Hello, ladies and gentlemen. Thank you for standing by, and welcome to 4D Molecular Therapeutics webcast presentation of interim safety and efficacy data from the Phase 1/2 ARROW clinical trial of aerosolized 4D-710 for the treatment of cystic fibrosis lung disease. At this time, all participants are in listen-only mode. Later, we will conduct a question and answer session, and instructions will follow at that time. As a reminder, today's call is being recorded. With that, I will hand the call over to Uneek Mehra, Chief Financial and Business Officer, who will make introductory comments. Thank you, operator, and welcome everyone to our webcast. A press release describing the results and development plans related to 4D-710 is accessible in the investors section of the 4DMT website, and a recording of this webcast will also be accessible on our website after the completion of this call. With me today are Dr. David Kirn, our Co-founder and Chief Executive Officer, who will provide introductory remarks. Dr. Alan Cohen, who recently joined 4DMT as SVP, Therapeutic Area Head of Pulmonology, who will review the program summary and next steps. And Dr. Jennifer Taylor-Cousar, Professor and Co-director, Adult Cystic Fibrosis Program, and Director, CFF Therapeutics Development Center, National Jewish Health, who will review the clinical data. Due to a previous commitment at the conference, Dr. Taylor-Cousar will only join us for the presentation portion of the meeting. She will present the interim data from the ARROW trial on Friday, November 3, at the 2023 North American Cystic Fibrosis Conference. As a reminder, on this call, we will be making forward-looking statements regarding our clinical data from our ARROW clinical trial, product development plans, research activities, and business plans. These statements are based on management's current expectations and are subject to risks and uncertainties that may cause actual results to materially differ from those forecasted. A description of these risks can be found in the risk factor sections of our most recent Form 10-K and Form 10-Q, which are on file with the SEC. With that, I would like to turn the call over to our CEO, David Kirn. David? Thank you, Uneek, and thank you everyone for joining us today. Before we dive in, we're proud to announce that 4D-710 will be featured tomorrow in the plenary session of NACFC for the second consecutive year, and also on Friday in a symposium presentation by Dr. Taylor-Cousar entitled Building a Path to the Cure: The Role of AAV Therapy. Today, we're pleased to share additional positive data and updates that have led us to strengthen our commitment to pulmonology. Our wholly-owned pulmonology franchise is powered by our aerosolized A101 vector and is currently focused on 4D-710 for cystic fibrosis lung disease and 4D-725 for Alpha-1 Antitrypsin, or A1AT, deficiency lung disease. In terms of the clinical update on 4D-710, which is currently being studied in the Phase 1/2 ARROW clinical trial, today we'll present data from seven participants treated at 2 dose levels: 1 × 10¹⁵ vector genomes, or 1E15 vg, and 2E15 vg. To date, 4D-710 has generally been well-tolerated during dosing and with long-term follow-up for up to 17 months. We have seen promising and reproducible CFTR transgene expression in all 34 lung samples collected from all seven participants. The CFTR protein expression levels were significantly higher than normal controls, with 98% of airway cells expressing CFTR, including in basal cells and secretory cells, and at levels approximately 450% of normal lung controls. This profile significantly exceeds our target expression profile for 4D-710. In cohort 1, we have observed durable clinical activity with follow-up through 12 months. Regarding next steps, we have selected the cohort 1 dose level of 1E15 as one of two dose levels to continue into phase II development. The second dose level is yet to be determined. Of note, given the excellent expression profile seen to date, we now have the opportunity to investigate even lower doses with additional dose-ranging cohorts while continuing the follow-up of participants in cohort 2 with a dose level of 2E15. We have dosed the first patient in a new cohort 3 with 5E14 VGs. In terms of the development path for 4D-710, we are discussing potential plans for monotherapy and for modulator combination regimens with the FDA this quarter, and we expect to share this feedback in the first quarter of next year. A brief reminder that the aerosolized A101 lung vector is one of three novel, highly targeted next-generation AAV vectors invented at 4DMT that now have proof-of-concept data in clinical studies.... A101 is a key value driver for the company, and 4DMT owns all worldwide rights to A101-based products. We leveraged our Therapeutic Vector Evolution platform to invent A101, a next-generation lung delivery vector. Prior AAV gene therapy approaches for lung gene therapy have failed, and none of these approaches have achieved gene expression within the lung. These approaches were hampered by a variety of limitations of conventional vectors, including poor mucus penetration, inefficient airway cell transduction, suboptimal tissue tropism, and susceptibility to clearance by pre-existing antibodies. We invented A101 at 4DMT to overcome these limitations. A101 has remarkable properties, including efficient mucus penetration and transgene expression, the ability to transduce multiple airway cell types, including basal cells, high specificity for lung tissue, and resistance to pre-existing human AAV antibodies in the population. On the right panel, as shown in our product design schematics, our lung products are comprised of the A101 vector carrying a therapeutic payload for each specific disease. We then deliver the product using the FDA-approved AeroEclipse II breath-actuated nebulizer, which produces stable and reproducible droplets that distribute evenly throughout the large and small airways of the lung, plus the alveoli. Using this modular approach, we are pursuing CF and A1AT deficiency lung diseases as our initial indications. Given our increased commitment to cystic fibrosis and pulmonology, I'm excited to announce that Dr. Alan Cohen has joined the leadership team as Senior Vice President and Therapeutic Area Head of Pulmonology. Alan brings over 30 years of broad pulmonology expertise, including in cystic fibrosis, as a board-certified pediatric pulmonologist, lung transplant, and cystic fibrosis physician. Alan's faculty and biopharma industry experience on this slide speaks for itself, and in the short time he's been with us, we've been energized by his leadership and his presence. Welcome, Alan. I will now hand the presentation over to Alan to talk more about CF lung disease. Alan? Thanks, David, and I'm delighted to join the talented team at 4DMT to build and advance a pipeline of next-generation lung programs. As a reminder, CF is caused by genetic variants that result in a dysfunctional cystic fibrosis transmembrane conductance regulator, or CFTR protein. Without properly functioning CFTR, cells are unable to effectively move chloride from inside the cell to the cell surface. This results in thick, tenacious mucus with unremitting airway inflammation, frequent lower airway bacterial infections, destructive airway events with bronchiectasis, culminating in progressive respiratory failure and death. The median life expectancy of people with CF in the pre-modulator era was approximately 40, which reflects the reality of many modulator and eligible people today. CF affects over 100,000 individuals worldwide, and approximately 40,000 are in the United States. People with CF currently receive intensive and time-consuming daily airway clearance therapy, mucolytics, inhaled antibiotics, and bronchodilators. Additionally, for many people with CF, twice-daily oral CFTR modulators can partially restore mutant CFTR function, but these are only available for those who have eligible variants. It is worth noting that modulator therapies have been rapidly adopted and have generated approximately $9 billion of global sales in 2022, and the market is growing. Our initial target population, using 4D-710 as a monotherapy, is the population with the highest unmet medical need. This represents an estimated 15% of all people with CF, of which 10% are not eligible for CFTR modulators and 5% are intolerant to their side effects. In addition, it is estimated that around 20% of people who take modulators appear to have a suboptimal response, generally defined as less than 5% improvement in percent-predicted FEV1. We believe this additional unmet medical need represents a potential future for 4D-710 study population. Lastly, the remaining balance of modulator-treated people with CF that have a demonstrable response could still potentially benefit from 4D-710, given the potential durable nature of gene therapy compared to a daily oral treatment. Ultimately, with 4D-710, we believe we have the opportunity to potentially treat all people with CF, regardless of their CFTR variant, both as a standalone therapy or in combination with current standard of care modulators. On this slide, we show the design of the phase I/2 ARROW clinical trial. The goal of the trial is to conduct dose ranging to ultimately identify two doses for late-stage development, including the minimal effective dose based on safety and tolerability, lung biomarkers, and clinical activity endpoints... Our dose range includes Cohort 1 at our mid dose, 1E15, Cohort 2 at our high dose, 2E15, and Cohort 3 at a lower dose of 5E14 vector genomes per participant as a single dose. We enrolled eight participants to date, including seven across the first two dose levels, and the first participant has been dosed in Cohort 3. In the study diagram below, you can see 4D-710 aerosol administration on day one. Bronchoscopy is performed at week four to eight in order to collect multiple lung tissue samples for assessment of transgene delivery and expression. Transient mild immunosuppression is given as a 40-milligram prednisone taper over four weeks, starting on day -1. Now we will share interim data from all Cohort 1 and 2 participants. Currently, participants have been in this study for 4-17 months. Now I'd like to hand the presentation over to Dr. Jennifer Taylor-Cousar, Lead Principal Investigator for the trial, to present the data. Thanks for being with us, Dr. Taylor-Cousar. Thanks, Dr. Cohen. I'm really excited to work with you and the whole team on this trial. This table shows key baseline characteristics of the seven participants enrolled in Cohorts 1 and 2. Ages range from 20-69 years old. Of note, these participants generally had mild lung function impairment, with percent predicted FEV1 of up to 94%, and quality of life, measured by the CFQ-R respiratory domain, of up to 89 out of a potential 100 points. Two participants has neutralizing antibodies to the A101 capsid pre-dosing. In the future, as we enroll participants in later stages of development, we anticipate engaging participants with more advanced lung disease. This slide shows a post-dosing bronchoscopy sampling plan scheduled for week four to eight. Numerous lung tissue samples are collected for assessment of 4D-710-mediated transgene delivery and expression. The table on the left summarizes the number and location of lung samples collected by biopsies and brushings of both lungs at multiple regions. The diagram on the right shows locations of all four protocol-defined biopsies in green. These biopsies were taken at the entry to the upper and middle lobes on the right, and at the entry to the upper lobe and lingula on the left. In pink, lung brushing locations are shown in the lobes bilaterally. Biopsies were obtained for PCR, specifically for transgene DNA. In addition, both types of samples were obtained to measure transgene RNA expression using in situ hybridization, or ISH, and to measure CFTR protein with immunohistochemistry, or IHC. Based on the lung sample analysis to date, we've significantly exceeded our target expression profile going into the study. The first goal was to achieve widespread and reproducible distribution in all major epithelial cell types. We achieved this in all 34 tissue samples collected from seven participants. Our second goal was to achieve robust expression regardless of baseline antibodies to A101. In both participants with pretreatment antibodies, gene expression and transduction were high and equivalent to that of other participants, despite the presence of these antibodies. Finally, we believe from in vitro and human data that our minimum target expression level is the equivalent of approximately 15% CFTR function, which has been associated with clinical improvement. We significantly exceeded the profile, with more than 98% of cells expressing CFTR, and at levels higher than those expected found in commercially available normal lung controls and CF controls. On this slide, we show high levels of CFTR expression as measured by RNA and protein on biopsies. Quantitation of staining is performed using the Visiopharm machine learning software. On the left, we show transgene RNA as measured by ISH, which is highly specific for our transgene. On average, in Cohort 1, 40% of cells were positive, and in Cohort 2, 53% of cells were positive. On the right, we show CFTR protein levels as measured by IHC, which is a more sensitive assay than ISH. Nearly all cells were positive for CFTR protein, and the protein levels were higher than those expected, found in commercially available normal lung controls and CF controls. Here are additional images demonstrating the cell types expressing CFTR. We see CFTR staining in all key cell types, including basal, secretory, and columnar ciliated cells. Importantly, expression in basal cells, which are the long-lived stem cells of the lung, will be critical for long-term durability. On the right, you can see the expression is appropriately localized to the apical membrane, which is a key interface between lung epithelial cells and the lung airway lumen. This slide shows serial spirometry and adverse events during the aerosol administration procedure for 4D-710, which was generally well-tolerated. On the right, you can see there were no significant declines in percent predicted FEV1 during administration. Cohort 1 participants received their dose on day one, and Cohort 2 participants received their dose in two consecutive days... In Cohort 1, there was one reported case of transient, mild dry throat and fatigue. In Cohort 2, there was one case of rhinorrhea and one case of cough on the day of dosing. This slide illustrates safety data following dosing of 4D-710, with up to 17 months of follow-up to date. In people with CF, approximately a third of pulmonary exacerbations are triggered by contraction of respiratory viruses. Of note, many of these participants in this study were in strict isolation during the COVID pandemic. During the enrollment and the subsequent follow-up visit periods, some were being introduced to community pathogens such as SARS-CoV-2 for the first time. As such, it is not unexpected that these participants would be vulnerable to circulating viral pathogens. As a reminder, in our GLP toxicology studies in non-human primates, we've seen no lung inflammation or toxicity at doses fivefold higher than the cohort 2 dose of 2 × 10^15 vector genomes. Green boxes illustrate a lack of any reported 4D-710-related adverse events during that month. No inflammation was observed in any of the lung biopsy samples via third-party pathologist evaluation. In cohort 1, no 4D-710-related adverse events were reported in three of three participants over 13-17 months of follow-up. In cohort 2, no 4D-710-related adverse events were reported in three of four participants over four to eight months of follow-up. For cohort 2, participant 3, a single adverse event occurred at week 3, which was designated as serious due to hospitalization for less than 72 hours. The event was classified as pneumonitis, not otherwise specified, and the totality of clinical and diagnostic evidence was consistent with bacterial pneumonia. We will review this event on the next slide. The participant is a 33-year-old female with a baseline percent predicted FEV1 of 80% and a history of chronic bacterial infection, including I. limosus, requiring IV and oral antibiotics one to two times per year, alternating monthly inhaled antibiotics, and daily oral antibiotics for their anti-inflammatory benefits. At week 3, the participant experienced onset of dyspnea, including a percent predicted FEV1 decline of 18%. The participant was then admitted to the hospital for evaluation. Their white blood cell count was elevated at 14.6, with 84% neutrophils, and a high-resolution CT scan showed centrilobular nodularity with a differential diagnosis of atypical infection, as well as cryptogenic organizing pneumonia, according to the hospital radiologist. The participant was treated with oxygen and increased steroids and was discharged less than 72 hours later. Several days after discharge, a bronchoscopy with biopsy was performed, and bronchoalveolar lavage fluid grew 700,000 colony-forming units per ml of I. limosus. The lung biopsy showed normal tissue architecture and no inflammation or toxicity. She was prescribed a 2-week course of IV antibiotics, and the AE then resolved over the subsequent 10 weeks. This participant is now asymptomatic, with her percent predicted FEV1 returning to baseline. The PI reported this event as possibly related to 4D-710 administration. Before we summarize our clinical activity data, I first want to illustrate the typical course of these endpoints for people with CF. For spirometry, we focus on percent predicted forced expiratory volume in one second, or ppFEV1. Historically, the average annual rate of decline for people with CF was approximately 1%-2% per year, with inherent intrasubject variability of approximately 4.5 percentage points. In addition, small improvements of 2%-4% in ppFEV1 in modulator trials were associated with clinical benefit, including a reduction in pulmonary exacerbations in people treated with Orkambi and Symdeko. In people with CF, we measure quality of life by the Cystic Fibrosis Questionnaire-Revised respiratory domain, or CFQ-R RD. The validated minimal clinically important difference is four points, and historical data from the placebo arm of a modulator trial shows that untreated people with CF can experience an annual rate of decline of approximately four points. Now we show percent predicted FEV1 data for participants treated with 4D-710 in cohort one. As mentioned earlier, pulmonary exacerbations are often triggered by viral illness in people with CF. Nevertheless, reassuringly, when documented infections occurred, most participants tolerated these infections quite well post-treatment, as demonstrated by percent predicted FEV1 stability. We expect gene expression to be maximal by three months post-treatment. Therefore, it is promising to observe that there haven't been pulmonary exacerbations reported in these chronically infected people with CF documented in longer-term follow-up. In those with high baseline percent predicted FEV1, there is less opportunity to demonstrate an increase in this measure. On this slide, showing the Cohort 1 participants with mild or no impairment, we show durable stabilization of percent predicted FEV1, despite 4 respiratory events documented over 12 months for participant 3.... On this slide, in the Cohort 1 participant with moderate baseline lung function impairment, we show durable 1%-10% improvement in percent predicted FEV1 over 12 months, including 5%-7% improvement at month 9 and 12, despite 2 documented viral infections, including COVID-19 at month 1. This slide shows the durable improvements in the CFQ-R respiratory domain quality of life score during evaluable time points, showing an average 8-11 point improvement over 12 months, which is consistently above the minimally clinically important difference of 4. To summarize, in contrast to historical data showing deterioration in lung function over time as a natural course for people with CF, 4D-710 treated participants experienced durable, stable, or improved percent predicted FEV1 measurements, and all the participants had clinically meaningful improvements in quality of life. We believe this data is very encouraging early evidence of durable clinical activity for a single aerosolized dose of 4D-710. I'll now hand the presentation back over to Dr. Cohen to discuss the summary of the data and next steps. Dr. Cohen? Thanks, Dr. Taylor-Cousar. To summarize, we've seen strong clinical proof of concept for 4D-710, which gives us confidence to further advance the program rapidly. 4D-710 was generally well-tolerated at both acute dosing and long-term follow-up through upwards to 17 months. We saw promising, reproducible, and above normal CFTR expression levels. Cohort 1 clinical activity was durable through 12 months, and we continue to follow patients in Cohort 2. Given the results seen to date, we've selected the Cohort 1 dose level of 1E15 to continue development in phase II. Our stellar expression profile to date enables us to explore lower doses in the ongoing dose-ranging stage of the ARROW study, and we have dosed a patient in Cohort 3 at 5E14. We will collect biopsies and assess the safety and clinical activity profile of that dose level to help inform an additional dose to develop moving forward into phase II. In addition, we have now the opportunity to add several additional functional benefit measures beyond% predicted FEV1 and quality of life to further characterize 4D-710's physiological effects, such as high-resolution computed tomography, or HRCT, with functional respiratory imaging, lung clearance index assessments, measures of change in Mucociliary clearance, and number and severity of bacterial pulmonary exacerbations. We also believe repeat dosing of 4D-710 and a combination with modulators are both additional opportunities to continue to explore as we rapidly advance this important development program. Finally, we are discussing the development path for 4D-710 as a monotherapy and in combination with modulators with the FDA in Q4 2023, and we expect to share this feedback in Q1 2024. I'd now like to hand it back over to David. Thanks, Alan. We're excited to continue advancing our pulmonology pipeline. This slide highlights the significant progress expected over the next few quarters, including sharing FDA feedback on the next stages of development in Q1 next year, and additional interim data updates in mid 2024. Furthermore, we look forward to providing a program update on the 4D-725 program for A1AT deficiency lung disease in the coming year. Now I'd like to acknowledge and thank our trial participants, their families, our principal investigators and study staff, and the Cystic Fibrosis Foundation Therapeutic Development Network. To close, I'd like to further thank the CFF for their unwavering research and financial support for our lung delivery programs and for 4DMT as a company. With a recent amendment to our research grant, we're gratified to have now received over $20 million in financial commitment from the foundation. Thank you everyone for your attention today, and we look forward to answering your questions. Operator? For our Q&A session today, we'll be utilizing the Raise Hand feature. The Raise Hand icon can be found on the taskbar at the bottom of your Zoom window. Please select that icon, and we'll call upon you by name and allow you to unmute. You can then unmute locally and ask your question. We ask that you please limit to one question and one follow-up. Our first question will be from Lydia Erdman, Goldman Sachs. Hi, yeah, this is Lydia on for Salveen. Thanks so much for taking our question. What gives you confidence that the SAE was dose-related and would not be an issue at lower doses? And is there anything in particular related to this participant that made them more susceptible to the SAE? Thank you. Well, thanks for the questions, Lydia. So first of all, we don't think it... This, you know, we did a full detailed assessment of this patient, looking at all data, you know, clinical, radiographic, bacterial cultures, and our biopsy during the event. And based on the totality of the data, it's our assessment that this was clearly a bacterial pneumonia, and our assessment is that this was not due to 4D-710. So we don't believe this event was due to 4D-710, and we don't believe that- ... at lower doses, we would there would be an issue with this event. Now, it's important to remember, in this patient, she had a long history of recurrent bacterial infections and pneumonias requiring IV antibiotics and oral antibiotics and hospitalizations, and in addition, was on bimonthly prophylactic antibiotics and daily antibiotics to try to get these bacterial infections under control. Her hematology was consistent with a bacterial infection, her HRCT or high-resolution CT scan was consistent with bacterial pneumonia. The high colony count of I. limosus, which she is known to be colonized with, is entirely consistent with a bacterial pneumonia. And importantly, you know, we have biopsy samples from the lung during this event in areas that show very, very high CFTR expression from our transgene, and there is no evidence of inflammation or toxicity whatsoever. Importantly, no other patient has had anything like this during the study. This patient, once they got through this, has recovered completely and has not had any episodes such as this in the study. We're really thrilled at the lack of any inflammation on any biopsy of the lung in these patients after dosing in this same window. Importantly, another interesting feature here is that we're not seeing pulmonary exacerbations reported, you know, after that 3-month ramp-up of transgene expression. So we've got patients now in cohort one out to, you know, roughly 15-17 months of follow-up with no exacerbations, which is unusual in this patient population, in our opinion, is highly encouraging. I think I answered all of your questions, but please, feel free to ask a follow-up if I didn't. Thanks so much. You definitely answered it. Just a quick follow-up. What led the PI to believe that this could have been related to the therapy? Just the temporal relationship. The temporal relationship. And, you know, we support the investigator in that, in the sense that it's impossible for the investigator to rule out a relationship, and so it's appropriate to report it as, you know, possibly related in this case, given the temporal relationship. But again, if you look at the frequency of pulmonary exacerbations and infections in these patients historically, it's not surprising that one would have one of the 7 patients might have a bacterial infection in this time frame. But we're very gratified that once transgene expression is ramped up, we haven't seen any lung infections in any patients out to 15-17 months of follow-up. Understood. Thank you so much. Thank you. Our next question will be from Josh Schimmer, Cantor Fitzgerald. Thanks for taking the question, and congrats on another strong update here. For the patient who did have the Inquilinus limosus infection, did they get their follow-up bronchoscopy, and what did you see in terms of CFTR expression, and was the infection in any way counterproductive to the gene therapy effect? And then, do you have any patients who have been followed up longer that you have been able to get follow-up bronchoscopy samples for, to be able to gauge durability of expression? Thank you. Yeah. Thank you, Josh, for that, that question. So overall, we, you know, in all patients, all 7 patients where we've done our scheduled lung biopsies, in that 4- to 8-week window, we've not seen any, any evidence of inflammation or toxicity. We've seen reproducible, promising, high-level expression of CFTR in all the patients, in all biopsy samples, in all 34 total lung samples, if we include the brushing. So really remarkable reproducibility. In this patient specifically, it's interesting to note they still had very high-level expression. There wasn't any evidence of, you know, the, the bacterial pneumonia somehow clearing the expression. And again, in the, in the regions where we had high, very high-level expression, there was no evidence of inflammation or toxicity related to that expression, which is important. I'm gonna have Alan, our therapeutic area head for lung, speak to, you know, plans for repeat biopsies over time. Yeah, and thank you for the question, and you raised a very important point, which is there is additional value, besides showing baseline, vector transfection and protein production within that window of four to eight weeks. In fact, we are moving forward with subsequent patients in the protocol and intend to do a repeated biopsy downstream, more so to look for evidence of, durability and to assess whether or not over a time frame, we hope of anywhere from a year to two, that there remains persistence, durability, continued production, and evidence that we still have activity, in particular in the basement cells in the basement membrane cells, where we would hope that this persists for extended periods of time, which would allow us to diminish the frequency of redosing, if at all. Yeah. And if I can ask one more quick one. In the cohort one, you did start to see early signal clinical improvement in FEV1, and I believe symptoms within the three-month time frame. Many of these cohort two patients have been followed up for that long, so can you give at least a directional sense how things may be trending, and if you also have some early signals of efficacy consistent with what was seen in the data in the cohort one population? ... Yeah, thanks, Josh. You know, as we said, you know, we believe that the transgene should be maximally expressed and fully functional by 3 months, but we certainly see expression activity as early as 2 weeks into treatment. So it's, you know, it's not surprising that in a patient starting at a moderately diminished FEV1, that we could see a more rapid improvement in that patient that was sustained throughout 12 months. In terms of data on FEV1, I just want to reiterate, this is a somewhat noisy endpoint, and, you know, patients can have sort of ±4% from time point to time point. So we want to make sure that when we report out efficacy data on cohort two, just like we did on cohort one, we want to make sure we have at least three to four follow-up time points, especially after that ramp-up of expression. So, consistent with what we did last year, yeah, we're reporting initial safety and gene expression in cohort two, and then, yeah, we expect sort of mid-2024 to give an update on cohort two clinical activity. We just want to make sure when we report out data, it's robust and interpretable, and we have multiple time points. Alan, anything to add to that? Yeah, I just one additional point, and Dr. Taylor-Cousar actually mentioned this in her presentation, but I think worth re-emphasizing it and expanding on it may be appropriate here. You know, at this point, one of the measures that I think is proven to be very helpful, important, and actually is proven to be necessary for approvals for inhaled antibiotics, for modulators, for other therapies, including Pulmozyme, dating back to when I was still a resident and a fellow many years ago, is the time to next pulmonary exacerbation, the frequency and severity of those events. Although, you know, we're talking about small numbers here, we have eight patients enrolled currently, but of the three that we currently have data on that's over a year, what has been impressive and notable, when I started looking at the data set, was the observation that patient 1, we're out 17 months, and there have been, since month 3, no discernible evidence of bacterial pulmonary exacerbations. And in the other 2 patients, it goes out 15 months. And you would expect, in particular, those subjects who have a baseline lung function that's lower, to be expressing events like this more frequently, even if they're less severe, and we just simply haven't seen them. It's going to turn out to be a very important measure, and one that, by the way, was used in all of the studies for the modulator therapies and will continue to be, if you think about it, one of the most important values for quality of life, frequency and lability of those exacerbations, and the impact they have on school, work, and overall life. Got it. Thank you. Next question will be from Daniel Giraldo, Bank of America. Hey, guys, this is Daniel, and for Tahseen. Congrats on the data. Just a quick question on sort of next steps. So you mentioned you're opening the third cohort and enrolling patients in the phase two with the phase—the cohort one dose. So I'm just wondering how you're thinking about sort of enrollment or prioritizing enrolling patients into those two cohorts, and if you're considering also opening a fourth cohort, exploring maybe an even lower dose, depending on what you see with cohort three? Well, thank you, Daniel, for the question. I'll kick it off, and then Alan can weigh in. To answer your second question first, the protocol is designed to allow for even lower dose levels. You know, so we're currently in cohort three. We'll see what the totality of the data, including the biomarker expression, is at that dose level, and decide whether we want to explore even lower doses to determine the minimal effective dose. What's important to remember when we do these studies is in collaboration with FDA and investigators, our goal is to start at therapeutically active and safe dose levels, and then based on the totality of the data, to have the optionality of going up in dose or down in dose. So this is not a traditional small molecule dose escalation. It's more of a dose exploration. And what's interesting is, you know, we've with all three vectors that we've taken into the clinic across five different products now in the clinic, in each case, our vector has not only, you know, performed equivalently to what we see in non-human primates, it's actually exceeded and outperformed and allowed us to explore even lower doses. This is what happened, for example, in 4D-150, where we were able to actually decrease the dose, and now we're at about 1% of what other groups are using in the eye. And so we view this very similarly here, is that the vectors just continue to outperform in humans and allow us to explore these lower dose levels. Again, we don't know whether this gene expression profile is going to be linear or not. So, you know, we've dropped the dose by half from the cohort 1 dose into the cohort 3 dose, and then again, based on the totality of the data, we could either stay at that dose level and treat up to 3 patients, or we could explore even lower doses. You know, so we're excited to have, you know, a high dose of 1E15 that's clearly been safe and highly active, and now with some durability out to 12 months. We're waiting on 2E15. We're excited to see what that shows. Then, yeah, we're also interested in determining the minimal effective dose at the other end. And, you know, our current thinking is it may make sense to take two doses into either a phase II accelerated approval study or phase, and/or phase III, and we'll look forward to FDA feedback on that. And, I'll just, Alan, anything to add on that? No. Well, the only thing I would emphasize is that, you know, having just recently joined 4D, the situation I have never found myself in is where you're not actually dose escalating in a phase I, but in fact, you're doing such an extraordinarily efficient job of delivering this to such a broad range of airway cells, that in fact, we're actually in the position that we feel it's appropriate and necessary to dose down. I would say, from my perspective, the position we're in right now is actually a good one, because now it really just becomes a question, as David had mentioned, of optimizing the dose, looking for the most appropriate, lowest effective dose, and make sure that we continue to maintain that kind of safety and start seeing greater efficacy endpoints as time goes on in these other dose-ranging studies. Okay, got it. That's super helpful. And just, just one follow-up. So as you're thinking about optimizing the dose, would you be looking for sort of stability as you have seen with some of these patients? Or would the goal be to eventually show improvement on, on FEV? Well, so I'd say, first of all, we've seen improvements. All three patients had significant improvements above the minimal clinically effective difference, or MCID, in quality of life, and that was sustained over 12 months. So that's remarkable, and we believe in a randomized controlled study, that would be an approvable endpoint. We're excited about what we've seen in the one patient who had an FEV1 in the range where you'd expect to see an improvement. You know, patients who start in the normal range or very mild, there's just not much room to see improvement, and there the goal would be stabilization. Alan can speak to our plans as we go forward to enrolling you know, sicker patients and patients who maybe have less adequate lung function at baseline. Right. So just to expand on what David was just saying, and I think your question is an important and a good one. Besides looking at one measure, percent predicted FEV1 or spirometric measures, you know, this is such a multifaceted disease that's such a complex airway and such an abnormal airway, unfortunately, in the majority of these patients, that we fortunately now have a variety of other measures that we can do that are not as invasive as repeated bronchoscopy with biopsies, such as, besides high-resolution CT scanning, which obviously can give us radiographic evidence of the anatomy at fixed periods of time. There's now software packages and computational fluid dynamic capacities doing things like functional respiratory imaging, which will allow us to maximize what we learn from high-resolution CT images and can actually give us more specific serial information on regional airway volume, airway wall volume, airway resistance, lobar volume, air trapping, and even blood flow and mucus plugging, all of which are negatively impacted in these patients and may be subtle, but we could easily start to discern demonstrable differences in relatively short periods of time using these approaches. One last point is things like lung clearance index, which has been enormously helpful in getting the modulators, for example, approved, in particular in children who are unable to reliably and reproducibly perform spirometry. These measures also can be very effective and helpful because if you think about it, they're measuring the exact thing we're interested in fixing, which is Mucociliary clearance and how the airways deal with bacteria and debris in their airway and move it in a more normal fashion. So these are non-invasive tests, other things that we're going to be introducing into the study, as well as the historical information that we already presented of their natural history of the disease, both prior to transfection and post. Okay, got it. Thank you. Our next question will be from Kostas Biliouris of BMO. Hello, everyone. Thanks for taking our question, and congrats on the data. A couple of questions from us. The first one is on the levels of CFTR protein. You mentioned that these levels were 450% higher than the normal controls. Can you talk about the sampling in the normal controls? Was the sampling occurred with the same way as in your trials? And are there any safety concerns around overexpression of CFTR in this case, or not necessarily, and the higher the better? And then I have a follow-up. Good to hear from you, Kostas, and thanks for the question. So in terms of the safety levels with the protein expression that we're getting, no one has achieved protein expression from a transgene in a gene therapy vector in the lung in patients, to our knowledge, ever, let alone in CF, which is felt to be probably the most difficult. So we're blazing new ground with this kind of success and this level of expression. What I would say is, in primates, we went up to five-fold higher than in the equivalent dose in primates than our cohort two dose level of 2E15. And we saw a massive overexpression there, and we did not see any evidence of inflammation or any toxicities in the lung or elsewhere in the body. So it's been remarkable, clean safety in primates at very high doses above where we are in the clinic. And then again, on the in the clinic, all we can say is that it's been extremely well-tolerated. There's been no evidence of toxicity or inflammation in these biopsy samples showing this very high level expression up around 450% of normal. So it's really remarkable... and to date has been extremely safe. So we'll continue to be vigilant, and we'll continue to watch, and you know, we do want to explore lower doses as well. But to date, there's no evidence that overexpression of CFTR is toxic. In terms of the, I think your second question again, Kostas? The question was whether in normal controls- Oh, right the sampling Yeah, yeah was done the same way as in your trial. Yeah. Thank you. Yeah, it's as close as possible. Some of these are samples obtained from lung transplant patients, others are from biopsies. So we're as close as possible. It's not the perfect control, it's but it's as close as possible, and we think it's very, very, very likely that a baseline biopsy in these CF patients would give very similar results. Importantly, the CF controls that we have, which again, were as close as possible to what we're doing in the clinic, were even lower. You know, were 50% of normal levels or so. So we were... in those patients, were up almost tenfold higher. So we think it's highly, you know, highly, highly likely that this is true overexpression of the CFTR protein. It's a protein that's been shown to be highly functional, and we also do have the in situ hybridization, which is a probe that is highly specific just for our transgene and would not cross-react with the normal. Thank you, David. Very helpful, and maybe one follow-up on AATD since you mentioned it. Can you maybe help us understand how could you leverage the learnings from CF in the AATD program? Because we know it's also a very challenging indication with high unmet need, and different investigational treatments are there using different modalities. So any read-through from your CF program to AATD? Thank you. Thanks, Kostas. A huge read-through. I mean, one of the beauties of this platform is that it's modular. So everything that we learn with a certain vector, whether it's safety by distribution, how to manufacture it, stability, safety in humans, gene expression in humans, is directly applicable to the next product using the same exact vector, and in many cases, the same exact promoter. So there's huge learnings there, and we're very excited about the Alpha-1 Antitrypsin opportunity in lung disease, specifically, with the same vector, A101, and I'll have Alan Cohen, our pulmonologist, weigh in on Alpha-1 and the unmet need there and the size of the population. Right. Well, you know, once again, I, I'm glad to hear that you're as excited about this as I am. This was one of the other, one of the other draws for me in the platform when I joined. Besides being a physician who's managed patients for 30 years with cystic fibrosis, having run lung transplant programs that were, life-saving, but obviously not the answer, not the answer for most patients. Alpha-1 Antitrypsin is one of those diseases that's hiding in plain sight, and sadly, is almost often misdiagnosed or undiagnosed for the balance of most people's lives, and they just get treated with standard of care, COPD drugs, which really don't give them much in the way of satisfactory resolution. And the current therapies, as you know, augmentation therapy, have really been inadequate for the majority of these patients. So there is a huge opportunity here, as David said, to take our platform, correct the genetic abnormality, improve normal production, and protective production of the proteins necessary to reduce the emphysematous changes in these patients, and ideally, give them a more normal, if not completely normal, life from that point in life that we've transduced them moving forward. So I, I'm in complete agreement, and it's one of our... it, it's one of our, most exciting opportunities because if you think about it, just the size of the population that's out there. In fact, the number of COPD patients is woefully underdiagnosed, so one can only imagine that there's a similar percentage of people that, within the context of COPD, remain undiagnosed and undertreated. There are millions of patients with Alpha-1 out there inadequately being managed and cared for, and current therapies are falling short. So we see a huge opportunity and one we look forward to taking on next. Thank you. Our next question will come from Mani Foroohar of Leerink. Hey, guys. Thanks for taking the question. I wanted to dive in a little bit on target population as we think about commercial opportunity. Obviously, we've talked about the percentage of patients out of the total CF population who are modulator ineligible. But looking at the population of patients that you guys have enrolled tends to skew towards those with a closer to normal, or in some cases, quite near normal, percent-predicted FEV1. Can you talk a little bit about the patient population of those who are modulator-ineligible writ large, and what is the split of typical FEV percent-predicted FEV1s amongst that population? Should we think of that population as mostly being close to normal, typically more severely affected than these patients? Like, how should we think about that? Well, thanks, Mani, for the question. I'll give some introductory comments and then turn it over to Alan. Yeah, this is a. You know, there's a lot of opportunity here. Despite the success of the modulators, there's still huge unmet need out there, and almost all patients do not return to normal lung function. So as you correctly point out, we start out in the 15% or so that are modulator-ineligible, either due to mutational status or intolerance, and then you know, we also expect to move into the patients who are on modulators, but having really inadequate responses clinically, you know, less than 5% improvement on FEV1. That's another quarter of these patients, at least. So we really do see, you know, a broad spectrum of patients amenable to this. And as you know, there's about 100-- over 100,000 patients worldwide and 40,000 in the U.S. And in this case, you know, from a market standpoint, we have the opportunity to re-dose, which allows us to continue to benefit these patients. In terms of the specifics on this population, I'll turn it over to Alan to give more color. Yeah, and I think you raise a very important question, and more importantly, an enormous potential opportunity to help more patients. Now, I’m old enough to have remembered almost 30+ years ago, when the average survival of these patients on average was, if you made it into your early mid-20s, you were lucky, and you were a minority. There was a reason that a third of the patients I transplanted when I co-directed the lung transplant program at WashU in St. Louis were cystic fibrosis, and it was because most of them never made it into adulthood. So obviously, the lowest hanging fruit in the first group that made the most sense for us to employ our platform is in those ineligible modulator patients for whom the current therapies are not benefiting them, and they're just simply not usable and beneficial. The next group, I think, is going to be populations for whom physicians and caregivers are of the opinion that they're not optimally improving, or it doesn't appear that their disease is making as much of a demonstrable, stabilization or improvement, and they're not acting normal life. The challenge here is that, once again, this disease is currently uncured, and current therapies are not cures. So right now, what we're going to end up doing is reducing the next cohort of patients that we're studying within the modulator ineligible to those with lower, more advanced baseline lung disease, so lower FEV1. We hope and expect that that will allow us to show greater changes in their baseline lung function, as well as frequency and severity of exacerbations. And then the plan is to look at populations for whom modulators have been used, but perhaps have had a less than 5% improvement in their baseline FEV1. This population also, interestingly enough, tends to show less substantial improvements in their sweat chloride test on modulators. So that group that still have levels above 60 are a natural population to go into next. And lastly, I hearken back to my early days during my residency and my fellowship, where we first reported at University of Colorado and National Jewish, evidence of inflammation in newborns long before they were infected in the lower airway with any pathogens that were identifiable. So there appears to be low-grade inflammation in these patients right from the get-go. And there have been recent papers in the Blue Journal as recently as this week, showing that even on modulators, inflammation still seems to be persisting, in particular in those patients who are sicker. So those seem like obvious natural populations for us to target. Ultimately, I would envision us taking our therapies into the healthiest patients as early as possible before there's establishment of bronchiectasis and advanced disease, so they can live a longer, fuller, more normal life. But that, you know, that it's gonna be a stepwise process, and we have a couple of studies to do long before that goal and aspiration is achievable. Great, that's really helpful. I think provides a lot of nuance and color. I want to circle back on a follow-up, looking for a little bit more of a narrow and concrete answer. So when we think about the baseline FEV values amongst patients that are modulator-ineligible for genetic reasons, specifically, what should we think about the typical baseline FEV values of those patients entering a study such as a potential Phase II study for this asset at either of the doses you're moving forward? Right. Understood. So currently, we're enrolling because of the nature of the study for safety. We're looking at patients from 50% up to 100% predicted FEV1. The next group of patients we'll be looking at will be going down to 80% or less, and just like in the modulator studies, we're most likely going to go down to as low as 40% predicted. And then we would be going into those in combination that are already on modulators, but are still, as I mentioned, having those degrees of instability and frequency of exacerbations, where the benefit is discernible, but modest at best. Mani, just to make sure we answer your question, the vast majority of patients in this population will have FEV1s less than 80%. It's just that we started with patients a little bit healthier because it's a first in human safety study. Great. I think that's what I was trying to get to, like, what proportion of patients fall into those three brackets? Obviously, the majority fall below 80, but these patients are mostly above 80. So is the above 80 population, like, 2% of these patients, 1 in 100, 1 in 3? I'm just trying to get a sense of... Because the data thus far is largely addressing patients above 80, which is useful, but, you know, it's larger. We're seeing what this drug might look like in a population of patients that is a minority of the most obvious target. So I'm trying to get a sense of, is that minority 1/6 of the, of the ineligible patients, 1/100? And just what your perspective on the epidemiology is in a world of current standard of care. Yeah, I guess I would say, here's the good news: The CF Foundation is going to be making public its registry. It's always a year or two delayed. So we're gonna be having new epidemiology of the mix of patients that are currently out there in the United States and the quartiles of their severity of disease. But the answer to your question is that in the adult age ranges, the overwhelming majority of these patients undoubtedly have lung function below 80, and ideally, are humming above 35 or 40%. Once you start getting down to those lower ranges, your disease is fairly advanced, you probably have other complicating matters to other organ systems, and you may or may not even be eligible for a lung transplant. Great. That's really helpful, guys. I'm gonna hop out because I know you have other analysts waiting. Thank you. We're out of time. We'll hand it back for closing remarks. No more questions. Well, thank you so much, everyone, for your attention today and your interest, and we look forward to continuing to update you on 4D-710, as well as our other pulmonology products as we move forward. Thank you for your attention today.