Hello, ladies and gentlemen. Thank you for standing by, and welcome to our investor webcast today. As a reminder, today's call is being recorded. With that, I will hand the call over to Julian Pei, Head of Investor Relations, who will make introductory comments.
Good morning, and thank you for joining our webcast to discuss interim phase I data from our AEROW trial in cystic fibrosis. Before we begin, I encourage everyone to visit our Investor Relations website, where you can find a press release describing this update. A recording of this webcast and presentation materials will also be accessible on the website after the completion of this call. We remind you here we may be making forward-looking statements. For further details, you can visit our website or our SEC filings. On the call today with prepared remarks will be Dr. David Kirn, our co-founder and CEO, Dr. Jennifer Taylor-Cousar from National Jewish Health and lead principal investigator in the AEROW trial, and Dr. Felix Ratjen, Co-Head of the Cystic Fibrosis Center at SickKids Research Institute of the University of Toronto.
After the prepared remarks, Christian Humer, our Chief Financial Officer, and Melissa Colton, our Vice President of Early Stage Product Development, will also join us for Q&A. With that, I'll now hand the presentation over to David.
Thank you, Julian, and good morning, everyone. It's great to be with you today. Thanks for joining us. As a reminder, our mission with 4D-710 is to deliver a durable, variant-agnostic, disease-modifying treatment for people with cystic fibrosis lung disease who still face high unmet needs. Our five headlines and participants in the most recent lower-dose cohorts, three and four, will be described today and are summarized here. First, 4D-710 was well tolerated. Second, clinically meaningful lung function activity improvements were demonstrated through one year of follow-up by two validated and complementary endpoint measurements. Third, clinically meaningful respiratory-related improvements were demonstrated through one year of follow-up by a validated Cystic Fibrosis quality of life questionnaire. Fourth, phase II enrollment is now underway, with the phase II dose level being 2.5 E14 vector genomes, and this is the cohort four dose level that you'll hear about today.
This was the lowest dose used in phase I. Fifth, understanding durability is critical for lung genetic medicines and due to expected cell turnover in lung epithelium, and therefore we do expect to eventually have the opportunity to redose patients. We're excited to share, for the first time to our knowledge in medical history, paired biopsy data from CF participants in this trial treated with 4D-710, and these data show that CFTR expression not only is robust at one month but persists for at least one year and remains within or above our target therapeutic range. This reinforces the platform potential of our A101 vector technology for cystic fibrosis and other lung diseases. On the next slide, you'll see a summary of the cystic fibrosis disease condition.
Cystic Fibrosis is a life-shortening genetic disease, and variants in CFTR lead to thick, sticky mucus, chronic lung infections, and progressive respiratory failure. In addition to modulators, when available, supportive treatments are very intensive, burdensome, and time-consuming for patients that they need to carry out every single day of their lives. Historically, before CFTR modulators, life expectancy was just 40 years. Over 100,000 people worldwide, including 40,000 in the U.S., face this daily treatment burden. And while modulators have changed the course of disease for many people with CF, tens of thousands remain without effective options and don't benefit fully from modulators. The need is urgent, and that's why we're here, to deliver a truly disease-modifying, durable therapy for every person with CF lung disease to alleviate this high burden. The concept of gene therapy in cystic fibrosis is not a new one.
Unfortunately, over the last two decades, all of the approaches have failed to date, and the reason is simply due to ineffective gene delivery and expression. The need was clear when we started this program nearly 10 years ago, and that is there's an urgent need for truly effective AAV vectors for gene delivery and expression to unlock clinical benefit for these people with CF. Here's the 4D-710 design and how we administer it. Our vector technology solves the problem that the field has had in CF. We used a Nobel Prize-winning technology called directed evolution to invent A101, a novel AAV vector to be mucus-penetrant, to transduce all airway cell types, and to resist pre-existing immunity. We then administer this vector via the FDA-approved and routinely used AeroEclipse II breath-actuated nebulizer, and this ensures reliable and widespread airway delivery of droplets throughout the airways containing 4D-710.
Next, our CFTR transgene. We use an extremely well-validated transgene payload with a minimal targeted modification to fit within the AAV vector while preserving its normal channel function, normal structure, and regulation. This highly functional design has been developed and validated by numerous investigators in the field for over 20 years and has demonstrated correction of CF disease phenotypes in numerous preclinical models, including the ferret and the pig model of CF, as well as human airway models. Now, with 710, we've combined our next-generation A101 vector, a highly functional CFTR transgene, and an FDA-approved nebulizer system for efficient pan-airway delivery. In summary, we believe this gives us the opportunity to deliver a potentially durable, reducible, variant-agnostic, disease-modifying therapy directly to the lung airways of people with CF. I'll now hand the presentation off to Dr. Taylor-Cousar to review the ARROW study design and clinical data. Jen?
Thanks, David. I'm going to start by reviewing the study design and baseline characteristics of participants in the phase I trial. So let's first review the framework for this phase I trial. Our focus was really on dose finding. We focused primarily on the safety of 4710 and CFTR expression levels by studying lung tissue biopsies and brushings collected via bronchoscopy approximately four weeks post-dosing. Our goal was to identify a dose level that resulted in physiologically relevant cell transduction and CFTR localization patterns. Our control biopsy samples for these analyses are from people without CF. Finally, we also looked for evidence of clinical activity using multiple complementary pulmonary endpoints. Based on the totality of this data, we selected our phase II dose. As previously disclosed, our dose ranging started at 1 times 10 to the 15th vector genomes, which was well tolerated.
We then escalated to 2 times 10 to the 15th vector genomes. This dose level was discontinued for further study due to both high transgene expression that also ended up within the lung interstitium, not one of the target tissues, and one related serious adverse event that subsequently resolved. After careful review of the data from the higher doses with the safety review team and the Cystic Fibrosis Foundation, we proceeded to explore lower doses. We also amended the protocol to add new clinical activity endpoints, including one called lung clearance index, as well as optional bronchoscopy at a minimum of one year post-dosing to evaluate the long-term durability of transgene expression. The additional lung assessments include more sensitive measures of early disease, the lung clearance index that I mentioned, measured by multiple breath washout.
We really wanted to better capture clinical activity and subtle improvements in small airways in the small number of participants that we're studying. We'll review these in more detail in the coming slides. Now, let's review data from the lower-dose cohorts, 5 times 10 to the 14th and 2.5 times 10 to the 14th vector genomes. This first slide shows the baseline characteristics of the participants who received one of the two lower doses. Eight of nine were variant ineligible for CFTR modulators. The lung disease, based on percent predicted FEV1, ranged from mild disease to moderately severe dysfunction, but notably, all participants had abnormal lung clearance index, or LCI, that measure that's very sensitive to detect early disease, especially in the small airways. Earlier, David mentioned quality of life.
So we used a validated cystic fibrosis quality of life measure, particularly the respiratory domain, and it's assessed on a scale from 0 to 100, with 100 being the best. You can see that there was a wide range in the baseline quality of life scores, with most people being below 80 points. Now, let's move on to safety and tolerability. First, we're going to look at the immediate safety through day 14. We saw adverse events commonly associated with nebulized therapies that resolved within minutes to about a week. The lower dose is half that of the higher dose, so administration is under an hour for that dose, which is very much appreciated by participants, particularly when thinking about dosing it again. This slide actually looks at the longer-term safety and tolerability. Overall, excellent safety and tolerability beyond the immediate post-dosing period.
There was one non-pulmonary adverse event in the five times 10 to the 14th vector genome cohort, possibly related to steroid administration rather than 4D-710. There were no 4D-710-related adverse events beyond day 14, except in one participant with a transient grade 1, so very mild elevated liver enzyme value that resolved completely within a month, and this can be typical of underlying CF, as we frequently see increases and decreases transiently in this patient population, so we talked about the clinical safety data. Now, let's look at the expression data. We've presented this data previously but wanted to provide you with a quick summary of our analysis methods for lung biopsy and for what the two methods are used. In situ hybridization, or ISH, measures CFTR mRNA expression as highly specific and most useful for quantitation for dose selection purposes.
Immunohistochemistry, or IHC, is highly sensitive and is useful to confirm translation into CFTR protein and is used to qualitatively study expression patterns. That being said, as reviewed before, based on our best knowledge from review of literature, our target expression profile is shown here, where we aim to really achieve widespread expression across all collected lung epithelial samples and no impact from pre-existing immunity. Specifically, we believe that achieving expression in approximately 10%-25% of cells is a reasonable target, and we want to see a normal staining pattern and minimize expression in undesired cell types like in interstitial cells. First, we use our ISH method on commercially available non-CF and CF lung samples to establish an expected level of endogenous CFTR mRNA. Non-CF samples showed approximately 10% of cells positive, and this measurement is consistent with target functional ranges that are described in the literature.
Here, we show the mean % positive epithelial cells following single-dose administration of 4D-710. We were very pleased to observe a consistent dose response and expression levels in cohort 4, the 2.5 times 10 to the 14th vector genome dose, meet our target of 10%-25% cells positive. So now, let's look at the IHC, or immunohistochemistry data, which again stains for protein. As shown before, here's what non-CF and CF lung samples look like with the IHC assay. So the non-CF is on the top. Again, we believe overexpression may not be ideal, as it could lead to protein mis-sorting and, as a result, reduce protein function and even unfavorable altered ion balance in the cells.
So looking at the staining in our highest dose in contrast with a normal lung sample shown on the right, you can see abnormal staining patterns, including staining in the interstitium, as indicated by the red arrows. Let's compare that to the opposite end of our dose ranging at the lowest dose of 2.5 times 10 to the 14th vector genome in cohort 4. We see normal localization patterns, including minimal interstitial staining. Again, control lung tissue is shown in the photomicrograph to the right. So putting all three of these image panels side by side, the highest dose, the selected phase II dose, and non-CF control, we believe we're at an optimized dose for further development in phase II.
In summary, in combining the safety data reviewed earlier with a complete set of biopsy and brushing data, we feel confident in our selection of the lowest dose of 2.5 times 10 to the 14th vector genomes going forward. So let's move into the clinical activity data, and I'll invite Dr. Ratjen to join me in presenting this section as he has been a pioneer in the field on MBW or multiple breath washout.
Okay.
First, let's take a...
No, sorry. Go ahead.
First, let's take a step back and review the different ways we study lung disease and CF and what they measure. It's important to understand that CF is a disease that affects the entire lung but starts in the small airways and eventually progresses into the large to mid-airways. Historically, for more than a decade, FV1 has been the gold standard for clinical trials and clinically accepted primary endpoint to measure lung function and correlate to disease progression, particularly survival. This has primarily been driven by precedent success in CF trials and routine use in current CF care infrastructure. However, it does measure the large airways rather than the small airways. The field is now moving towards less effort-dependent, less variable, and more sensitive methods to complement FV1, and that is lung clearance index, so we added this to the AEROW trial.
Looking at quality of life endpoints, the CFQ-R respiratory domain remains the most validated endpoint for pulmonary symptoms, which are people's reporting of the day-to-day impact of their disease. This instrument has generally not been associated with significant placebo effects. Finally, we're also looking at high-resolution computed tomography scans in an exploratory fashion, which can show structural improvements. While initial data look promising, we're still performing comprehensive, detailed analyses, and we will share these at future medical conferences. I'll now hand it over to Dr. Ratjen to review LCI in more detail.
Thank you, Jen. Hello, everyone. I'm Felix Ratjen. I'm the program head in translational medicine at SickKids Research Institute, professor at the University of Toronto, and co-head of the CF Center at SickKids in Toronto, Canada. I've spent most of my career focusing on developing and validating clinical endpoints for cystic fibrosis, especially those that help us better understand lung function and disease progression, such as the lung clearance index that I will talk about now. Before we dive into the clinical data from the AEROW trial, I'd like to briefly set the stage for why we measure lung function, particularly using FEV1 and LCI, has been so central to CF research and care, and how these endpoints actually complement each other in capturing both larger and smaller airway disease. Let's first look at FEV1, or forced expiratory volume, in one second.
It's measured by Spirometry, and primarily, it reflects large airway disease, so how well the large airways are functioning. It is effort-dependent, meaning it requires good patient cooperation, and while it's well correlated with clinical outcomes like survival and exacerbations, it is not very sensitive to early or mild disease. That means subtle changes, especially in the small airways, can be missed with this technology, so let's look at LCI, and this is where it comes in, so LCI means the lung clearance index, and the measurement is done using multiple breath washout, and it measures how effectively a gas is cleared from the lungs, and it is a marker of small airways rather than large airway disease. It is not effort-dependent because it's measured while the participant is breathing at rest.
It makes it easier for a broader range of participants, including children, and it's much more sensitive to early changes in lung function, even when FEV1 is still normal. LCI is increasingly recognized by regulators, especially for pediatric studies, and it's now the primary or key efficacy endpoints in many trials in cystic fibrosis. In summary, while FEV1 remains the gold standard due to its history and regulatory acceptance, LCI 2.5 provides complementary information, especially for detecting early disease and subtle treatment effects. Using both together gives us a more complete picture of lung health and treatment impact in Cystic Fibrosis.
This is why there's a growing interest in LCI as an endpoint, and the CF Foundation is supporting a national resource center for studies using this endpoint, as well as collecting this data and REACH its natural history study, which is a natural history study intended to be used as an external comparator for future CF registration trials. So I mentioned that FEV1 is linked to survival, and LCI has also been linked to other endpoints. So LCI has been shown to be abnormal in people with CF with normal FEV1 in more than 20 studies now, and it predicts future. It does predict future outcomes. It is linked to later abnormalities in spirometry and FEV1. It predicts pulmonary exacerbations and has also been shown to predict survival, as shown on this slide.
I will now show you some data from clinical studies that have looked at LCI and how it captures treatment effects. This is demonstrated on this slide for a treatment called hypertonic saline. In this crossover study of only 19 patients with cystic fibrosis, LCI showed a statistically significant improvement with hypertonic saline, a treatment that we know has a modest treatment effect compared to isotonic saline as an inactive control, with an effect size of 1.16 units. Notably, this sample size was much smaller compared to what would have been required for FEV1, which we looked at as well in this study, which showed a modest benefit of 1.8% with a standard deviation of 12, highlighting the high variability of the assay. The required sample size to achieve statistical significance would have been 351 as opposed to 19 or less with LCI.
This really underscores why LCI is increasingly valued as a sensitive and less variable endpoint for capturing meaningful changes in lung function, even when otFher measures may not show significant differences, and to highlight that, I will show you some data from the Orkambi trials in pediatric patients with Cystic Fibrosis. As I mentioned before, in pediatric studies, LCI has now become an established primary efficacy endpoint. What you see here are data from the trial with the CFTR modulator Orkambi, where LCI robustly demonstrates treatment response at every time point, and you can see how it differentiates from the placebo group without overlap of the confidence intervals. In contrast, FEV1 shows more variability and greater overlap between the treatment and placebo groups, making it less sensitive for detecting changes in this population.
Looking ahead, ongoing longitudinal studies like REACH will provide prospectively assessed data in individuals not on Trikafta, serving as a contemporary control for nucleic acid-based trials such as gene therapy trials. Importantly, these studies also include LCI as a key outcome measure, further reinforcing its value in both clinical research and future therapeutic development. I'll now hand it back to Jen to review some clinical activity data from the ARROW study.
Thanks, Felix. So going to the next slide, this is the summary of the available results for the participants who dosed with 5 or 2.5 times 10 to the 14th vector genomes. We're showing the mean changes at all available time points between 3 to 12 months versus baseline per group in % predicted FEV1, LCI, and CFQ-R. All data points showed greater improvements in those dosed with 2.5 times 10 to the 14th vector genomes, the dose we selected for phase II, versus 5 times 10 to the 14th vector genomes. So at this point, I'd like to show you some participant-level activity, starting with the dose of 5 times 10 to the 14th vector genomes. This first participant is one with normal baseline FEV1. Her LCI was not available since she was enrolled prior to the LCI amendment.
Although the participant had an initial decline in FEV1 and CFQ-R from six to 12 months, there was a small improvement in percent predicted FEV1 and CFQ-R. In CFQ-R, time points above the minimal clinically important difference of four points are outlined in green on the right. The next participant had a baseline FEV1 of around 80%. She had a small decrease in her percent predicted FEV1 and quality of life score, but subsequent improvements, which correspond with decreases, which is an improvement in LCI. Due to an exacerbation at the month 12 visit, as indicated by the open circles and the bar, we show her 15-month visit. The next participant is a 34-year-old male with moderate disease to a baseline lung function in the 60s.
He had fluctuating percent predicted FEV1 over a small range of 2-4%, but an improvement in his LCI and in his quality of life. Because the participant's LCI didn't pass the quality control at month 12, another measurement was performed at month 15 and is shown here. His respiratory specific quality of life improved greatly, again shown on the right, and well above the MCID of 4 points. So now, let's look at some individual participant-level data with the 2.5 times 10 to the 14th dose, our selected dose for phase II. The first participant, a 26-year-old male with moderate disease to an FEV1 at baseline under 60%, showed a meaningful improvement in his LCI and CFQ-R respiratory domain scores across multiple time points. His FEV1 improvement was greatest at 6 months.
He had a pulmonary exacerbation at 12 months, and the site was asked to bring him back again to repeat his lung clearance index at the 15-month visit. His respiratory specific quality of life improved greatly and again well above the MCID, as shown on the right. The next participant is a 54-year-old female with mild disease. She demonstrated consistent response in FEV1 of about 7% at three different time points, and that correlated with an improvement in her LCI, so decrease. Her CFQ-R score was also above the MCID at two time points. The next participant, participant 3, was dosed by the site off protocol because the person was actually having a pulmonary exacerbation at baseline, resulting in a low baseline measurement compared to their prior screening values. Nonetheless, the participant lung function and CF quality of life scores rebounded after dosing with 4D-710.
Because of genotyping of a relative, this participant was actually able to gain access to the recently approved triple combination modulator, Trikafta, and began that drug at month 8, which made clinical activity confounded and not further evaluable. However, encouragingly, the combination was safe and really interestingly, the participant's lung function and respiratory symptom score remained well above baseline while on the combination, so to summarize the interim phase I update, all data points showed greater improvements in those dosed with 2.5 versus 5 times 10 to the 14th vector genomes, and again, this is the dose we selected to use in phase II, so in conclusion, the focus of phase I of the program was to establish safety of inhaled administration of the transgene, show that it achieved physiological and relevant CFTR expression levels, and evidence of clinical activity.
The focus of our ongoing enrollment in phase II of the program is to demonstrate that inhalation of 4D-710 leads to stability and/or improvement in large airway disease as measured by FEV1, improvement in small airway disease as measured by LCI, and improvement in respiratory symptoms as measured by the validated CFQ-R respiratory domain score, and then to show improvement or evidence in other measures of pulmonary disease, such as decreased mucus burden on high-resolution CT scan, which we didn't have time to show today. I'll now hand it back over to David.
Thanks, Jen. This slide presents first-time data showing that our AAV-based approach delivers durable CFTR expression in the lung, even at the lowest phase II dose for one year or more. Participants underwent optional bronchoscopy at one year beyond, showed persistent expression levels in airway epithelial cells measured by ISH, which remained within target therapeutic range at one to three years, matching those seen in non-CF controls. This validates both our lung biology hypothesis and the effectiveness of our vector strategy. So why is this important? This is the first time that paired lung biopsies have been obtained in CF participants. These data confirm durable transgene expression after a single dose for anywhere from one to three years. And importantly, this durability is observed even at the lowest dose level of 2.5e14, supporting our decision to move forward with this dose in phase II.
Now, looking ahead, because lung epithelial cells naturally turn over, we anticipate that repeat dosing will be an opportunity for us to maintain therapeutic benefit in these participants. The durability data here inform our future redosing strategy, and we're actively collecting more paired biopsy data at the phase II dose. The bottom line is that this is a major validation of our AAV platform in the lung, so stay tuned. We'll have more data on durability and redosing coming soon in 2026. Now, we couldn't do this alone. We have amazing KOLs and PIs at our sites, such as you've heard from today, and we continue to be gratified to have a very productive long-term relationship with the Cystic Fibrosis Foundation, and this really continues to deepen with their recent $11 million investment round. We're extremely grateful for their collaboration and for their support.
In summary, we're on track to complete phase II enrollment in the first half of 2026 while continuing to collect additional paired biopsy data at the selected dose to inform our redosing strategy. As the program advances, we'll finalize our approach based on emerging durability and clinical activity data, and we plan to share a comprehensive program update in the second half of 2026. We're excited to continue generating meaningful data and moving closer to making 4D-710 available to people with CF as a durable, variant-agnostic, disease-modifying treatment for those with remaining high unmet need. Stay tuned for more milestones and updates as we move forward. Thank you for your attention. Thanks to Dr. Ratjen and Dr. Taylor-Cousar, and we'll now take your questions. Operator?
Thank you. At this time, if you would like to ask a question, please click on the raise hand button, which can be found on the black bar at the bottom of your screen. When it is your turn, you will receive a message on your screen from the host allowing you to talk, and then you will hear your name called. Please accept, unmute your audio, and ask your question. We will wait one moment to allow the queue to form. Our first question is from Jonathan Miller from Evercore. Please unmute your line and ask your question.
Hi, guys. Thanks for taking my question and congrats on all the data. I guess just the high level for me, the patient-level data that you gave today does highlight how variable both patient journey and monitoring can be, even for outcomes like LCI, which is clearly a more sensitive measure. So can you talk a little bit about the phase II strategy, what we should be expecting in terms of the homogeneity of patients there, and what we should be expecting about the number of patients needed to get reliable measures for LCI and FEV1 in the phase II? And then just secondly, why is expression decrease over time not proportional with dose? It seems like the 2.5d14 dose is somehow more durable than 5d14, at least based on the one slide that you showed. Just curious about that too.
Thanks, Jonathan, for that. I'll answer the first question quickly and then turn it over to Jen for the questions around phase II. I think it's probably too early to say exactly what the kinetics will be of gene expression decreasing over time by dose. We certainly notice the same thing, that we're gratified that the phase II dose, the lowest dose, continues to be in the therapeutic range at 12 months. But I think with more data, we'll see if those kinetics of decay of the expression vary based on dose or not. But that's certainly suggested here. So I think over time, we'll get more data at the lowest dose, our phase II dose, and we'll understand better. This will really inform redosing, right?
This plus the clinical activity will determine whether the redosing is somewhere between 12 to 18 months, as we initially believed, or even longer. But that's sort of how we think about that. So stay tuned on that, and we'll see if that holds up over time. Jen, do you want to speak to sort of phase II and how the patients will be selected and how we'll look for consistent results on LCI and other outcomes?
You know, it's a great question and observation that there is a lot of variability. We're planning to add an additional six participants for the phase II dosing at that level, and we'll again limit the number of people who can be in the study based on FEV1, but we don't want to limit it so much that we can't enroll this phase of the study, so again, we'll have people who have lung function above 40% and less than 100%. There will be some variability, but we're hoping with the addition of six more participants that we can see a more consistent response and a continued trend in the right direction.
Thank you. Our next question is from Ryan McElroy from Leerink. If you'd like to unmute your line and please ask your question.
Hey, guys. You have Ryan on for Moni. Thanks for taking our question and congrats on the update. Maybe just between the expression and the clinical data, we obviously saw some wide error bars. Can you just talk about any correlation you're seeing at this phase II dose between those two? And then maybe just one on the regulatory front. Can you just talk about any of your initial conversations that you've had with the FDA and where they stand on this FEV1 versus LCI debate as an endpoint moving forward? And do we plan to get more clarity on that in the second half of next year? Thanks for taking our question.
Yeah, absolutely. Thanks for the question. So you raised a number of important points there. In terms of regulatory interactions, we've had very productive interactions with FDA throughout development of this 4D-710, and we'll definitely have more in 2026 to really hone in on what that phase III design will look like. As Felix said today, the LCI has been used as the primary efficacy endpoint in pediatrics for both European and U.S. studies and is really emerging as a very useful endpoint. So stay tuned on that after we have further conversations with FDA. Jen, do you want to speak to kind of correlation between transgene expression and LCI and other clinical endpoints?
Yeah, it's a great question. And it goes back to the first answer, really, that in people with CF, their response is not always consistent. So for example, I have a lot of experience with designing and running the modulator trials. And you can have somebody who has a huge response in their sweat chloride and a more subtle response in their FEV1 and vice versa. Don't expect that we'll see 100% correlation between outcome markers in any circumstance. And we're seeing that here. And again, this is a very small number of participants. Again, we hope to see trends of those things correlating, but we know in people with CF, both without treatment and with treatment of various different treatments, that their responses are not always 100% correlating with each other based on varying outcome measures.
Thanks, Jen. And Felix, do you want to?
Thanks again.
Yeah, thank you for the question. Felix, do you want to just comment on use of LCI as a regulatory endpoint?
Yeah, I think that's an important question and a bit of a moving target. So the EMA has already accepted that as a primary efficacy endpoint in the pediatric studies. And I think so the FDA is more and more open to this endpoint as well. And some of the ongoing studies, such as REACH, which I mentioned, which is really designed to provide contemporary controls using adults as well, where there's currently a bit less information for LCI. And there have been discussions with the FDA, and they are more open to it. So again, the way to look at this is more that we look at this as complementary approaches, not just using one endpoint. And we see this also for LCI versus FEV1, that different people show efficacy in one versus the other endpoint, with more overall showing effects in LCI.
Thank you, Felix. And if you wouldn't mind just maybe commenting on kind of the range of LCI improvements that you think are clinically meaningful, as it's a relatively new endpoint for some people.
Yeah. And you can look at this both in the absolute and relative terms. Most of the studies have looked at absolute changes in LCI and have seen changes between 0.5 and 2 LCI units. And I showed you some of the Orkambi data, which showed about one LCI absolute change. So what is seen in the current data, albeit in a small sample size, is in the range of what we've seen in previous studies of interventions that are established in the field of Cystic Fibrosis.
Yeah, I think that's a very important point. Thank you, Felix. Next question.
Thank you. Our next question is from Gena Wang from Barclays, please, if you'd like to unmute your line and ask your question.
Okay, thank you. So I think, David, we had a debate in the past regarding this approach. So when I look at the data, I know you're using Orkambi. We are discussing about the CFQ-R as a potential approvable endpoint. But the bottom line is FEV1, we already follow this 12 months to 15 months. If we see such a modest FEV1 benefit, I know we have to try to understand better of the CFQ-R, which Orkambi actually is not a fair comparison. It's such a modest clinical benefit. I can foresee this will phase out very quickly. We have a much better drug already coming to the picture. So here, my question is, is that really the do you think that this is really viable moving forward?
And also, I know you do have very good funding from others so that you do not spend too much money from your own in terms of investment moving this forward. So maybe just give us a sense of how much that will cost going to the next stage.
Thanks, Gena. I'll answer that and then turn it over to Jen. But we think very much this is a very strong clinical activity signal in these patients. Obviously, these are very small numbers, but you have patients with modulator range responses on LCI at multiple time points and even FEV1 in some patients at the phase II dose. So we think there's very much a strong activity signal here. In terms of the finances of the company, we are very fortunate to have this fully funded by our partners at the Cystic Fibrosis Foundation into the second half of 2026. So from a company burn rate, there's really no impact of this program at this time. And based on further data, we'll make decisions on further funding as we go towards phase III.
Jen, could you kind of speak to the effect size we're seeing here and how these patients compare to maybe patients who are eligible for modulators?
Absolutely. I think it's really important for us to go take a step back to where we were. Back in 2012, when Ivacaftor was approved, it was approved for only people who had the G551D mutation. And all the rest of the people with CF could see that that group of people had this amazing new therapy, and they didn't have anything. When Orkambi came along, yes, the effect was more modest, but it stabilized a huge group of people who previously had nothing but symptomatic therapies. And so it improved their FEV1 modestly. It improved their quality of life modestly, but it did decrease their pulmonary exacerbation rate, which we know correlates with survival. Again, with that modest improvement, half the patients in the United States had a drug that at least stabilized them.
The people right now who don't have a modulator at all feel incredibly desperate, as I see over 90% of people eligible for these other very effective therapies, and so even stabilizing that group of people so they're not having so many hospitalizations, not missing so much school, not missing so much work would be a huge gain for that group of people who is really desperate right now with no other option for therapy.
Thank you. I have a quick follow-up regarding, I think you said enrollment criteria 40 to less than 100 for FEV1. Wouldn't that be too wide a range that cover too many different types of patient population? We do know Trikafta, they now show superiority on FEV1 versus the, sorry, I'm blanking out the previous triple combo.
Right now.
But it did show sweat chloride.
Yeah, right.
So because one part of the reason is FEV1, you basically could reach the peak. It depends on what kind of baseline you enroll. So that could be a very important data point to think about. And then the other important data point that everyone's checking is the sweat chloride. Have you thought about that as well?
So to answer your second question first, so sweat chloride is impacted by systemically administered therapy, so it would not expect to be actually affected by an inhaled therapy. So we won't measure sweat chloride for this administration because we're just administering to the lungs. It's not getting into the other tissues, as we've shown previously from the non-human primate models. In terms of your first question, we're using the standard range of FEV1 that we use in most of our trials in cystic fibrosis. So yes, there is a range, but we want this drug to work for people in that range. Over 100, it's very hard to show a difference in FEV1.
But in that range of 40 to less than 100, we have been able to show it with multiple different theories, even if you go back to the days of Pulmozyme, for example, or the inhaled antibiotics. So we think that's a reasonable range to also have enough participants to enroll the study.
Thank you.
Thanks, Jen. And thanks, Gina, for the question. And Jen, just a follow-up on that. Obviously, small data set here, but if these results with LCI and FEV1 and quality of life were to be reproduced in larger patient numbers, how do you think patients who have no modulator therapies available would think about this, and would they be willing to try it?
Yes. As I was mentioning, this group of people is really feeling quite desperate, and their quality of life is highly impacted. There have been several different studies by different groups showing how difficult daily life is and how high the symptom burden and treatment burden is in this group. So I think people would be very interested in trying this therapy as soon as it became available.
Thanks, Jen. Okay, operator, next question.
Thank you. Our next question is from Tommie Reerink from Goldman Sachs. If you'd like to unmute your line and ask your question, please press star six to unmute your line.
Thanks so much for taking our question. This is Tommie on for Salveen, and congrats on the progress. We were wondering if you could just give us a bit more color on your redosing strategy and how that factors into your future development, and if there's anything that you can update us on on a potential accelerated path here. Thanks so much.
Thanks, Tommie, to you and Salveen for the question. Maybe I'll take that, and then Jen can weigh in as well. In terms of redosing, there's very good data from multiple groups, including our own in primates and in the ferret model, to show that aerosol redosing with AAV is feasible. In fact, we don't expect any lower expression with repeat dosing. We can get into the biology of why that is. It's very clear from those studies that redosing should be highly efficient and give us similar expression levels as the first dose. The real question then becomes, when do we redose? I think that will be driven by the data on gene expression durability.
We're thrilled that we're seeing expression out to 12 months or more, all the way out to three years, but at 12 months at least with the phase II dose. So we'll get more data on the durability of this profound LCI effect we're seeing and on transgene expression and then decide on redosing. Going into this, we hypothesize it'd be roughly 12 to 18 months. And I think our data certainly today, while early, is consistent with that. In terms of the potential for accelerated approvals and how we expect to go to phase III, I think after we get additional phase II data and more durability on phase I, we can go back to with the Cystic Fibrosis Foundation support and have conversations with the FDA around accelerated approvals.
We are excited to be able to leverage access to this REACH study, which can serve as an external control group for phase III. Jen, would you like to amplify on any of that?
I agree with everything you said, David. I think I would just add that we will be working also with the FDA on the redosing plan. So for sure, we want to look at the durability of gene expression, but also it would be incredibly helpful to look at the changes in LCI over time, and we'll gain more experience with that with this expanded dose cohort over time.
Thanks, Jen, and thanks, Tommie. Operator, next question.
Thank you. Our next question is from Daniel Giraldo from Bank of America. Please unmute your line and ask your question.
Hey, guys. Good morning. Thank you for taking our question, and congrats on the update. I just wondered if you could speak a little more on the LCI as an endpoint for adults. And maybe you talked about how it's been used for pediatric patients and maybe milder disease, but how well do you think it is at measuring clinical benefit in more advanced or severe patients? And how are you going to take that into account for the enrollment criteria for the next patients? Is there going to be sort of a range you're looking to enroll in terms of the LCI for that next cohort? And maybe more long-term, how are you thinking about developing this program fully, or is this something you would consider partnering after you acquire more data next year?
Thanks, Daniel, to you and to the team. Great questions. Maybe I'll take the business development one first and then turn it over to Felix. I think in terms of developing this, we're thrilled to be partnered with Cystic Fibrosis Foundation, and we're happy to be driving it forward together and retaining 100% of the worldwide rights. Over time, we'll be opportunistic about whether or not we partner this or maintain U.S. rights. I think we're open to both, and we just really want to get more data before we make a final decision there. But I think I expect over time there'll be increasing interest in partnerships on this program.
In terms of your question for Felix, one of the first questions I asked him when I met him, as I said, if we were starting CF modulator therapies today, what would your primary endpoint be if you kind of ignored the historical precedent? If we're starting over today, would you use LCI or FEV1? And he immediately said, "Well, LCI. It's more sensitive, and it's more reproducible, less variable." So that was very telling to me. But Felix, do you want to speak to kind of the use of LCI as an approvable endpoint and kind of where have we been and where are we going?
Yeah. So I mean, thank you for the question. And I think it was mainly geared towards adults in terms of how well it performs in this age group. And just to look back, I mean, the reason many of the data on pediatric patients is because we didn't really have another endpoint to work with, and so we had to move on and use LCI. But it doesn't mean that it's not a useful endpoint in adults as well. I didn't show you the data for the open observational study that was done by the CF Foundation, which was called PROSPECT after Orkambi became available to patients. And that included both pediatric and adult patients. And it was consistently seen that both in children and adults, LCI was able to show about three times the treatment effect that you saw with FEV1.
I think, and the REACH data that will now become available, and we will take a first dive into these data early next year when we have repeated measures for the adult population, will also help us to further define the natural variability of this measure in contemporary patients, and especially adults, because for pediatric, we already have those data. I think it has been a bit of a moving target, but things have changed in CF because overall, the disease is so much better treated in both children and adults. The need has also changed in terms of the outcome measures. Regulatory authorities have recognized that and are now more open to it. They still want to see data on FEV1, no question about it.
But again, looking at this as a complementary data set, that could be very helpful, is certainly the way I would look at it. And it is more sensitive, and it will capture more patients responding to therapy.
Thanks, Felix. And thanks, Daniel, for the question.
Thank you. Our next question is from Clara Dong from Jefferies, if you'd like to unmute your line and ask your question.
Hi. Good morning. I'm scrolling through my questions, and congrats on the progress. So maybe just a follow-up question on the redosing. So how are you thinking about the epithelial cell turnover rate in CF lungs, and what does it really imply for the optimal redosing interval in your view? And then how are you thinking about LCI as an early trigger for redosing, especially if expression persists? But what if we see LCI begins to drip, and then if there are minimal expression floors, what would you consider redosing kind of mandatory, even if clinical metrics are still stable? Thank you.
Thank you, Clara, for the question. So the way we think about redosing is really going to be looking at that durability data. Again, we're thrilled to see expression out to anywhere from a year out to three years, depending on the dose level. So I think we'll continue to get more data on paired biopsies at 12 months or beyond. In mice, the lung turnover half-life is about a year and a half. So humans should be at or above that in terms of timing for lung turnover. But again, in CF being inflammatory, that could shorten it. So we estimated we'd be in a 12-18 months redosing window, and our data certainly today, while early, is consistent with that.
I think, Felix, my feeling is that LCI would be a much better measure to follow to determine when we should redose, when a treatment effect is wearing off, because I think it'd be a leading indicator before we see changes in FEV1. Do you agree with that?
Yeah, I concur with that because the early changes are always in the small airways, and this is reflected by mucus plugging, and LCI is very sensitive in capturing changes in mucus plugging. So I think it will be helpful in that sense. I mean, the reality for the epithelial cell data is that there aren't a ton of data, longitudinal data in CF that you can rely on. So I think this program actually gives us novel insight into that.
All right. Thank you, Felix. So thank you all for joining us today. I think we're out of time, but we really appreciate your attention and interest. We thank Doctors Ratjen and Taylor-Cousar for their incredible insights today. We thank you for that. And of course, we thank the Cystic Fibrosis Foundation, all the participants on our phase 1/2 AEROW trial. We look forward to hearing from all of you. Please reach out anytime to Julian Pei, our head of investor relations, or our CFO, Christian Humer. And we look forward to hearing from you. And thank you for your.