB407 delivery via inhalation has been well tolerated in all patients to date after single and repeat administration. No adverse events or dose-limiting toxicities have been observed. Any KB407-related or possibly related adverse events have been mild to moderate and transient. We have also seen no evidence of neutralizing antibody response. With this positive safety data, through two cohorts, successful gene delivery of KB408, and now with conditional sanctioning from the TDN, we look forward to building momentum beyond KB407 and sharing our first molecular data update on the program in the first half of 2025. I will now hand the call over to Krish. Thank you, Suma. Although today's update includes data from only a few initial patients, it's important to realize these findings have a profound read-through to our broader pipeline targeting diseases of the lung. At Krystal, we're all excited about what this means for our platform, our company, and the patients with rare and severe respiratory diseases that we aim to serve. Suma mentioned this in our opening. The lung has been a notoriously hard tissue to target directly with gene therapy, not only due to the many physical barriers that exist, but also the challenges of repeat dosing to a tissue that turns over. With today's data, we believe we have clearly demonstrated that our vectors can be safely administered via repeated inhalation and that even with a single dose, we can transduce a clinically significant portion of airway epithelial cells. And that dose is administered via a nebulizer with a short nebulization time. Now, focusing more closely on our KB408 program, we believe we are clearly in a clinically relevant dosing range and are excited to have achieved not only high nanomolar concentrations of free AAT, but to also have demonstrated that this AAT is functional and binds to its target neutrophil elastase. And considering that this patient was not on background IV augmentation therapy, to achieve these levels within a few days of the first dose is particularly encouraging. We look forward to acceleration of our development efforts with parallel enrollment in cohort two to confirm the data we have seen today and investigate a higher dose in cohort three. We're also pleased to announce that we have conditional sanctioning from the TDN on our phase one protocol for KB707 for the treatment of patients with cystic fibrosis. We hope to finalize this shortly, and this will definitely accelerate enrollment for us and give us access to sites with bronchoscopy capabilities. And we do believe we have a very strong value proposition, especially for CF patients with a lung mutation. Thank you. That ends the presentation, and let's turn over to Q&A. Certainly. At this time, we will be conducting a question-and-answer session. If you have any questions or comments, please press star one on your phone at this time. As a reminder, during the question-and-answer session, there will be a limit of two questions per participant. We ask that while posing your question, you please pick up your handset if listening on speakerphone to provide optimum sound quality. Please hold while we poll for questions. Your first question for today is from Sami Corwin with William Blair. Hi there. Congrats on the data, and thank you for taking my question. I was curious if you could elaborate a little bit more on the durability of AAT expression, either in the epithelial lining fluid or the serum. And then I guess I just also wanted to get your thoughts on if you would consider going to a higher dose or utilize a kind of loading dose and repeat administration similar to what you're doing with cystic fibrosis. Thank you. Thanks, Sammy. With respect to durability, since it's a secreted protein and the protein itself has a short half-life, the closest proxies to look at NHP data from our CF study where Suma mentioned we saw expression up to 28 days. So our starting hypothesis that 408 could potentially be a once-a-month nebulization. We'll get more clarity on this when we go into the redosing part of the study shortly, but that's the starting hypothesis. And on the second question with respect to a loading dose versus a maintenance dose. Yeah, I can address that. I mean, obviously, we are in cohort two, and we have the mid dose. We know it's safe. So we have the opportunity to go into the higher dose. We do want to look at the higher dose and evaluate what are we seeing, other levels, higher difference. So I think we need some more molecular data to make the decision. But from a safety perspective, we have different strategies as we know what we have learned a lot from VXJUVEK and even in our three or four studies. Even with the adverse events with initial administration, with repeat administration, it gets well tolerated, and we've seen this, and safety does not become an issue. So we feel with the knowledge on the safety of our vector and the ability to do loading doses and the ability to adjust to optimize the risk, the safety versus the efficacy gives us that flexibility to adjust accordingly. I will say, Sammy, one last point. Given we are in the 750 or so nanomolar range, if we time our redosing properly, we may not need a loading versus a maintenance dose and just a once-every-month type dosing to maintain AAT levels. Great. Thank you. Your next question is from Andrea Tan with Goldman Sachs. Good morning. Thanks for taking the questions, and congratulations. Suma, one question here for you. How much read-through do you see from these first two patients that were dosed with 408 to potentially what you could see with 407 in CF patients? Yeah. I think that's a very good question. We are super excited. If you look at the data, maybe Trevor can talk a little more about it. We see expression across the entire lung, upper lobe, lower lobe, and we see expression not only just in the lumen but also in the interstitial layers. So again, I think based on the data that we see from 408, I mean, and the broad distribution, we are actually really excited about 407. We think this is going to even transfer better to 407 because 407, we just need to be in the cells that we see, like the secretory cells and the cells. We see good expression. So we believe it should completely translate into 407. Trevor, do you want to add anything? Yeah. I would say for a program like 408 for AAT, where the proteins are created, I think the percentage of cells that are transduced with our vector is not necessarily critical as long as we get sufficient levels in the lumen and in the interstitium. But what I was most excited about the data was to see in a human, we get to 30%+ of the airway cells. And I think that's a very meaningful number when thinking about 407 delivery. And I think really could have a profound therapeutic effect if we achieve that level with our 407 dose. So I think really what most excited me when looking at the data was actually that percentage and what that means for our CF program. Yeah. And again, to add, I think we need higher levels of AAT for this indication. But for 407, I mean, we are looking at even lower, we don't need that level of transduction. So I think seeing what we see in AAT, we are really excited about 407. I think, as Trevor mentioned, the level and the area of the lung surface that we see with active transduction gives us real hope for 407. Your next question for today is from Dae Gon Ha at Stifel. Hey, good morning, guys. Thanks for taking the question, and congrats on the data as well. Sorry for the ambient noise here, but just two questions per the instruction. I guess looking ahead, Krish, what's your inclination of introducing the amended protocol for these current patients right away just to see what the repeat administration can bring from an expression level increase as well as any other functional benefit? And then secondly, when we think about regulatory strategy, I know it's early, but given that you do see serum AAT increase as well, is that a potential path for you to contemplate in terms of accelerated approval based on serum AAT increase despite the lung administration? Thanks so much. Hey, Dae Gon. I'll answer the first and turn it over to Suma to talk regulatory. I mean, the plan, like you alluded to, is to almost immediately, I mean, as soon as possible, get the patients in cohort two into a redosing type paradigm. Even the two other patients we talked about to confirm maybe possibly part of the redosing protocol. We do want to try one or two patients in cohort three to see if the serum levels go up, and we saw 750 or so nanomolar. Maybe it gets past 1, 1.2, so both are going to happen as fast as we can execute. We're pretty stoked about the data. We hear the same feedback from our investigators, so yes. With respect to the regulatory strategy, Suma. Yeah. Absolutely. I mean, again, if we come back to the molecular data, I think very promising from what we saw. But we do need to do additional patients, higher cohorts, I think. Once we have a good idea about what the levels that we see both in the lung as well as what are the levels translating into the serum. I think once we have that, obviously, we are going to have a meeting with the FDA. I mean, as you guys are completely aware, I mean, the OTAP division is now very open and amenable to biomarkers as they are for an accelerated pathway, and you look at AAT. I mean, talking to Dr. Sandhaus and our experts, I mean, I've been working in this space for the last 10, I mean, 15 years ago. And there was, I mean, there has been nothing. There's been no drug beyond augmentation. So I think the agency has opened up their mind. And with the biomarker approach, I think, and with the new guidance that's just come out, we feel the division is very open to that. So I feel very hopeful, but I want to have solid data so that we can sit down with the agency and absolutely discuss an accelerated path for this particular indication. Great. Makes sense. Thanks so much. Your next question is from Joseph Pantginis with H.C. Wainwright. Hi, good morning. This is Sarah on for Joe. Thanks for taking the question. My question is regarding the patient on background augmentation and the KB408 study. You had mentioned there were challenges with the live sample on this patient. I just wanted to get a sense of how will you be stratifying for against this as you progress into your further cohorts maybe to mitigate against these challenges that you saw? Thank you. I mean, before I give it to Trevor, obviously, when we talk to our KOLs and experts with bronchoscopy, typically, you see 20%-30% subject failure in collecting lavage. So it's a little tricky situation. So it's not uncommon to see that. So I just wanted to add that. And Trevor, you can. Yeah. I think there is a proportion of patients who are relatively late in their disease where lavage has become difficult to collect. And unfortunately, we saw that with this one patient where we were going to enroll a small number of additional patients. But we feel really good about the data that we got. I think we very clearly demonstrate delivery, meaningful AAT expression. We want to confirm that in one or a few more subjects. Difficulties in lavage are kind of inherent to this patient population, but we feel like we have the appropriate end for the study to get the data we need to go to the FDA. Okay. That's helpful. Thank you. Your next question for today is from Gavin Clark-Gartner with Evercore ISI. Hey, guys. Thanks for taking the question. Just starting with a couple detailed ones on the data itself. Sorry if I missed this in the presentation, but for the serum AAT level, you noted 270 nanomolar, 5.3 micromolar. What was the value in between those two for the third patient? And what was also the serum level for the patient on IV augmentation? Yeah. So the values ranged. It obviously is variable between patients. We had, I think, 270 nanomolar. We had 4 micromolar, 5 micromolar, and then I think it was a high nanomolar for our fourth subject that got the mid dose at baseline. The augmentation patient was higher because they were on augmentation therapy. They're at about 32 micromolar pre-dose. We got that up to it was about a 7 micromolar improvement post-dose. So even in the context of high serum AAT, we could still see the added benefit of AAT after KB408 dosing in augmentation. But they were much higher than the remainder of the patients, which makes sense given that they were receiving IV augmentation. And just, I'll add to it. These patients received augmentation two days prior to the bronchoscopy. So they had just had their augmentation. Got it. Okay. That's helpful. They were in the peak level of AAT. Yeah. Expression. Yeah. Yeah. That makes sense. Thanks, Suma. And did you measure the serum neutrophil elastase inhibition and see how that correlated with the increases in the serum? So serum elastase inhibition, we did not measure as part of this study. It's something of interest to us. Serum is a complex matrix to do those kinds of assessments in. But really, for us, the lung neutrophil elastase, activity of neutrophil elastase in the lung is what drives disease. And so really, the focus for us was showing inhibition of neutrophil elastase in the lung, which we thought a meaningful decrease with a single dose. And that's really kind of where we focus our understanding. And I'll just add, I mean, when we shared the data with the KOLs, the most exciting part of it is that we could see the level in the interstitial, and that's why it translates into plasma. So we feel like, increasing dose, repeat administration, we have the flexibility to get there. But the most important part is that we do see it in the interstitial. So that means we are in the right area. We see the expression of AAT. So that's critical. Yeah. Got it. And just overall, I'm just wondering about the concordance of the different measures for the data that you do have. How did the expression align with the BAL levels, with the serum in some of the specific patients? So I think that we're still early in our dosing to understand kind of a correlation between lung and serum levels across multiple patients. So that's part of the assessment that we're continuing to do and enrolling the remainder of cohort two. But I think we're encouraged by the fact that in our non-augmentation patient, we see very clear delivery by the bronchoscopies. We see very clear AAT expression by the lavage. We see inhibition of neutrophil elastase by the lavage. And we see AAT in circulation, meaning transduction of the airway surface, got AAT both into the lumen through the interstitium into the lung. So I think we're seeing everything about our data is directionally indicating we're getting good delivery. We just need a couple more patients to really confirm the levels and the association between ELF and serum and talk to the FDA about an accelerated path from there. That makes sense. And just a final one for me, just on the regulatory engagement. Is your current plan to wait for those additional two patients from cohort two, or are you going to wait for the cohort three patients? And also, how much redosing data do you need before you go have that discussion? I mean, I think we do want to finish the cohort two and do some more patients and go into cohort three. So we believe, I mean, we don't need much, but we have meaningful data in four to five patients. I think it's enough for us to sit down and meet with the agency to have a meaningful discussion that is productive for a clinical path and a direction that we can get agreement on. Because our goal is when we sit down with the FDA, I mean, is absolutely nail down and get a regulatory path. We want to do an accelerated path. We want to go with that mindset with the agency. So we want to be prepared with a protocol design, with a clinical development plan. I think if we can get four, three, another couple of patients in cohort two and a few in cohort three, I think hopefully by the middle of the year, we can see hopefully we can meet with the agency. Very helpful. Thanks. And congrats on the data. Your next question is from Yigal Nochomovitz with Citigroup. Hi, Nochomovitz. Hi. So it's very interesting data. I guess you could make the argument you mentioned that you don't need more efficacy. And also, you've got a really good safety profile. So I mean, I guess you could make the argument that you don't need to go higher. You could even make the argument that you could go lower, perhaps. I don't know. I mean, this is an interesting, unusual situation you don't always see. So I'm just curious, are you going to just go with the dose with AATD? And does that impact how you're thinking about what you'll need for CF? I mean, you make a fair point, but we have the opportunity to go up one more dose to see if the 750 nanomolar gets into the 1 to 1.5 range. But we have the option. And at the same time, like you pointed out, maybe with redosing, if you start at a base level of 750, we potentially get to that point in the redosing part. And because, as Suma mentioned, we'd like to take a comprehensive package to get the accelerated approval pathway, I think it's prudent to do both. Not a complete cohort three, but at least the patient on two to get some read into it. But the going forward path, I mean, for the most part, is you start redosing cohort two, get a couple more patients. Now you have two to four patients. You point to cohort three as being incrementally better. I think she'll have a great set of molecular data to go in front of the agency. I think that optionality is good to have as opposed to ignore. Yeah. And also, I would add, we also want to understand, can we go into higher dose? And maybe the frequency of administration may reduce instead of so that's important to us. So work for us to go to higher dose if the frequency or duration of administration can be cut down. So I think it's a balance between frequency of administration, what is the dose we need to do, all of that needs to be just optimized. Okay. And so these patients had never had the I mean, correct me if I'm wrong, but this was their first experience with this nebulizer setup. Is that right? I mean, they didn't have any issues with dealing with that or how to do that? That was pretty straightforward. Yeah. No, not at all. I mean, many of these patients, no, because they're not like CF patients. CF patients are more used to nebulizers because they get antibiotics and others. No issues. So easy. Five minutes, we can nebulize the product. 10 minutes, five to 10 minutes. So I think, no, very little training. I mean, think about it. You're doing it in the CF patients. There are seven or seven patients. So the device is the same device and the same. Okay. Got it. Thank you so much. Thank you. Your next question for today is from Ritu Baral with TD Cowen. Good morning, guys. I have an efficacy question, and then I have a safety question. On the efficacy, Krish and Suma, how are you thinking about that cohort three dose? What are you trying to triangulate into at this point? Is it a particular sort of nanomolar level of AAT, or are you thinking about the%-free elastase, like a threshold of%-free elastase in the lavage fluid? And as far as the durability of the level that you're looking at, can you use serum assessments to track durable expression since it's certainly a lot easier than lavaging these patients repeatedly? I'll let Trevor answer this question. Yeah. So I think to answer your second question first regarding tracking serum, because obviously, serum samples are much easier to harvest. And so it's something we're keenly interested on. We want to show a correlation between lung AAT expression and neutrophil elastase inhibition and then serum levels over time in a few patients. And we would take that to the FDA. But I think ideally, we would see that correlation and then use serum as a biomarker moving forward to go on the accelerated approval pathway. I think regarding dose escalation to cohort three and whether there's a particular nanomolar AAT level or a particular percent neutrophil elastase number that we're trying to hit, for us, like Krish had said, there's potential to push the nanomolar level of AAT in the lung up to one, 1.5. We would like to see neutrophil elastase activity go to zero. I think that's something we can achieve either at maybe a higher dose or with repeat dosing. But I think ultimately, we're looking to find a dose that is feasible and easy for a patient to do repeatedly. Maybe we can decrease durability with higher dose levels, and so we're just trying to understand and optimize dose frequencies, not a particular number at this stage. Okay, and back to the serum just for a second. The question was less for regulatory and more for monitoring of durable expression and how that might inform the treatment frequency. Is that something that is part of the protocol right now, repeat serums and assessments, and is that something you'll disclose? Yes. Yes. They are all part of that. Yes. Yes. Okay. Got it. And then the safety question, can you just elaborate a little bit on the moderate events that you saw, especially sort of how proximal they were to administration? And one question on safety that I've been getting from clients is if there's going to be any assessment for potential lung inflammation and anything similar. Thanks. Obviously, when you are exposing viral vector to these patients, you are going to see some sort of effect, and that's what, as I consistently say, we saw this with BRAF. We see this with our aesthetic programs. We see this across all our programs, so yes, the first dose when you give them for a very short period of time, they do see some sort of inflammatory reactions. They do sometimes a little bit of immediately. That means it's a good thing. That means our vector is getting there. It's infusing till they begin to start tolerating, so they may have chills, a little bit of feeling feverish, but it's very transient. It's like a couple of hours and boom, you're fine, but again, with repeat administration, we consistently see that impact. It's completely the second they tolerate it. Initially, and we can even control it, right, by giving them Tylenol or something prophylactically so we can even minimize this. We have learned that. But anything lung specific, Suma, like cough or dyspnea or anything like that? We haven't seen cough. I mean, again, remember, it depends on the patient, right? Some of these patients are severe. So it depends on how severe these patients are. If they have underlying COPD and in their natural history, then you're not going to wipe that out with one dose, right? So part of that is part of the natural history where they do have cough because part of the disease. So that's what you may see to continue, but it's not something that is drug-induced. Got it. Got it. So it's not elevating. Can you comment on what those moderate adverse events were? As I said, chills, a little bit of fatigue. Okay. Got it. Very. Thank you. This is something we see across all our platform products. Thanks for all the colors. Once again, if you would like to ask a question, please press star one. Your next question for today is from Ry Forseth with Guggenheim. Can you comment on the comparability of lung distribution for KB408 relative to augmentation therapy? Any notable differences that may be advantageous for 408? Yeah. I think the way that we think about the benefit of an inhaled delivery like 408 versus kind of IV augmentation is we feel like we are getting the AAT to the site that drives progressive disease, right? So AATD is caused by uncontrolled neutrophil elastase on the lung surface and in the lung interstitium. And so by delivery of 408, transduction of the airway surfaces and expression of AAT on the airway surface and then through the interstitium into circulation, we're really delivering the protein exactly where it needs to be to prevent lung progression. And I think there's a question that remains whether augmentation therapy giving it systemically in circulation, does that get the AAT to meaningful levels that will inhibit the lung progression that we're looking for? And I think we think of a more directed delivery system with 408 than what we do with augmentation. I'll just add one more point. If you look at our data from our augmentation patients, and Trevor, I don't know if you must have seen the slides. If you look at their baseline, you don't see any AAT levels in their lungs, right? I mean, it's pretty. But when we nebulize in this particular patient, you're clearly seeing expression of AAT in our brushing and in our biopsies from these patients. So again, we can see that from augmentation, even though augmentation happened two days prior to bronchoscopy, you're not seeing the levels of AAT in these patients in the lung. Thank you.