Thank you for standing by, and welcome to Krystal Biotech's clinical update call for Cystic Fibrosis Program KB407. At this time, all participants are in a listen-only mode. After the speakers' presentations, there will be a question-and-answer session. During the question-and-answer session, there will be a limit of two questions per participant. As a reminder, today's conference is being recorded. I would now like to hand the conference over to your host, Stéphane Paquette, Vice President of Corporate Development.
Good afternoon, and thank you all for joining today's call. Earlier today, we announced positive interim clinical results for Krystal Biotech's Cystic Fibrosis Program KB407, including molecular confirmation of wild-type CFTR protein expression in patients' lungs. The press release is available on our website at www.krystalbio.com. Both the press release and today's presentation have also been filed as an 8-K with the SEC. Joining me today will be: Krish Krishnan, Chairman and Chief Executive Officer; Suma Krishnan, President of Research and Development; Trevor Perry, Vice President of Product Development; David Sweet, Director of Clinical Development; and Dr. Jorge Lascano, Professor of Medicine, Associate Director of the Adult Cystic Fibrosis Program and Director of the Cystic Fibrosis Therapeutics Development Center at the University of Florida. This conference call will, and our responses to questions may, contain forward-looking statements.
You are cautioned not to rely on these forward-looking statements, which are based on current expectations using the information available as of the date of this call and are subject to certain risks and uncertainties that may cause the company's actual results to differ materially from those projected. A description of these risks, uncertainties, and other factors can be found in our SEC filings. The agenda for today's call is outlined here. Krish will provide a few remarks to open the call, after which Dr. Lascano will share his perspectives as a practicing clinician and thought leader on the unmet need that remains among cystic fibrosis patients unable to benefit from modulator therapies. Suma will then provide an overview of our lung delivery platform and the potential of our KB407 program to fill this treatment gap.
David Sweet, clinical lead for our KB407 program, will walk us through today's clinical update and confirmation of CFTR delivery to patients' lungs. Suma and Krish will close the call with an overview of next steps for the program and Krystal. Trevor Perry, our Head of Product Development, will join all speakers in the Q&A session. With that, I will turn the call over to Krish.
Thank you, Stéphane. Good afternoon, everyone, or welcome to the call. We are very excited to share a long-awaited milestone for our Cystic Fibrosis Program today. We have now confirmed the successful delivery and expression of wild-type CFTR protein in multiple patients with cystic fibrosis, a breakthrough for the field made possible by the unique attributes of our HSV-1 platform. With the wild-type payload and already confirmed functionality in multiple preclinical models, today's readout gives us a conviction to move rapidly into repeat dosing. We're working closely with the Cystic Fibrosis Foundation to initiate repeat dosing before mid-year. Thanks to the FDA's familiarity with our HSV-1 platform, we also believe there is an opportunity to accelerate development of KB407 towards a potential approval. As Suma will share, we are discussing study designs with the Cystic Fibrosis Foundation and the FDA to make the repeat dosing study registrational.
Our urgency is driven by the clear unmet need that exists among patients with cystic fibrosis. We estimate that the number of patients ineligible or otherwise underserved by modulators is in the tens of thousands. Dr. Lascano will expand on the burden these patients face in the absence of corrective therapy. I will also take this opportunity to flag the platform implications of today's readout. The lungs of patients with cystic fibrosis are widely regarded as some of the most difficult to access with a nebulized therapy. Successful delivery with KB407, combined with prior clinical evidence from our Alpha-1 antitrypsin program, KB408, and the lung cancer program, KB707, underscored the tremendous potential of HSV-1 for the treatment of a wide range of lung diseases. With that, I'll hand it off to Dr. Lascano to share his perspectives on the urgent unmet need that exists among modulator-ineligible patients with CF. Dr. Lascano?
Hi, good afternoon. My name is Jorge Lascano. I'm a Professor of Medicine at the University of Florida. I'm also the Associate Director for the Adult Cystic Fibrosis Program and the Director of the Cystic Fibrosis Therapeutic Development Center at UF. Thank you for the opportunity to speak today. I'm a pulmonologist by training. I have spent most of my career taking care of individuals with cystic fibrosis. My role today is to provide some clinical context on why, despite all the tremendous advance in the care of CF patients, there still remains a persistent unmet medical need. Over the next few minutes, I'll briefly review how CF treatment has evolved during the modulator therapy era and identify the population that has not benefited from these therapies. I will also discuss why nucleic acid-based approaches, despite some historical challenges, continue to remain clinically relevant today.
My comments are generally based on published data, data from the registry, and clinical experience, and they're intended to frame the importance of the work that you will hear about shortly. Next slide. To begin, let me acknowledge the importance and how transformative CFTR modulators have been for many patients with CF. Data from various strong clinical trials have shown how sustained improvement in terms of lung function, reduction in pulmonary exacerbations, improving nutritional status, and increased survival, all these in patients who are eligible for highly effective modulator therapy. From a clinical perspective, the modulator era has literally changed the expectations for many of our patients. Individuals who previously experienced lung function decline, repeated exacerbations, have now maintained or even improved their health status, including their pulmonary status, over time. However, there's still a subset of patients for which modulator therapy really has not been beneficial. Next slide.
Despite the success of modulators, at least 10%, if not more, individuals with cystic fibrosis either cannot receive or cannot tolerate modulator therapy. So this population includes patients with rare or minimal function mutations, such as nonsense mutations, that do not produce CFTR protein. And even if they are or they have mutations that are receptive to this therapy, some patients just don't get the meaningful benefit that other patients do. Next slide. So for patients who do not benefit from CFTR modulators, the clinical burden of CF remains substantial. Registry data shows continuous decline in lung function, higher rates of pulmonary exacerbations, and persistent chronic airway infection in this group. Many continue to require hospitalizations, prolonged antibiotics exposure, and intensive daily therapies. Importantly, these patients do not share the same survival gain in modulator treatment populations.
In clinical practice, this translates into early considerations for lung transplant and ongoing uncertainty regarding long-term outcomes. From a patient perspective, this group of patients experience high treatment burden with limited disease-modifying benefit and experience the contrast sharply with the progress seen elsewhere in the CF community. In general terms, these patients feel that they have been left behind. Next slide. Cystic fibrosis is fundamentally a monogenic disease caused by a defect in the CFTR gene. CFTR modulators work by improving the trafficking of the function of certain mutant protein, but they cannot address all mutation classes. For example, for mutations that do not produce a functional CFTR protein, alternative strategies are required to address these issues. Nucleic acid-based approaches offer the theoretical advantage of addressing the disease upstream from protein dysfunction.
Importantly, this strategy has the potential to be mutation-agnostic, which is particularly relevant for patients with rare or previously unaddressed genotypes. Next slide. Gene-based nucleic acid therapy for cystic fibrosis is not a new concept, and it's important to recognize that many efforts did not result in clinically meaningful benefit. Prior programs encountered several well-documented challenges. This included difficulty delivering therapeutic material through thick infected airway mucus, limited transduction of the airway epithelium, vector cargo limitations given the size of a full-length CFTR, and immune responses that limit the ability to repeat dosing. That said, these efforts were not failures in the scientific sense. They generally allow us to learn more, give us critical insight into the airway biology, vector design, delivery routes, and clinical trial methodology. Much of what the field understands today about what does not work in CF gene therapy really came directly from these previous programs.
Next slide. The unmet medical needs for patients who do not benefit from modulators remain unchanged. At the same time, the broader field of gene therapy has evolved considerably. Advances in vector engineering, manufacturing, scaling, and our understanding of pulmonary biology have altered the landscape compared with early attempts. From a clinical perspective, the question is no longer whether alternative disease-modifying therapies are needed for cystic fibrosis, but how the lessons learned over the past several decades can be applied to develop approaches that are safe, effective, and durable. With that context in mind, I will now turn things over to the Krystal team to discuss their gene therapy program and share an update on their progress.
Thank you, Dr. Lascano, and good afternoon, everyone. I'm very happy to be sharing today's update, which we believe significantly de-risked our KB407 program for the treatment of cystic fibrosis. As Dr. Lascano just touched on, the lung has been a difficult tissue to target with gene therapy. Many gene delivery modalities are not amenable to nebulization, and if they are, they must contend with multiple barriers which may limit access to target epithelial cells. Then there is the issue of cell turnover requiring the ability to repeat dose. Finally, in the case of cystic fibrosis, there is the additional challenge of large genetic cargo.
We have long believed that our clinically validated HSV-1 vector, already FDA-approved and shown to be safe, effective, and suitable for repeat dosing of patients with dystrophic epidermolysis bullosa, has broader potential as a gene delivery solution for other high turnover epithelial tissues, including the lung. This belief has only been strengthened with the recent clinical readouts and evidence of successful gene delivery with KB408 and KB707 in patients with Alpha-1 antitrypsin deficiency and lung cancer, respectively. With today's readout, we have now also demonstrated successful gene delivery with KB407 in our patients with cystic fibrosis. Delivery to a cystic fibrosis lung is the highest potential bar for our platform and a critical step towards our goal of bringing the first mutation-agnostic therapy to patients with cystic fibrosis.
As a brief introduction, KB407 is our inhaled genetic medicine designed to deliver two copies of the full-length CFTR gene through the lung and thereby restore CFTR-mediated ion transport, mucus clearance, and lung function. The program is supported by a robust preclinical data package in which we have shown across a variety of models that KB407 efficiently transduces clinically relevant cell populations. KB407 encoded CFTR is full-length, properly localized, and functional, and as demonstrated in our GLP enabling toxicology studies in NHPs, KB407 is amenable to nebulization, well tolerated, and broadly distributed in the airways with payload expression persisting for at least 28 days. We saw no notable toxicity in our NHPs studies and did not reach an adverse dose, underscoring the attractive safety profile of our HSV-1 platform.
Collectively, these data provided clear support for progression of KB407 into the clinic and, more recently, sanctioning of our phase 1 study protocol from the CFF TDN. I will now hand it off to our KB407 clinical lead, David Sweet, to walk through our CORAL-1 phase study design and today's data update. David.
Thank you, Suma. The Phase I CORAL-1 study was designed to evaluate preliminary safety and tolerability of ascending doses of nebulized KB407. Cohort 3 also assessed molecular correction by the highest KB407 dose. The study schematic is provided on the right. We provided a safety update for Cohorts 1 and 2 previously. KB407 was well tolerated by all patients dosed in those first two cohorts. Today's update is focused on safety and molecular assessments from patients in cohort 3. The key enrollment criteria for cohort 3 included adults with a confirmed diagnosis of CF, a lung function of 40%-100% as assessed by percent predicted forced expiratory volume in one second, or ppFEV1, and no more than three patients in this cohort being on concurrent modulator therapy.
Patients received 10^9 plaque-forming units of KB407 via nebulization once daily for four consecutive days and then underwent a post-dose bronchoscopy one to four days after last KB407 exposure. Endobronchial biopsies were examined for any aberrant histological features as well as to establish evidence of vector transduction and consequent molecular correction via immunofluorescence detection of a viral marker and/or human CFTR protein where feasible. Patients were then followed for eight weeks, and samples were collected for vector shedding and immunogenicity analyses. Seven patients were ultimately dosed with KB407 as part of Cohort 3 and had post-dose bronchoscopy performed, six of which were successful, meaning the bronchoscopy yielded biopsy samples containing suitable airway histological features that allowed for substantive molecular analysis. The demographics of all seven patients are shown here. Three of the seven were modulator-eligible.
Lung function, as assessed by spirometry, ranged from 45%-82% across patients. Endobronchial biopsies were collected from the left and right lungs of each patient, with clinical sites required to collect at least four and up to ten biopsies, if tolerated by the patient during the procedure. As noted previously, bronchoscopies were conducted 24-96 hours after the last dose of KB407, allowing for flexibility to account for availability of a bronchoscopy suite and scheduling for both the physician and the patient. Biopsies were then immediately preserved in paraformaldehyde and shipped to Krystal, where they were embedded in paraffin, sectioned, and stained as appropriate. For patients without confounding endogenous CFTR expression, in other words, patients with Class I mutations, biopsies were stained to detect exogenous CFTR.
The remaining patients were assessed for successful vector delivery to the airways via immunofluorescence detection of a viral marker, ICP27, which is expressed from KB407's backbone soon after cellular transduction. The key readout for this interim analysis was the percentage and distribution of KB407 transduced conducting airway cells based on expression of full-length human CFTR where possible or expression of the viral marker. Here, we see representative CFTR protein staining via immunofluorescence in airway biopsies harvested from a healthy donor and a patient with CF harboring G542X homozygous mutations, serving as positive and negative controls, respectively, for the study. The positive control biopsy was procured commercially while the CF Foundation provided the sample used as the negative control. Additionally, the protein staining was conducted using the CF's protocol and preferred antibody for CFTR visualization, Clone AD596.
The data suggest that CFTR can be specifically and predictably detected via IF based on the underlying genotype. It's important to note that all patient samples from the CORAL-1 study were stained and imaged in parallel to these controls, so all results are directly comparable. Key findings from endobronchial biopsies harvested from the first cohort 3 patient with two Class I mutations are shown here. This patient is heterozygous for a frameshift mutation and premature stop codon in CFTR, with a baseline lung function of 64%. A post-dose bronchoscopy was conducted 96 hours after the last day of KB407 administration, and seven biopsies with acceptable airway histology were successfully collected for CFTR protein analysis.
All seven biopsies were positive for human CFTR, and when quantifying the proportion of DAPI-positive cells that were co-positive with CFTR in these samples, 42.1% of cells at the conducting airway surface were found to be positive for the KB407-encoded human transgene. On the right are representative H&E and IF images of a biopsy harvested from the right middle lobe of this patient. Broadly disseminated CFTR signal across the conducting airway surface with an apical distribution pattern can be seen. Shown here is the second set of representative histology and immunofluorescence images from a different biopsy site in this patient, demonstrating consistent apical delivery of the full-length human CFTR expressed from KB407. Parallel stained negative control samples were devoid of meaningful CFTR signal, as expected. We next sought to define the cell types of the human airways amenable to KB407 transduction.
Previously, we showed that both ciliated and secretory cells, the cell types that express the bulk of CFTR in the airways, were positive for the vector in non-human primate lungs after receiving nebulized KB407. Those findings extended to humans, as can be seen here. Our null patient samples were co-stained for human CFTR and cell type-specific markers of ciliated, club, and goblet cells. All three cell types were found to express CFTR after KB407 exposure, demonstrating a broad airway cell tropism for our vector platform technology that has positive implications for both KB407 and our pipeline of inhaled programs. Results for our second null patient are shown here. The patient has two Class I CFTR mutations and is heterozygous for premature stop and start loss mutations, with a baseline lung function of 45%.
A post-dose bronchoscopy was again conducted four days after KB407 exposure, and five usable biopsies were obtained. Again, a meaningful proportion, 29.4%, of cells at the conducting airway surface across these five biopsies were found to be positive for KB407-encoded CFTR with an apical expression pattern, as can be observed in the representative images shown on the right. Importantly, a broad distribution of the transgene to all tested lobes was observed in this low lung function, non-modulator patient, indicating successful vector delivery to notoriously difficult-to-access and treat tissues. Shown here are additional histology and immunofluorescence images from a second biopsy site in this patient, again demonstrating consistent apical delivery of full-length human CFTR expressed from KB407. Given the potential for background CFTR expression in the remaining four patients, analyses of KB407 transduction were conducted on expression of the ICP27 viral marker.
Results for each patient are briefly summarized on the following slides. On this slide, we have the results from our third cohort 3 patient. This patient is ineligible for modulator therapy with mutations including poly-T tract variation, as well as polymorphism at the M470V locus, which contributed to baseline lung function of 45%. A post-dose bronchoscopy conducted one day after last KB407 exposure, and five usable biopsies were obtained. Transduction in over 36.5% of conducting airway cells was observed in line with the high rates of transduction observed by CFTR staining in null patients. Similar levels of transduction were seen throughout the lungs of patients in cohort 3, irrespective of genetics, baseline pulmonary status, or concurrent modulator use.
Here, patient 4 is someone who is ineligible for modulator therapy, who has a premature stop codon as well as a missense mutation leading to baseline pulmonary disease with ppFEV1 of 69%. Twenty-four hours after their final dose of KB407, bronchoscopy revealed successful transduction of 33.8% of cells. Patient 5 is homozygous for F508del mutations, who is concurrently on modulator therapy with baseline ppFEV1 of 54%. Seventy-two hours after their last dose of KB407, they exhibited 36.8% of conducting airway cells positive for KB407 transduction. Finally, patient 6 is also homozygous for F508del on modulator therapy with baseline pulmonary function of 59%. This individual also had bronchoscopy performed 72 hours after their last dose of KB407 and had 31.4% of cells positive for KB407 transduction. A summary of the findings from all cohort 3 patients is provided on the next slide.
Consistently, transduction of the conducting airways has been demonstrated in all biopsied patients via staining for either CFTR or a viral marker as feasible. While patient-to-patient variability in transduction efficiency was observed, as would be expected, over 29% of cells were positive post-dose for all treated patients, exceeding the approximately 5%-15% target number that is currently predicted to provide meaningful functional correction of the CFTR defect underlying lung function loss in CF. The apically localized staining pattern of CFTR in Class I patients post-dose is suggestive of proper post-translational modification and successful trafficking of the transgene. In addition, the vector tropism established by cell type-specific staining indicates delivery to the clinically relevant cells that are known to express the bulk of CFTR in healthy patients.
Finally, the favorable pharmacokinetic profile implied by robust detection of CFTR signal up to four days post-dose is a positive indicator for potential patient-friendly weekly dosing of patients in upcoming studies. Turning to safety, KB407 continued to exhibit a favorable tolerability profile. Importantly, we continue to note stable percent predicted ppFEV1 levels throughout the eight-week study period, underscoring the safety of the top dose. All KB407-related adverse events were transient, with all but one being mild to moderate in severity. Of note, one serious adverse event was reported 24 hours after bronchoscopy for one patient. The Independent Data Monitoring Committee reviewed the case and deemed the adverse event as related to bronchoscopy procedure and not KB407. As with other AEs, this event was transient in nature, resolving within five days of onset.
Neutralizing immunity against nucleic acid-based therapies continues to be of particular interest, as this can decrease efficacy of some vectors with repeat dosing, thereby affecting durability of chronically administered therapies. Consistent with data seen across Krystal's programs, no significant neutralizing antibody response has been observed after KB407 administration, suggesting that long-term administration of this inhaled therapy will not become less efficacious over time. Finally, data from cohort 3 continue to demonstrate that inhaled delivery of KB407 is highly localized to the lungs, as evidenced by lack of systemic vector distribution. Altogether, the safety and tolerability data, paired with exciting evidence of molecular correction, has provided confidence in advancing KB407 into repeat dosing. To discuss next steps, I'll pass it back to Suma.
Thank you, David. We believe that today's update clearly demonstrates that KB407 can safely and efficiently deliver CFTR to the lungs of patients with cystic fibrosis. Moreover, we saw a high degree of reproducibility, broad airway dissemination, with all usable biopsies positive for CFTR or viral marker. Encouraging durability with CFTR protein expression detected at least as far as 96 hours post-dose, and a CFTR protein distribution pattern suggests appropriate apical localization. Building on these exciting results, we have already started working with CFF TDN on a repeat dosing CORAL-3 study design, which has been submitted to the FDA.
The final study details will be disclosed once alignment with the FDA is reached, but the overarching goal will be to assess the functional impact of repeat KB407 dosing by spirometry without the confounder of bronchoscopy. We believe we also have an opportunity to shorten the path to a potential approval. The unmet need for modulator ineligible patients is evident. This is a debilitating and ultimately lifespan-shortening disease for which no corrective therapy is available.
With our HSV-1 platform already significantly de-risked, we believe KB407 presents a risk-benefit profile suitable for potential accelerated development. As a result, we are working closely with CFF TDN and the agency to explore potential study designs that could support registration on success. We expect to align with the FDA on the study design in the months ahead and initiate a registrational study in the first half of this year. We also expect to file for platform technology designation for KB407, which may bring additional efficiencies to the program and potential BLA filing. The results we are reporting today parallel our Phase I-II findings for B-VEC, where we confirmed the successful delivery and expression of full-length and appropriately localized type VII collagen in the biopsies of patients. These findings ultimately translated to profound clinical benefit in our Phase III GEM-3 study.
With KB407, we have again confirmed expression and appropriate localization of our gene of interest, and we look forward to advancing KB407 into a registrational repeat dose study soon. I would like to thank our study investigators, the CFF, and most importantly, our patients for their support and participation in this study. I will now hand the call back over to Krish.
Thank you, Suma. I would like to close today's call by highlighting the growing momentum in our clinical pipeline of rare disease medicines. With today's readout confirming full-length CFTR gene delivery to the lung, we are putting KB407 on an accelerated path towards a potential registrational data readout and filing. Success with KB407 would open up a $2 billion+ market for Krystal without competing head-to-head with modulators.
And alongside KB407, we also have our rare ophthalmology programs, KB803 and KB801, both of which could deliver registrational data readouts later this year. With momentum building across all three of these programs, plus our newly announced KB111 program for Hailey-Hailey disease, we're well on our way to building a true portfolio of high-value rare disease medicines. Rare disease is an area we understand well and an area where we can unlock significant value through expedited development and our global commercial infrastructure. I look forward to sharing additional updates on all of our rare disease programs in 2026. Thanks for listening, and I'd like to now open the call for Q&A.
Thank you. At this time, we will be conducting a question-and-answer session. If you have any questions or comments, please press star one on your phone at this time. We ask that while posing your question, you please pick up your handset if listening on speakerphone to provide optimum sound quality. Once again, that's star one if you wish to ask a question. And please hold while we pull for questions. And the first question today is coming from Ritu Baral from TD Cowen. Ritu, your line is live.
Hi, guys. Apologies for the background noise. Thank you for taking the question. Krish, am I putting the dots together correctly? Are you going to approach FDA with a potential approval on CFTR biomarker? It's something you and I have discussed before. Could CFTR expression serve as a biomarker for approval, and is there a way to do it without invasive bronchoscopy that would still preserve the ability to measure, even on a relative basis, lung function in these patients?
And also, when might we get first lung function from the repeat doses or even these patients if they are turned over to repeat doses? And my second question has to deal - it has to do with biofilm distribution and transduction through the biofilm or around the biofilm and how that might relate to outcomes. Thank you.
Thanks, Ritu. To be very clear, I think our approach right now is we have submitted, as we mentioned in the call, we're talking to the FDA. We intend to get - we intend to make the repeat dosing study registrational, and we're looking at an endpoint. We're looking at an FEV1 endpoint, not a biomarker-based. And I'm going to turn it over to Suma to provide some more clarity. But the objective is, based on the data, working closely with the TDN and with the agency, we align on a study design on repeat dosing that would be registrational and looks at FEV1 as an endpoint in this study.
Yeah. For clarity again, I think expression is really important to demonstrate, and this is something what the CFF and TDN have been asking for because I think that, as you know, is a proxy for clinical benefit or clinical effect. And I think we have clearly demonstrated that in all our patients that we have biopsied across different portions of the lung, like upper lobe, middle lobe, and we consistently see expression.
As you know, these biopsies are like tiny little biopsies across the large surface area of the lung, and it's pretty impressive that we see ranges of 30%-40% of cells positive for full-length CFTR. So that's very encouraging, and I think that also addresses your second question regarding biofilms. Remember, these patients are very sick. Some of these patients had FEV1 as low as in the 40s. So they're pretty sick, and they have high thick mucus. So in spite of this, we were able to deliver, through nebulization, our product and see expression. So I think we are very encouraged by that. So even with a single dose, we were able to show that. So I think with repeat dose, as we keep repeat dosing, we feel that with the clinical benefit improving, it's going to improve the efficiency of transduction and administration.
So we're not concerned. I think this is something we are sharing this with the agency. We are sure we have basically demonstrated expression, function, and nebulization reproducibility. So I think these are the key factors. And obviously, this is an unmet need. We are still in negotiations with the agencies. There are several approaches that the TDN has suggested to expedite this particular program because they have, TDN has met with the agency and has communicated the need for these patients, the need for something for these patients because this is a patient population that's been left behind, and these are severe patients. So I think we have come up with some creative study designs. I mean, we're not ready to speak about it right now, but TDN has recommended, and we're very confident we have a very accelerated path for these studies.
So again, once we have some agreement and clarity, we will communicate that. So along with expression, some sort of a hybrid model that we have shown expression along with some sort of clinical benefit, we are certainly exploring an accelerated pathway for the registrational trial.
Thank you. And the next question will be from Roger Song from Jefferies. Roger, your line is live.
Great. Congrats for the data. Very impressive. Two questions from us. One is, I think the CFTR expression is exceeding the initial expectation and the initial guidance, 5%-15%, 10% threshold. My question is, how do you think about this higher expression level going to correlate with lung function potentially down the road? Is that proportional, or do they reach a certain level, and then as long as you're reaching a certain level, you get a similar functional benefit?
So that's number one question. Number two, just clarifying the registrational path here is you used the accelerated path. Is that a correct interpretation? Is you are pursuing the accelerated approval path plus future confirmatory trial, or this is the way of getting the full approval, potentially full approval? Thank you.
Yeah. I can take this question. With regards to CFTR expression, you have to remember these patients do not have any expression. We're going to start with the null patients. So in rare diseases, you hear numbers like even 10% is good enough. Any CFTR expressions that can aid with clinical benefit, I think, is beneficial. And we saw that even with Vyjuvek or with B-VEC. We didn't need full collagen seven. I mean, we biopsied patients and subset of anchoring fibrils enough for them to show healing and good clinical benefit.
So you don't need 100%, but we are very impressed because even with a single administration, we see anywhere between 25%, 30%- 40%. And this is in a very small section of the biopsy. So if we see 30% across the entire lung, I think, I mean, we would expect to see benefits. So I think the numbers we see, we feel good. And I think the beauty of our product is that we can repeat administer. So we can sustain those levels, right, by weekly administration. We know that there is no effect, immunological effect, where the drug can, well, it is still effective with repeat administration. We have shown that with B-VEC and other products. So again, with that ability to repeat dose and sustain effect, we see this is not an issue.
With regard to your second question on approval path, yes, obviously, we are going to, I mean, as you know, with the agency, I mean, we've been working with this agency very closely. They're very familiar with our platform, and we have several applications with this particular division. And I think this division is sensitive to rare diseases with unmet need. And they have clearly communicated pathways for accelerated pathways for drugs that unmet need. So obviously, we are going to explore those pathways. So we will discuss with the agency. As I said, I don't want to say anything more till we get complete agreement with them, but we are going to evaluate that to see if there's some sort of a hybrid where we can get something approved and then post-marketing continue to evaluate efficacy. This is something that's on the table.
Excellent. Thank you.
Thank you. The next question will be from Alec Stranahan from Bank of America. Alec, your line is live.
Hey, guys. Congrats on the updates today. Really great to see the progress from the pipeline. Two questions from me. First, what kind of frequency do you see as being the ideal profile for a therapy such as this? Is that weekly or maybe something else? And given the good tolerability you've seen at the highest dose level, will you select one schedule and one dose for the registrational study, or would you aim to enroll a few different dosing regimens, maybe even at a higher dose in the study? And then second, could you give us a sense of the viral fill rate for 407 or any color around assays that you're using to ensure appropriate encapsulation?
Is there a situation where a patient could screen positive for the viral marker but maybe not have a transduced CFTR gene? Thanks.
Okay. So the first question I'm going to have David address, and the second question, Trevor, you can answer that question.
Yeah. Thanks, Suma. Thanks, Alec. So yeah, it's too early to say at this point, or at least we can't talk too much about it, about the dosing frequency ideally. What I will say is we are encouraged by the fact that in patients with null mutations, we're seeing expression of full-length CFTR even 96 hours after the dose of KB407. That gives us confidence that at least weekly dosing should be sufficient to kind of get these levels where we need them to be at, right, over that 5%-15% of wild-type CFTR expression. I think this does give us a good launching-off point on how to choose our dosing strategy very thoughtfully. That's kind of what we're in discussion with the CFF TDN as well as in the FDA. TBD on specifics, but yeah.
I'll just add to David's point. I mean, again, I think for us, the best bet is going to go weekly because I know from a safety perspective, we have done this with our 707. There is no safety concern because we have given more frequent dosing, and we see our vector is conducive to that. Again, keep in mind, it's easy. These patients are nebulizing anyway because they have constant infection, and use of nebulizer is consistent with these patients. We will, again, just like Vyjuvek, we are targeting home dosing.
We are using a nebulizer that will be conducive to home dosing, and these patients will be able to, again, home dose at the, so from an administration standpoint and ease of use, this is going to be very practical if this drug gets approved for commercial purposes. So Trevor, can you answer the second question?
Yeah. So the second question related to the viral marker we're looking at. So that viral marker is delivered as a gene in the genome that packages CFTR. It's not a protein that is delivered in that's packaged into the virus, but it's expressed from the genome once the genome is successfully delivered to the nucleus of the target cell. So the only way that you can see viral marker expression is if you see the successful delivery of the genome into that cell and then subsequent marker expression.
That genome inherently also packages two full-length copies of CFTR. So we think it's clear that if the vector can express ICP27, it will be co-expressing CFTR in the same cell.
Thanks. And congrats again.
Thank you. The next question will be from Gavin Clark from Evercore. Gavin, your line is live.
Hi. This is Gautam on for Gavin. Thank you for taking our question. Two quick questions from our side. One on the safety here for the patient with asthma exacerbation. When was their bronch done after dosing? The idea is that if it's done longer after dosing, it could be less likely to be dose-related. So just wanted to get some clarity on that. And then on the adverse events, can you give us some more color on any signs of causing acute FEV1 declines? And if so, to what degree?
David, can you answer this question?
Yeah. Definitely. Thanks, Gautam. So yeah, so for this patient with the asthma exacerbation, their bronchoscopy, I believe, was 72 hours after their last dose of KB407. And then they experienced that asthma exacerbation 24 hours after that bronchoscopy. Yeah. As mentioned, the data monitoring committee reviewed that case pretty extensively and came to the conclusion that they did that it was related to bronchoscopy, but that was kind of the timing of things. With regards to your second question about acute FEV1 changes, we don't see anything significant. Certainly not outside of the normal variability of spirometry. We're tracking these things quite closely, obviously, and we don't see any signal that nebulization of KB407 should lead to considerable decrease in FEV1.
Yeah. Perfect. Thank you.
Thank you. And the next question is coming from Sami Corwin from William Blair. Sami, your line is live.
Good afternoon, guys. Congrats on the data. I was curious how you're thinking about the cadence of enrollment and treatment in CORAL-3. I think the CF Foundation was a limiting factor when enrolling and conducting CORAL-1, so just wanted to get your thoughts there. And then I think this was asked a bit earlier, but I missed the answer. How are you kind of thinking about when we might see some initial functional data from CORAL-3? Thank you.
Okay. Again, I'll just take the second question first, and then I'll have David answer the first one. I mean, again, we are working with the agency on this registrational trial. And as we announced that we intend to start the study second half, sorry, first half of this year. So as soon as we, I mean, we are in communication. Very quickly, very soon, we should be coming to some agreement with the agency. So we intend to start the study. I think we have sites ready. We are aligned with the TDN, so I'll have David talk about enrollment. But hopefully, as soon as we enroll patients, our goal is to get this study moving as quickly as we can because, again, because of the unmet need and there's a patient population. I mean, the toughest part was getting the bronch portion of the study. Even then, we had patients volunteering. There are now even more patients with the bronch. But I think once the bronch portion is done, we have patients aligned to ready to do the repeat dose administration. So David, can you talk about the first question?
Yeah. Definitely. So yeah, we've been very pleased with recent conversations with the CFF of late. We've had several really productive interactions with them, and that has really developed into getting multiple sites on board with us. We have several large academic centers that are excited to begin enrolling. Yeah. And to Suma's point, I think no longer requiring bronchoscopy as a requirement for CORAL-3 is certainly going to increase patients' excitement and enrollment, right? And especially since we're talking about repeat dosing and the fact that we're looking for functional improvement from a spirometry standpoint, FEV1 standpoint, I think that's very appealing to patients, or I would predict it would be. And so I'm anxiously looking forward to beginning that enrollment process because I think it will be much more efficient and fruitful once we get the ball rolling.
Great. Thank you.
Thank you. The next question will be from Joe Pantginis from H.C. Wainwright. Joe, your line is live.
Hey, everybody. Thanks for taking the question and a very nice update today. So first question is, I know you said you'll be providing more of the study design criteria in the future, but I was just curious if you could disclose, are there any key factors that you consider outstanding that are still being discussed right now? That's the first question. And then the second question is, I just want to look to push the envelope a little bit. Very encouraging to hear that you didn't really see evidence of significant neutralizing antibodies. So me pushing the envelope here is, do you have any evidence in animals for KB407 or any of your pipeline assets that after repeat dosing over a decent amount of time, that you see differing or no levels of neutralizing antibodies?
I can answer the second question on neutralizing. Our biggest example is Vyjuvek, right? I mean, Vyjuvek is we administer Vyjuvek into open wounds, the most immunogenic area, right? Skin, open wounds, a lot. And we have dosed now over so many patients, repeat dose over three years. We haven't seen any kind of safety signal from antibodies or worsening or any effect. So that's our real true testing of repeat dose administration. And obviously, as Trevor mentioned, I mean, he can talk to you a little more. I mean, we do look at patients' samples, blood samples to look at antibodies and neutralizing effects. Maybe Trevor, you can talk a little bit about that. In all our programs, we continue to monitor them. And I'll let Trevor talk, provide some color on that.
Yeah. So this is a question that obviously we're very interested in and regulators are interested in. We monitor neutralizing antibodies platform-wide in all of our clinical programs. It's something we'll look at in the 407 study, but we're confident from all the human data to date, we see no meaningful neutralization of our vector upon repeat dosing kind of irrespective of route of delivery.
Thank you. The next question will be from Yigal Nochomovitz from Citigroup. Yigal, your line is live.
Hi guys. Congrats on the update. I have a few questions. So first of all, just with respect to the primary endpoint for the phase two trial for FEV1, do I understand correctly that ahead of that study, you're not going to have any preliminary measurements of FEV1 in some of these early patients and that you're confident that based on the CFTR expression, that will translate in the pivotal study? That's the first question.
Yes, we are because, again, we will circle back to our Vyjuvek. We showed expression of the protein translated into efficacy. I mean, obviously, these patients are missing the protein. So if we are expressing the correct protein in the right region, we expect function. I mean, obviously, with a single dose, we don't expect to see FEV1 improvement because we have to get into a repeat dose, and that's where we're going to demonstrate FEV1 improvement. So we feel good about expressing protein, and maybe Dr. Lascano can talk a little bit. Dr. Lascano, are you on the call and give your opinion on this?
Yes, I'm here, so it's probably too early just for one dose three days later or so to get an improvement on the FEV1. So I think the important part is that repeat dosing is probably when you're going to see that particular change. I don't know if that answers the question, but it's just too early at this point to see that the FEV1 will jump right away.
Yigal, I will say, look, just based on one dose, I think David mentioned this prior. We were happy with the FEV levels from a safety perspective, not only at the point of administration but several days, weeks later. So while we are ecstatic about what we quickly saw in these three male patients, the real answer to your FEV question will come from the registrational study. And that's why we're talking to the FDA. We do believe, as Suma said, the molecular expression is a great proxy, at least internally to us, with respect to efficacy. We saw the same thing with KB103 or B-VEC.
And since we've called for two full-length CFTR genes, we feel—and we've seen this across multiple programs—so based on the level of expression, which was honestly much higher than we expected it to be going into the study, based on our prior experience with other encoding, other genes, and the protein being expressed, we're pretty excited to align with the FDA and get the repeat dose registrational study going.
Okay. No, that's super helpful. Thank you. Then my other question is, obviously, you nicely showed the 29%-42% above the 5%-15%. I was curious if, based on the imaging data or based on any of the other molecular techniques that you have at your disposal, if you could look at the amount of CFTR expression per cell and how that correlates with a non-affected individual. Is that information you have access to, or is the assumption that it's on the order of what you would expect in a normal individual?
Trevor, can you answer the question because you have looked at it?
Yeah. So that is something we've looked at previously. We compared expression levels of CFTR from bronchial cells and small airway cells from healthy patients versus from CF patients. And we do see that the relative level of CFTR expressed from our vector is at least as high as wild-type CFTR, if not supraphysiologic expression. So we do expect every cell that's CFTR positive is expressing at least wild-type levels of CFTR.
Okay. Great. Thank you very much.
Thank you. And as a reminder, once again, it is star one if you wish to ask a question on today's call. The next question is coming from Andrea Tan from Goldman Sachs. Andrea, your line is live.
Good evening. Thanks for taking the question. Maybe just a clarification point on the last question and answer, but does this suggest that you plan to engage with the FDA on a potentially registrational trial design without having the functional FEV1 data on hand? And if so, what is your level of confidence that the agency would feel comfortable aligning on such a trial design and that you could power a trial appropriately without first seeing that key dataset?
Again, our confidence comes from our interactions with TDN. I mean, I think they have worked with the agency on creative study designs, and we are aligning, helping with the TDN. We are working on the design. So this is not something that, I mean, I think has been discussed with the agency. So it's a path or a design that has been presented, and the FDA is open to it.
Yeah. Andrea, I'll just add, think risk-benefit profile here. Obviously, a patient population of high unmet need. Our vector has been very well behaved in the lung and other tissues, well tolerated, of course, in this phase one study. You can find that with clear molecular evidence of wild-type gene delivery and shown function of CFTR in multiple preclinical models. We think the basis is there to push for a design that more robustly evaluates FEV because the risk with a relatively volatile endpoint is you do an underpowered study to get a directional signal. It's a little unpredictable. You almost might as well go the whole way.
Thank you. That does conclude today's Q&A session, and it also concludes today's conference. You may disconnect your lines at this time and have a wonderful day. Thank you for your participation.