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 I AERO clinical trial of aerosolized 4D-710 in patients with 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 August Moretti, Chief Financial Officer, who will make introductory comments.
Thank you, operator. Welcome everyone to 4D Molecular Therapeutics 4D-710 Interim Data Webcast. A press release describing the results and development plans related to 4D-710 is accessible in the investor section of the 4D Molecular Therapeutics website. A recording of this webcast will be accessible on our website after completion of this call. With me today are Dr. David Kirn, our Co-Founder and Chief Executive Officer, and Dr. Jennifer Taylor-Cousar, Professor, Departments of Medicine and Pediatrics, and Co-director, Adult Cystic Fibrosis Program, Director, Cystic Fibrosis Foundation Therapeutics Development Center, National Jewish Health. Dr. Taylor-Cousar is the Lead Principal Investigator on the 4D-710 AERO clinical trial. She will present the interim AERO data tomorrow at the 2023 European Cystic Fibrosis Society annual meeting.
As a reminder, on this call, we will be making forward-looking statements regarding our clinical data from our AERO 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 section of our most recent Form 10-K and Form 10-Q, which are on file with the SEC. I'd like to turn the call over to our CEO, Dr. David Kirn. David?
Thank you, Augie. Thank you everyone for joining us today. We're excited about our growing pipeline, powered by our efficient product design and development engine. Today, we'll focus on our pulmonology therapeutic area. This product portfolio is based on our proprietary vector, A101, that was invented for efficient aerosol delivery to the lung. Specifically, we're pleased to share with you positive updates on 4D-710 program, including interim clinical data from our AERO clinical trial for participants with cystic fibrosis lung disease in patients not amenable to modulators. Given results to date in this population with the highest unmet need, we plan to continue developing 4D-710, both for patients who are amenable or not amenable to modulator therapy. Here are the key takeaways for today.
In cohort 1 of the AERO trial, we treated three participants with an aerosol dose of 1E15 vg of 4D-710. 4D-710 is designed for routine outpatient treatment via an FDA-approved aerosol device, enabling widespread delivery throughout the lung airways. We're enrolling participants with the most severe mutations, with the highest unmet need, who have no disease-modifying therapies available. Regarding safety and tolerability, 4D-710 was well tolerated, with no 4D-710-related adverse events following dosing, with follow-up of nine-12 months. For lung biomarker analyses, bronchoscopy was performed at four-eight weeks, and multiple airway biopsies were collected in each participant.
We observed widespread and reproducible CFTR protein expression in over 90% of airway cells in all samples, and at levels that were well above normal and highly statistically significant compared to controlled tissues from people with or without CF. Promising evidence of clinical activity was demonstrated by following spirometry and quality of life endpoints. One participant had a baseline percent predicted FEV1, or ppFEV1, of 69. This ppFEV1 is considered to be moderate CF lung disease. In this population, the historical annual rate of decline in ppFEV1 is roughly 2.5%. Following 4D-710 treatment, this participant's ppFEV1 showed a meaningful and sustained improvement of 7% over nine months of follow-up. Two participants with normal or mild impairment based on baseline ppFEV1 were maintained with stable disease over nine-12 months follow-up.
Critically, all three patients showed meaningful and sustained improvement in quality of life, as measured by the respiratory domain of the validated CFQR instrument. Quality of life increased by six to 22 points, which was well above the minimal clinically important difference for this instrument. Cystic fibrosis is caused by mutations that result in 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 thickened mucus, inflammation, frequent infections, and ultimately progressive respiratory failure. CF affects over 100,000 individuals in the world and approximately 40,000 individuals in the U.S.. Patients currently receive intensive and time-consuming daily airway clearance therapy, mucolytics, inhaled antibiotics, and bronchodilators. Twice-daily oral CFTR modulators can partially restore mutant CFTR function in people with CF who have eligible mutations.
The modulator market generated approximately $9 billion of sales in 2022. The market is growing. Our initial target population includes approximately 15% of all people with CF, including those who are not eligible for CFTR modulators or who are intolerant of modulators. Modulator side effects include neuropsychiatric and hypersensitivity disorders. Ultimately, with 4D-710, we believe we have the opportunity to potentially treat all people with CF, regardless of CFTR mutation status, both as a single agent and in combination with modulators. The field typically describes reduced CFTR function at two levels: minimal function, where little to no CFTR protein is at the cell surface and consequently no CFTR function is present, versus residual function, where there is some function of CFTR protein at the cell surface. Here we show the impact of the CFTR mutation and modulator treatment status on percent predicted FEV1.
In people with minimal function mutations, ppFEV1 declines approximately 75% more rapidly compared to those with residual function. Overall progression in ppFEV1 was assessed in a phase III study of ORKAMBI modulator treatment in patients with eligible mutations. Untreated patients declined at an average of 2.3 points versus 1.3 points per year for treated patients. Together, these results suggest that the initial target patient population for 4D-710 has lung disease that progresses rapidly, given the lack of disease-modifying therapies for them. Prior AAV gene therapy approaches in cystic fibrosis relied exclusively on a conventional AAV2 vector. In a 51 patient phase II clinical trial of aerosolized AAV2 carrying the CFTR transgene, safety was demonstrated. No transgene expression was observed within lung tissue samples. No benefit was demonstrated in terms of FEV1 or other lung-related endpoints.
The investigators noted that effective aerosol-delivered AAV vectors were clearly needed. We took a very different approach. Rather than relying on a nonspecific, naturally occurring AAV vector, we invented a novel synthetic AAV vector that was customized for efficient aerosol delivery to the lung. We used our Therapeutic Vector Evolution platform in non-human primates, or NHP, to invent our customized vector, A101. Our target vector profile for lung diseases included routine aerosol delivery at safe dose levels, penetration through the mucus barrier, resistance to antibodies present in the human population, and efficient transduction of multiple airway cell types. 4D-710 comprises our proprietary A101 vector, carrying a transgene payload with ubiquitous strong promoter upstream of the CFTRΔR transgene. This slide illustrates the strong performance of A101 and 4D-710 in preclinical models. In the top left, we show A101's strong resistance to human antibodies compared to wild-type AAV serotypes.
On the bottom left, we show 4D-710 as a high degree of specificity for NHP lungs after aerosol administration. On the right, we show the broad and widespread delivery and transduction with 4D-710 in NHP. Now for a brief summary of the payload in 4D-710. CFTRΔR is identical to the wild-type human CFTR gene, except for a targeted partial deletion in its regulatory domain. In various in vitro and in vivo models, the protein has shown comparable function and regulation to wild-type CFTR. CFTRΔR was highly effective in the pig model of CF lung disease, which mirrors the human disease. 4D-710-mediated CFTRΔR was able to generate dose-dependent CFTR functional activity that was equivalent to TRIKAFTA. These data give us confidence that this protein has potential to restore CFTR function in patients.
For delivery of 4D-710, we selected the commercially available AeroEclipse II Breath-Actuated Jet Nebulizer. This device generates stable and reproducible droplets that distribute evenly throughout the large and small airways, plus alveoli. I'd like to now hand the presentation over to Dr. Jennifer Taylor-Cousar, Primary Investigator for the trial, to present the trial and the data. Thanks for being with us today, Dr. Taylor-Cousar?
Thanks, David. The key objectives of the AERO phase I/II study are to assess the following: the safety, tolerability, and immunogenicity of a single nebulized dose of 4D-710, CFTR transgene delivery and expression throughout multiple regions of both lungs in participants, clinical activity over 12 months as determined by changes in spirometry, including ppFEV1, and quality of life assessments. Finally, to determine the recommended phase II dose. Inclusion criteria included adults with CF variants not amenable to CFTR modulator therapy or based on intolerance to CFTR modulator therapy. Overall, it is estimated that approximately 15% of people with CF fall into this subgroup. We therefore are treating participants with high unmet medical need on this trial. In this first-in-human trial, participants were required to have a baseline ppFEV1 of 50%-100% and resting oxygen saturations of 92% or higher.
Here is the design of the phase I/II AERO clinical trial. The phase I dose exploration phase is designed to assess two dose level cohorts, 1e15 and 2e15 vector genomes per participant as a single dose. In the study diagram below, you can see 4D-710 aerosol administration on day one. Pre-dose procedures include airway clearance technique, a nebulized bronchodilator called albuterol, and pre and post bronchodilator spirometry. Bronchoscopy is performed at weeks four to eight in order to collect multiple lung samples for assessment of transgene delivery and expression. Transient immunosuppression is given as a prednisone taper over four weeks, starting on day -1. Based on preclinical data, we believe that transgene expression can increase over eight to 12 weeks before stabilizing.
Today, we will share interim safety, lung tissue biomarker, and clinical activity data from all three cohort 1 participants. As of the data cutoff, participants have been on study for approximately nine to 12 months. This table shows key baseline characteristics of the three cohort 1 participants. Ages range from 20-36 years old. One participant was intolerant of modulators, while two had CFTR variants that were ineligible for modulators. Of note, these participants had mild to moderate CF lung disease, with percent predicted FEV1 of approximately 69%-95%. In the future, as we enroll participants in dose expansion, we anticipate enrollment of participants with more advanced lung disease. Moving on to safety and tolerability results to date. No DLTs or 4D-710-related adverse events were reported after completion of dosing administration. Dosing was well tolerated.
During aerosol administration, a single participant reported transient mild dry throat and fatigue. This slide shows serial spirometry and adverse events during the nebulization procedure for 4D-710. You can see, there were no significant declines in lung function or adverse events during the procedure. This slide illustrates the safety data that's demonstrated to date post-dosing of 4D-710, with no 4D-710-related AEs, SAEs, or DLTs. Let's consider the lung biomarker data. Here we outline the target expression profile we hope to achieve in this study. Historically, 10% or greater correction of overall CFTR function corrected the mucus layer in CF-derived monolayers. In people with CF, the presence of 15% or greater residual CFTR function correlates with less severe disease. Given historical data, we also aim to transduce at least 15% of target cells.
We aim to develop a product candidate that could achieve widespread, reproducible distribution throughout the airways, including all major epithelial cell types with resistance to pre-existing antibodies. Finally, the cells that were transduced, we aim to achieve protein expression levels at least equivalent to normal observed levels. This slide shows the post-dosing bronchoscopy sampling plan scheduled for week four, with flexibility to go up later, depending on participant status at day 28. Bronchoscopy was performed to collect numerous widespread lung tissue samples 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 in multiple regions. Biopsy samples were obtained for PCR, specifically for transgene DNA.
Both biopsy and brushing samples were obtained for in situ hybridization, or ISH, specifically for transgene RNA expression and immunohistochemistry, or IHC, for CFTR protein within biopsy samples. 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 orange, lung brushing locations are shown in the lower lobe bilaterally. As reported previously at the North American Cystic Fibrosis Conference in November 2022, this slide shows detailed biopsy data demonstrating widespread delivery and expression of the CFTR transgene product in all three participants' lungs. All five biopsies were positive.
In the bar graph on the right, the Y-axis shows the percent of cells positive for expression by ISH in each biopsy, determined by machine learning-assisted image analysis software. These data show reproducibility among the three participants and throughout the lungs bilaterally. The range of percent cell positivity was from 36% up to 47% in these participants, with a mean of 40%. We again show clear biodistribution of CFTR protein in lung samples. All samples were positive for protein, including in all major cell types and notably in basal cells, which are long-lived stem cells of the lung. Importantly, protein was localized to the apical membrane, which is the key interface between lung epithelial cells and the lung airway lumen. Observed CFTR levels were above those in normal controls. This slide describes our immunohistochemistry, or IHC methodology, for analyzing protein expression in tissue samples.
We use the Visiopharm machine to analyze samples based on the IHC intensity. The right images show samples from 4D-710 compared to representative controls from normal and CF lungs. You can see clear above normal CFTR expression in samples from 4D-710 treated lungs. Here we show the quantified CFTR protein data from the scheduled biopsies. As you can see, based both on percent positive and intensity based on H-score, CFTR levels were significantly above that observed in normal and CF controls, with P values all less than 0.01. Controls included commercially available CF and normal lung control samples. Here are additional images demonstrating the cell types producing and the apical localization of the protein in one, basal cells, two, goblet cells, and three, columnar ciliated cells. Here we show our program objectives in terms of target expression profile.
In summary, we're encouraged to see that we achieved all of our target expression profile objectives for 4D-710. We believe that reproducible, consistent distribution and transgene expression above normal levels in airways should ultimately translate into benefit for people with CF. We'll now discuss the observed in vitro expression translated to clinical activity endpoints. 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 is 2.3% per year, with intra-subject variability of approximately 4.5 percentage points. This data suggests that a change greater than 4.5 points in an individual participant could be considered meaningful.
Participants 1 and 3 had percent predicted FEV1 values that were in the mild to normal range at baseline. In such participants, marked improvements in percent predicted FEV1 may be less likely, but stability over this timeframe would be clinically meaningful, particularly in a group of people without options for any currently approved disease-modifying therapies. As we demonstrate here, for nine to 12 months after a single aerosolized dose of 4D-710, both participants' percent predicted FEV1 values remained stable. Considering participant 2, who had a minimal function mutation and started with moderate impairment at baseline FEV1 of 69%, we were encouraged to see a clinically meaningful improvement of seven percentage points through nine months. The participant had two viral infections, but no pulmonary exacerbations to date. In approving new therapies, the FDA considers how a new therapy makes a patient feel, function, and survive.
Thus, the FDA considers improvements in quality of life when approving new therapies. In people with CF, we measure quality of life by the CF Questionnaire-Revised respiratory domain scale, or CFQR. The validated minimally clinically important difference is four points. Historical data from the placebo arm of a modulator trial shows the untreated CF participants can experience an annual rate of decline of approximately four points. The CFQR instrument is validated for patient-reported outcomes and recognized by the FDA as a meaningful clinical efficacy endpoint, supportive of product approvals with strong reliability, validity, and responsiveness to changes in disease. In the graph, you can see a pivotal study of approximately 150 participants taking Ivacaftor, the first approved modulator therapy for a small proportion of people with CF. The mean change from baseline at week 48 was +6 for treatment and -4 for placebo.
Considering response in our participants, we plotted out CFQR scores over time. Respiratory-related adverse events such as exacerbation or viral infections, which can significantly affect measurements, are indicated in gray. When considering the evaluable results, the maximum changes were all significantly above the minimally clinically important difference of four points. Maximal changes per participant ranged from +6 to +11 to +22. These highly encouraging data suggest that participants are experiencing benefits in their day-to-day quality of life. To summarize, in contrast to historical data showing deterioration over time in the natural course of CF, 4D-710 participants experienced stable or improved percent predicted FEV1 measurements, and all participants had clinically meaningful quality of life improvements. We believe this data is very encouraging, early evidence of clinical activity for a single aerosolized dose of 4D-710.
This slide summarizes all results for participant 2, who had moderate CF lung disease at baseline and most significant improvement on clinical activity measures. In this participant, we demonstrated widespread high-level CFTR protein expression, improved percent predicted FEV1, and improved quality of life by 22 points. For full review of this data, the presentation is available on the 4DMT website. This slide again summarizes all biomarker and clinical activity data we described previously. Now I'd like to hand the presentation back over to David.
Thank you, Dr. Taylor-Cousar. To summarize the data presented today, we enrolled three CF participants who had no available disease-modifying therapies, and we treated them with a single aerosolized dose of 4D-710 at 1E15 vg. 4D-710 was well tolerated, with no related AEs, DLTs, or SAEs after dosing. All 11 lung samples collected were positive for CFTR protein expression by IHC. 92%-99% of cells were positive. These values were highly statistically significant compared to control samples from people with or without CF. All major cell types, including ciliated, goblet, and basal cells, expressed CFTR protein, and correct localization of the apical membrane was observed. In terms of clinical activity, we saw clinically meaningful improved percent predicted FEV1 in the participant with moderate impairment at baseline and stable percent predicted FEV1 in the two participants with normal and mild impairment at baseline.
Historical data suggests these participants would otherwise have seen a decline of over two percentage points annually. In terms of quality of life, all three patients had clinically meaningful improvements, with increases of six to 22 points. Participants had quality of life improvements above the minimal clinically important difference at six of seven evaluable time points. Historical data suggests these participants would have otherwise had a decline of around four points. We're highly encouraged by these data, and we're excited to discuss our planned next steps to rapidly advance the 4D-710 program. Today, we shared interim cohort 1 data, and we're looking forward to present cohort 2 data for the high dose of 2E15 vg, which we expect will be at the North American Cystic Fibrosis Conference in November of 2023.
We expect to select the optimal dose for expansion in the phase II stage of the AERO trial in the H2 of this year. We expect to bring the totality of this data to the FDA in Q4 to discuss our pivotal trial design, including proposed approvable endpoints. Finally, we expect to provide a development plan update on studying 4D-710 in combination with modulators in Q4. Before we move into Q&A, I'd first like to acknowledge and thank our trial participants and their families, our principal investigators and study staff, and the Cystic Fibrosis Foundation Therapeutic Development Network. In addition, I'd like to thank the CFF for their unwavering support for this program and for 4DMT as a company. Operator?
At this time, if you would like to ask a question, please press star, followed by the number one on your telephone keypad. If you would like to withdraw your question, again, press star one. Thank you. Your first question comes from the line of Salveen Richter with Goldman Sachs. Your line is open.
Good afternoon. Thanks for taking my question. Two questions for me. One is, could you provide more detail on patient 3's respiratory-related AE? Secondly, just given the differences in gene therapy and CFTR modulator mechanisms, how would you envision the design of a pivotal trial? Could you use these two endpoints, or are you exploring other measures? If I could add to that, could you just speak to the validity and how you could reproduce the quality of life data, given the single-arm design? Thank you.
Well, thank you, Salveen . It's great to have you on the call today. Thanks for the question. In terms of the AEs, you know, there were no 4D-710-related adverse events whatsoever. I think you might be referring to the pulmonary exacerbations in patient 3, which are very common in these patients, and Dr. Taylor-Cousar can speak to. In terms of pivotal endpoints, you know, we're very, very excited about the quality of life improvements as well as the potential to improve FEV1. Why don't I turn these questions over to Dr. Taylor-Cousar to expand?
Hey, David. Sorry, I was off the line for a second. Could you repeat the question?
Oh, no worries. No worries. I think, yeah, Salveen was asking about the pulmonary exacerbations in patient 3, and, you know, are those typical, and can we describe those? You know, pivotal trial endpoints for the patients with, you know, this high-end medical needs who are not amenable to modulators.
Sure. Particularly over the last year, it has been an incredibly hard viral season for people with CF because, of course, everybody was masking, and then all of a sudden, everybody was not masking. We saw a huge increase exacerbations over this last year, because about a third of exacerbations in people with CF, both adults and kids, are triggered by viral infections. I think that's very typical, particularly given the last viral season. In terms of the endpoints, I'm personally ecstatic. I have a group of people who do not have access to modulators because of either intolerance or ineligibility, and I think a medicine like this that could stabilize or improve their lung function and improve their quality of life so much is really critical.
They are suffering right now, not just because they don't have a modulator, but because they know their colleagues and their friends and other people have it, and it's very hard on them emotionally. The fact that there is some very positive data from this trial is incredibly encouraging.
Thank you.
Sure.
Your next question comes from the line of Kostas Biliouris with BMO Capital Markets. Your line is open.
Hello, everyone. Thanks for taking my question and congratulations on the data. A couple of questions from me. You mentioned that 40%+ of the epithelial cells were positive in the lung biopsies, and then your target product profile would be 15% of the cells being transduced. I know this 15% probably refers to all cells, but is there any way for you to quantify to what extent you meet this 15% of cells being transduced in this first dose? What would you expect in the next dose? Thank you. I have a follow-up.
Well, thanks, Kostas, and yeah, appreciate the congratulations. We're very excited as well. Going into this, you know, the concept, you know, historically is if you look at CFTR lung function of about 15% or higher, despite the mutation in CFTR, those patients have much less severe disease. You're right that that 15% probably across all cells as opposed to 15% of cells. But that is directionally, you know, gave us a target. Now, we hit 40% on ISH, which is very specific for the transgene payload, but we know that that's not very sensitive because there's only typically a few transcripts per cell. What's more important here is that we had, you know, 92%-99% of cells staining positively by CFTR protein, by IHC.
That, you know, that's done by a, you know, an objective Visiopharm machine learning assisted analysis. That's incredibly rigorous. We saw a very high, you know, statistical significance, 0.001 or less, on both the percent to cells staining and also the intensity of staining for the protein. You know, I'd say we kind of blew right through that 15% target, and we hit over 90%. You know, we're seeing, you know, a well above normal levels per cell. I think in terms of a biomarker, you know, this is a home run.
You know, no one had shown expression in the lung, meaningfully ever before. Here at the very first dose level, we're seeing over 90% of cells expressing and expressing well, statistically above normal samples and CF samples.
Great. Thank you.
[crosstalk]
Oh.
Go ahead.
I was just gonna add that it wasn't just. It was across cell types as well, which I think is really important. I mean, again, as David said, this is the first time we've ever shown this transduction in the lower airways. We don't know exactly which cell types need to have it, but we saw it across cell types. I think that's important to note.
Thank you, Jen.
Thank you. Thank you. Maybe one more question on participant 3. They had neutralizing antibodies, moderate levels of neutralizing antibodies. Did you see anything that can help you understand whether you could potentially redose here with the gene therapy? First question. The second question is, this patient seems quite normal, and I'm wondering whether you would expect more patients like them to take the gene therapy in the commercial setting, because it seems that their FEV1 function is normal, and they're still opting for a gene therapy, which is somewhat risky. I'm wondering what your thoughts are around that. Thank you.
Thank you, Kostas. I'll answer the first one and then turn over to Jen for the second one. In terms of antibodies, you know, we did have data from primates to say that despite, you know, cross-reacting antibodies from other AAVs that are very common in primates, actually, you know, we did see some cross neutralization there in the assay in the blood, but we saw no impact on our ability to deliver by the airway. I think a lot of that has to do with the very high concentration of vector in each droplet, and then these droplets are essentially little protected droplets of fluid that then get distributed out the airway and then just need to go straight through the mucus to the target cell.
We have not preclinically seen any relationship between transduction and antibody titers, and we're thrilled to see here, you know, two of our three patients had some antibodies, you know, low and moderate, in the blood, you know, from cross-reacting from other AAVs out in the environment, and we saw no impact on transduction. We're, you know, we're thrilled, and we do think that that means that, you know, redosing likely is a possibility. We don't know if and when we're gonna need to redose. It may be, you know, anywhere from three to five years out based on the turnover of the mouse lung. We do think this is evidence that we almost certainly can redose if we need to. We're, we're thrilled. Thanks for the question.
Jen, over to you about the, you know, the question of how, you know, a participant comes on a study like this with 95% FEV1, and how you see that evolving over time.
Yeah, no, it's a great question. I think that the short answer is that to maintain that lung function of 83 or 95, those people are doing a lot of work every day. They're taking aerosol therapy, albuterol, for example, inhaled antibiotics, mucolytics for hours a day, twice a day, at least when they're well. Even though their lung function looks relatively preserved, it's at a big cost to them on a daily basis. They know that they're at risk at any time of having an exacerbation during which they don't recover to their baseline lung function.
About 25% of the time, people don't make it back to their baseline. I would say that, yes, people who aren't eligible for modulators would most definitely, even with mild lung dysfunction, want this therapy if they felt that it was safe and that it worked. Over time, as more data like this comes out, more people who have more moderate to severe disease are going to be willing to be in trials. Some of them may have been a little bit nervous about a new inhaled therapy in the fact that they had lower lung function, but I think both themselves and their doctors will be more confident in seeing this data in allowing them both to participate in the trial and get the therapy down the line if it were ever approved.
Great. Thank you so much, and, congratulations again.
Thanks, Kostas.
Your next question comes from the line of Nalin Tejavibulya with Jefferies. Your line is open.
Hi, congratulations on progress, and thank you very much for taking my questions. I have two, please. With CFTR expression seen in multiple cell types, you know, basal cells, goblet cells, and affiliated columnar cells, could you please talk about the implied durability, you know, what the implied durability would be for this therapy based on the lung cell turnover for cystic fibrosis patients before you observe loss of clinical meaningful efficacy? Thank you.
Thank you, Nalin, for the question and for attending today. You know, I'll sort of give my perspective and then turn it over to Jen. You know, as you correctly point out, we hit multiple cell types, which we think is a great idea, you know, great outcome, because again, no one knows really which cell types are preferred for expression or whether there's a benefit in expressing in all cell types. Certainly, we're thrilled to hit the basal cells, which Jen can speak to, are the, you know, the stem cells of the lung and should be relatively long-lived in the lung compared to other cell types.
In terms of the turnover lung, you know, the only data I'm aware of is in mouse, and that looks like it's about a year and a half, so maybe humans are three to five years. You know, whether that's different in a CF patient, you know, we don't know. I'll turn it over to Jen to answer that question and also comment on the basal cells.
Yeah, I think we are thrilled to see it in basal cells just for the reason that David stated. We think that it means it's going to be longer lasting. I will just reiterate that we don't know what the answer is. We don't know what the turnover rate of stem cells is in the lung in people with CF. You know, obviously the mouse doesn't develop CF lung disease spontaneously, even when you induce CFTR mutations. The mouse model may give us a little clue, as David said. I don't think that we know the answer again, because this is groundbreaking. It hasn't been seen before, part of it will be actually rebiopsying some of these patients later in time.
Got it. As a follow-up, sorry, second question. Regarding the use of 4D-710 in combination with CFTR modulators, what does the, you know, percentage predicted FEV1 shown here mean for those who are eligible for CFTR modulators, and what can we realistically expect from combination therapy in terms of FEV1 improvement? Thank you very much.
Thanks, Nalin. I'll answer the biological question, and Jen can answer in terms of the clinical outcomes. you know, biologically, we think there's a real chance for synergy here. The reason we say that is, with an effective modulator treatment, the mucus should be thinned. Therefore, we should get even better transduction, you know, potentially even at lower doses. That could give us an advantage in those patients. it's likely that, you know, many of these modulators will also bind our CFTR because, with the exception of a small regulatory region, you know, the ion channel is identical. you know, we may get a direct benefit from the modulators on our transgene as well. you know, we're excited about the combination there, and I'll let Jen speak to FEV1.
I think that, you know, it's really important to realize that although TRIKAFTA on average improve lung function by 10%, there's a wide range. If you go back and look at the Middleton paper, you can see that there is a very wide range of how much lung function improvement people saw. Particularly those people who didn't see a lot of lung function improvement, I think there is a possibility of seeing a combination effect with 4D therapy.
Any conjecture on what kind of range we might potentially be able to expect realistically?
Honestly, with only three people so far, that we've got these long-term data on, it would be just a guess. I mean, in vitro, the HBE model has been very predictive, so it's a possibility that we could study that in vitro and then make a better guess. Right now, with only three participants, it would be hard to say on average what that might be.
Understood. Thank you very much.
Your next question comes from the line of Tazeen Ahmad with Bank of America. Your line is open.
Hi, good afternoon, guys. Thanks for taking my questions. Maybe just a follow-up on CFTR modulators. Dr. Taylor-Cousar, a question for you. What would you think would be an ideal trial design here? Because it didn't include any patients that were on CFTR modulators. Do you think it would be wise to perhaps stratify by patients on and off modulators as part of that phase II? Maybe a question for David. In terms of the November data update, approximately how many patients are in cohort 2, and would we also be seeing follow-up data from the patients that you've already shown us today? Thanks.
Thanks, Tazeen, thanks for being here today. We appreciate the questions. I'll answer the first one, then turn it over to Dr. Taylor-Cousar. You know, we're not disclosing the exact number of patients we have on cohort 2. You know, we'll definitely update the totality of the data for cohort 1 and cohort 2, including additional follow-up from these patients at the November meeting, and I'm sure Dr. Taylor-Cousar will be making that presentation. We look forward to that. I'll turn it over to Jen to answer the second question.
Yeah, it's a great question. I mean, I think that we need to first figure out what our dose is going to be, obviously, between the two cohorts and make that decision once we have sufficient data to determine that, both in terms of safety and efficacy. Ultimately, I do think that we want to include people in the phase II, expanded phase II, with those who are on modulators. Yes, like, stratifying them to those who are on and those who are off modulators will be important in terms of looking at the outcomes. Again, we may be able to look at some pre-clinical data before that to help us make some of those decisions.
Okay, thanks. Maybe just one follow-up question. Just on FEV1, just clinical meaningfulness, how do you define that? For the two patients so far that were stable, do you consider that clinically meaningful? I know that in general, patients will deteriorate that average of two to 2.3 percentage points per year, but would you want to see something better than stable, ideally, or is that good enough?
You know, I liken this back to the ORKAMBI data. When ORKAMBI was approved, some people questioned about why it was approved, and it was really critical at that point because those patients had no therapy whatsoever that was disease-modifying. In people with CF, stability is a huge goal for a lot of people. Improvement is ultimately what we would like to see for every single person, but in some people, stability is a big change. Also, these improvements in quality of life we are seeing are higher than what we saw with ORKAMBI , and that's also critical because people are trying to go to school and go to work and have their lives.
Making them stable and have a much better quality of life is something that we consider important, and the FDA has said that they consider important, again, how they feel, function, and survive . I think it's clinically meaningful when someone doesn't have to go to the hospital or do less therapies and that they feel much better.
Okay. Thank you.
Thanks, Jen. Just, you know, I've learned this from talking to you, is that, you know, I think some of those ORKAMBI patients just sort of, depending on the mutation, might be even 2%-4% improvement, and that was enough in FEV1, and that was enough to get it approved. You know, especially with the quality of life associated with it can be quite small differences or even stable disease. Thanks for the question.
Absolutely.
Appreciate it.
Your next question comes from the line of Mani Foroohar with SVB Securities. Your line is open.
Hey, thanks for taking my question. I'm trying to project how to think about this in future studies. Obviously, this is certainly impressive evidence on delivery, expression, et cetera, but the clinical endpoints in question are highly variable in the case of FEV1, and subject to placebo effect, and other various sources of variability and quality of life. Would it be reasonable to expect a placebo-controlled trial in the future to control for these things? Practically speaking, how does one really build a placebo-controlled trial on top of TRIKAFTA, presumably, given the sort of narrower gap in terms of what's available in terms of FEV1 improvement?
If you can help me just think about design of a potential pivotal study, size and potential powering, or when you're talking about an effect size that starts to get narrowed as you get close to normal, et cetera.
Thanks, Mani, for the question, and thanks for being here. You know, maybe I'll answer this and also Dr. Taylor-Cousar can weigh in as well. I, you know, I think what's very heartening to us is that in other randomized studies, looks such as the ORKAMBI study, where they looked at the quality of life outcome, it actually went down and stayed down. It was down by about four points, whereas ORKAMBI gave us a +6. Here we have a +6, a +11, and a +22, and six out of seven data points actually showed that. You know, to us, that's meaningful, you know, given the lack of a placebo effect in other trials. That's a great question.
I think that Jen can comment on, you know, the possibility in these patients of doing a single-arm study for a pivotal trial approval, perhaps with, you know, accelerated approval, and then what a combination randomized trial might look like.
Yeah, yeah, I agree totally with you, David, about the placebo effect and quality of life. Like, we just don't see that in the CF trials. In the CF trials that have been done to date, the people who are in the placebo arm do go down with their quality of life. In terms of looking forward, I mean, I think it's gonna partly depend on what the regulators decide, because we are, again, as I said before, breaking new territory.
In terms of including people with TRIKAFTA, I think that we probably would wanna initially include those who didn't have a 30% lung function improvement, for example, and including those people who had 0%-5% improvement, because then that end that you're talking about wouldn't need to be quite the same as if we're not looking for somebody who may only go up 1% or not at all or just stay stable versus somebody who didn't have a huge TRIKAFTA response and has more room for improvement.
That's helpful. Given the relatively good safety profile, how do you think about dose selection? Are you dosing to a target efficacy profile? If you're dosing until you see a safety issue, that can take a very, very long time, given how safe the construct looks at this level.
Yeah. Well, we're thrilled with the safety to date. You know, we need to follow the patients at the higher dose level, 2x higher, and see what that looks like. You know, I think Jen and the rest of the experts will sit down and look at the totality of the data and ask the question, you know, Which of these two dose levels do we prefer to proceed? I'll turn it over to Jen for a commentary on that.
I agree, especially given the expression label data that we're seeing now with the lower dose. I think it really is gonna depend on what the safety looks like between the two doses to make a decision. I don't anticipate that there'll be multiple higher doses that we'll need to look at, given the expression that we're seeing, even at the lowest dose.
Okay, that's helpful. Thanks, guys, and congrats again.
Thank you, Mani.
Your next question comes from the line of Josh Schimmer with Evercore. Your line is open.
Hey, thanks for taking the question, congrats on the update. For the patient who had moderate FEV1 decline at baseline, they seem to have a very robust and near normalization of their quality-of-life scores. The FEV1 improvement in that patient was good but still not normalized. How do we think about the ceiling effect of FEV1 and why that patient might not have, you know, despite very robust uptake of the product, not had a stronger FEV1 signal, perhaps commensurate with the quality-of-life benefit? Second, would you consider evaluating a lower dose in addition to a higher dose?
Well, thanks, Josh, for the question. Thanks for being here. I'll turn that over to Jen.
Yeah, in terms of quality of life and the ceiling effect of FEV1, it is so variable between people with CF. You can have a huge improvement in lung function and lower than what we saw in this trial, improvement in quality of life and vice versa. I think that's very hard to say from participant to participant. I don't know that we've seen a ceiling effect. I mean, certainly with the modulator trials, we have seen people continue to slightly go up over time, as probably the mucus plugging continues to clear, and they have less exacerbations. I don't know that we've seen where this lung function improvement can go, but certainly we can see a disconnect between what happens with quality of life and lung function. They don't always exactly parallel each other.
In terms of going down to a lower dose, I don't know that we've seen at this point in these three people, we haven't seen any safety signals that suggest that we should be going down, and we're pretty happy with where we are with the expression. Again, we're seeing some improvement in somebody with more moderate disease and stabilization in people who have more mild disease. I don't think we've seen an indication that suggests that we need to go to a lower dose. I don't know, David, if you wanna add to that?
No, I think that's spot on. I think, you know, we're thrilled with the safety to date and the transduction and the quality- of- life benefits, yeah. Time will tell. Certainly, as you said, Jen, no indication we need to go up on dose, doses higher than the 2x that we're current, you know, in cohort 2. Sorry, Josh, go ahead.
Yeah, no, I just wanna probe a little bit further on a potential ceiling effect in an individual patient and, you know, why there may be FEV1 function that, you know, in this type of a patient, that just cannot be recovered. Does it reflect scarring or other features of the disease that just may be irreversible, or does it imply that there is an ongoing disease process that has not been fully corrected by the gene therapy?
Yeah, great point.
I see what you're saying, yeah.
That's one for you, Jen.
Yeah. Even... You know, if you go and look, so of course, during the modulator trials, we excluded people who had lung function that was less than 40% in those original trials, and then subsequently, we went and looked in people who had lung function that was less than 40%. Certainly, we did not see 14%, 15% improvement in those folks. Improvements were much lower, so there is some degree of irreversibility for some of these people. Again, on an individual basis, we can't predict who those people are going to be. Certainly, when you have established disease, some degree of it will be irreversible. I mean, that's part of the reason, like, all of us who are adult CF doctors know that we're gonna, unfortunately or fortunately, continue to have jobs even though we have the modulators right now.
If we had some therapy like this, we'd still have jobs because there is going to be some degree of irreversible damage in people who have had long-standing infection and bronchiectasis. We see that now, so even if you're on TRIKAFTA, you can still have pulmonary exacerbations, for example. I think part of that is just irreversibility in some degree for each person, and we can't predict that per person at this point.
Okay, got it. Very helpful. Thank you.
There are no further questions at this time. I'll turn the call back to Dr. David Kirn for closing remarks.
Well, thank you, so much, everyone, for your time and attention today, and thank you again to Dr. Taylor-Cousar for being here with us today. We really appreciate your expertise and dedication to this trial. Thanks again to all the patients, the families, and the sites, and once again to the Cystic Fibrosis Foundation, who've been just phenomenal partners, scientifically and clinically, with us throughout this journey. Thanks, everyone. Have a great day.
This concludes today's conference call. Thank you for joining. You may now disconnect.