uniQure N.V. (QURE) Earnings Call Transcript & Summary

Ladies and gentlemen, thank you for standing by, and welcome to today's top line data from HOPE-B pivotal trial of EtranaDez in hemophilia B. [Operator Instructions] I would also -- I also need to advise you that this conference is recorded today. Without any further delay, I would now like to hand the conference over to Maria Cantor. Please go ahead.

Good afternoon, and thank you for joining us as we review the initial clinical data from the HOPE-B pivotal study of EtranaDez AMT-061 being studied in adult patients with severe and moderately severe hemophilia B. These data were highlighted today in a late-breaker oral presentation featured at the virtual ASH Annual Meeting. Joining me for this event are Matt Kapusta, our Chief Executive Officer at uniQure; Dr. Ricardo Dolmetsch, our President of Research and Development; Eileen Sawyer, our Vice President of Global Medical Affairs; and Dr. Steven Pipe, Professor of Pediatrics and Pathology and the Pediatric Medical Director of the Hemophilia and Coagulation Disorders Program at the University of Michigan and the principal investigator of the HOPE-B pivotal trial of EtranaDez. The presentations on EtranaDez that were delivered at the virtual ASH meeting are available on the Investor page of uniQure's corporate website under Investor Downloads, and today's webcast presentation will be available on our website at the conclusion of this event. Please note that during this investor meeting, we will be making forward-looking statements. These statements are subject to factors, risks and uncertainties, including those that are detailed in our Form 10-Q for the period ended October 27, 2020, as well as subsequent SEC filings that may cause actual results to differ materially from those expressed or implied by such statements. Now let me turn the call over to Matt Kapusta, our CEO, for opening remarks.

Thanks, Maria, and good afternoon, everyone. On behalf of all the employees at uniQure, we are very pleased to have the initial data from the HOPE-B pivotal trial featured as 1 of 6 late-breaking presentations at ASH. These are the first data to be reported from a Phase III gene therapy study in hemophilia B and with 54 patients, the largest set of patients receiving a single gene therapy investigational product to be reported to date. The study also represents the first large-scale trial to enroll patients irrespective of their preexisting neutralizing antibody status, which is an exclusion criteria for other AAV gene therapy product candidates in clinical testing. HOPE-B began enrolling patients a little more than 2 years ago, and we are very proud that uniQure and the study investigators were able to fully enroll the study, complete the lead-in and treatment phases and manage patient follow-up visits in the midst of a global pandemic. Being able to deliver this positive data to you today is a testament to the dedication of our clinical and operations teams and to the close collaboration that we have established with the hemophilia caregivers and patients. We feel that EtranaDez offers significant value to hemophilia patients and to the medical community and has the potential to be both first and best-in-class. Beyond this, these results validate our technological platform by showing that AAV5 possesses a favorable immunogenicity and tolerability profile and can effectively deliver therapeutic gene to the liver that produces life-changing clinical effect on patients, irrespective of neutralizing antibody status. I will now introduce Dr. Ricardo Dolmetsch, our President of R&D. Ricardo?

Thanks, Matt, and good afternoon to everyone. As Matt stated, we are very pleased with the initial data from the HOPE-B pivotal trial, which Dr. Pipe will review shortly. I would like to highlight that we have also presented new clinical data on EtranaDez from the ongoing Phase IIb study that shows that a single administration of EtranaDez is well tolerated and leads to the sustained Factor IX activity of 41% at 52 weeks. 2 years after dosing, all 3 patients are free from Factor IX replacement therapy, and 2 of the 3 patients have had no bleeding events. A single bleed was reported in 1 participant. Clinical data from our Phase I/II trial of AMT-060 were also updated over the weekend. AMT-060 is our first-generation gene therapy for hemophilia B. It consists of an AAV5 vector carrying a gene cassette with a wild-type Factor IX gene. Up to 5 years into the study, AMT-060 shows steady, long-term, continued durability, including stable Factor IX expression, improved disease phenotype and substantial reductions in bleeding and factor consumption. These clinical data, together with the HOPE-B pivotal data, speaks to the strength of the uniQure platform. And we plan to improve them in the upcoming regulatory filings for approval. AAV5-based gene therapies have been demonstrated to be safe and well tolerated in a multitude of clinical trials, including 5 uniQure trials conducted in nearly 8 patients with hemophilia B and other indications. These data also reflects the strength of our proprietary in-house commercial scale manufacturing capability and our use of an insect cell baculovirus process that has now been shown to be safe and effective, and they can be replicated across multiple programs and clinical indications. We believe there is substantial value in our platform and look forward to talking more about this when we discuss our new research areas next year. Now it is my pleasure to introduce Professor Steven Pipe, a clinical investigator in our Phase IIb study of EtranaDez and the principal investigator of the HOPE-B pivotal study. Dr. Pipe, thank you so much for being with us today.

Thank you, and good afternoon, everyone. My pleasure to be a part of this afternoon's event and to go through the initial data from the HOPE-B study. So if you could advance to the initial slide here. I want to go over the goal of this program. So severe hemophilia is characterized by a lifetime risk for spontaneous bleeding, primarily in the joints, and this leads to chronic arthropathy, which can be very debilitating for patients later in life. The treatments for hemophilia B or Factor IX deficiency are limited to regular prophylactic IV infusions with Factor IX concentrates. So the goal of gene therapy for hem B is to deliver a onetime procedure that would establish a sustained Factor IX activity in the mild to normal range that should be transformative for the recipient. This would provide effective protection from spontaneous bleeding. It would eliminate the need for continuous prophylaxis, and there would be accompanying improvements in quality of life. Next slide. Etranacogene dezaparvovec or EtranaDez, as you've heard, was developed using the AAV5 serotype vector. This came from AMT-060. But what we've done is we've substituted the previously evaluated wild-type Factor IX transgene with a naturally occurring hyperactive Padua Factor IX variant. This enhances the activity of the Factor IX molecule by upwards to 6 to 8 fold. This builds on the efficacy and safety that's already been demonstrated by AMT-060, which as you heard, has shown stable expression of wild-type Factor IX for 4.5 to 5 years of follow-up, with no new late-emergent safety signals. The Phase IIb study that you've heard about, it uses this enhanced vector with the Padua transgene, this now AMT-061 is -- was evaluated in the 3 participants who participated in that Phase IIb study. They're continuing to show a main factor IX activity now 2 years out from dosing of 44% and again, no new treatment-related adverse events. Now the HOPE-B trial that I'm summarizing for you today, as you've heard, is the first Phase III study in hemophilia B gene therapy. And this is the largest cohort of gene therapy for hemophilia that's been recorded to date from anywhere. Next slide. The participants were adult males with a baseline Factor IX activity of less than or equal to 2%. So this is in the severe to moderate severe range. And the individuals had to have previously been on continuous prophylaxis for at least 2 months before coming into screening for the study. The participants were excluded if they had a history of Factor IX inhibitors, if they had active hepatitis infection or uncontrolled HIV. Notably, in contrast to all other AAV-mediated liver-directed gene therapies for hemophilia today, preexisting anti-AAV neutralizing antibodies were assessed, but they were not used as an exclusion criteria. The participants were evaluated in the lead-in phase of 26 weeks to assess bleeding events occurring during standard of care, continuous routine Factor IX prophylaxis. The participants were then dosed at 2x10^13 genome copies per kilogram as a single approximately 1-hour infusion. Then they were followed weekly for 12 weeks and monthly through the first year and then continuing every 6 months in the long-term follow-up, which will be through year 5. Next slide. The study has 3 co-primary endpoints to evaluate efficacy and durability. A central one-stage Factor IX clotting assay is reported at 26 weeks after dosing. And then also as a co-primary endpoint, the Factor IX activity at 52 weeks after dosing. This is to give us some assessment of the durability of that expression. And thirdly, to add to the efficacy, an evaluation of the 52-week annualized bleed rate that will then be compared to bleeds that were observed during the lead-in phase when they were on Factor IX prophylaxis. There are some secondary endpoints, which include rates of total, spontaneous, traumatic and treated and untreated bleeds. I'm going to give you some color about that later in the presentation. We are going to look at Factor IX consumption, correlation of Factor IX activities and safety levels with pre-AMT-061 anti-AAV5 antibody titers as well as overall safety. Next slide. So this is showing the patient disposition of the trial participants. 75 patients were screened. There were 8 screen failures, but this is mostly for failure to sign the informed consent form or they're assessed as not having been on stable prophylaxis for at least 2 months before screening. 67 participants entered the lead-in phase, however, 13 discontinued prior to dosing for several reasons. Some are deemed to be ineligible after we had an evaluation of their liver health using [ boring ] tools such as the FibroScan. Some are deemed ineligible based on disallowed concomitant medications or comorbidities or they withdrew due to the COVID-19 pandemic or they just simply withdrew their consent. So the full analysis population included the 54 patients who enrolled, completed the lead-in phase and were dosed with AMT-061 and provided at least 1 of the efficacy endpoint assessments. I am going to describe in the safety assessment that 1 participant only received 10% of the scheduled dose. Next slide. The participants in this study were a mean age of 41.5 years, but they ranged from age 19 up through age 75. More than 80% had the severe phenotype, so less than 1% Factor IX activity. And more than half had prior hepatitis B or C infection, roughly equal prior treatment with standard half-life and extended half-life Factor IX treatments. And notably, 42.6% of the participants had neutralizing antibodies directed to the AAV5 capsid. There was a max titer observed in 1 subject of over 3,200. This rate of positivity is in line with prior assessment of the seroprevalence of neutralizing antibodies to AAV5 from the published studies. Notably, the 54 participants reported 123 bleeds during the lead-in phase while they are in Factor IX prophylaxis. So if I could just pause here before we go on. I think this is a very representative study of the patients that we see in our clinic. We're showing here a mean age of 41.5 years. But with dosing as young as age 19 all the way through 75 and then matching that with the efficacy data I'm showing you shows that there really, I would say, isn't even necessarily an optimal age that this therapy can be applied because we're showing efficacy across the adult life span. The percentage of patients with severe by -- severe phenotype by testing, the breakdown of those with their hepatitis B and HIV status, those who are on the different forms of Factor IX replacement therapy, this is very reflective of the typical population of patients that we follow in the clinic. And then to have that matched with the 42.6% of -- who had the neutralizing antibodies to AAV, again, matching population seroprevalence studies that have been done previously. So I think what we got in this cohort is a very representative sample of the people who ultimately hopefully could get access to this therapy. Next slide. So here, we're showing the Factor IX activity of all the participants up through 26 weeks post dosing. Now the activity levels were centered in the first 2 weeks to account for residual Factor IX activity from the Factor IX prophylaxis prior to dosing. And keep in mind that some of those individuals, at least half of them, were on extended half-life. So it's appropriate to censor those weeks. But the expression was robust by 3 weeks post dosing, and we've measured a mean Factor IX activity level of 37.2% at week 26. This represents a change from baseline overall of about 36%. The boxes represent the bounds of the first to the third quartiles, the whiskers, as they're called, represent the minimum and the maximum reading at those time points. And the median and means are represented by the dash and the blue dot, respectively, on this graph. Next slide. Now this slide is going to give a different depiction of the distribution of the activity levels achieved. I think it's pretty informative. Now over 80% of the patients have achieved a Factor IX activity of at least 20% at 6 months. But further, 68% of the participants are at least 30% or higher, and 38% have Factor IX levels that are in the nonhemophilic range, if you want to call that the normal range, from at least 40% or higher. If we look at the graph on the left, this shows the number of participants at the various Factor IX thresholds from lowest to highest going from left to right. In the light orange, we're showing those who did not require the corticosteroid treatment. And in red, this indicates the 9 participants who did require corticosteroids due to transaminase elevation and where their Factor IX levels were salvaged through the corticosteroid treatment. Next slide. Now what we're showing in this graph is we're depicting the activity results for those participants who have now had follow-up beyond week 26. And these results show similar Factor IX expression continuing beyond week 26, with 1 participant who's reached 18 months of follow-up. Half of the cohort has now had observations well beyond the 6-month co-primary endpoint and no evidence of decline of Factor IX activity through this follow-up period. Next slide. As this is the only study that has not excluded participants with neutralizing antibodies to AAV, we had an opportunity to evaluate for any impact on the Factor IX activity achieved. In the vertical axis is the observed week 26 Factor IX activity. And what we're showing here are those who receive the full dose of vector. Patients with undetectable neutralizing antibodies are all plotted stacked on top of each other at 7 on the horizontal axis because that was the threshold of the assay. And then moving from there towards the right, we're showing the titers of the other participants over a range of neutralizing antibody titers up to 678. Now there was 1 participant who had a titer of over 3,200 who did not respond, and he's outside this graphic scale. But overall, what these results show is it confirmed the observations in the preceding Phase I/II study of AMT-060 and the Phase IIb study with this enhanced vector that there is no correlation with the Factor IX activity achieved based solely on the neutralizing antibody observed. I think this is importantly conveyed to people that we only had titers up to 678. That should not be taken as the threshold for patients who would respond. I think it would be a mistake to indicate that, that is the threshold. The fact that we only had 1 nonresponder and he happened to have a titer of 3,200, I think that will certainly give clinicians pause if they had someone test out at that level. However, our best assessments from population seroprevalence studies is this maybe 1% or so of patients who are going to have titers at that level. So what we would do with patients who test out above 678, I think that remains to be seen. And hopefully, there will be more data to come to inform of that in subsequent evaluations. Next slide. This table shows the bleeding events for the full analysis set observed during the 6-month lead-in when they were on Factor IX prophylaxis as compared to the first 6 months post dosing. And here, we're also including a breakdown of spontaneous traumatic and other bleeds. Now the total bleeds are what's indicated in the chart. The treated bleeds are indicated in the brackets. Now what do we mean by total bleeds versus treated bleeds? So not all bleeding events require a Factor IX treatment. Some patients might have minor bruising. They'll record that, but they'll indicate that they didn't have to give themselves a Factor IX treatment. So when we're talking about treated bleeds, that means that they either had an observation or they knew from their experience that the type of bleeding that they were requiring was going to require a treatment. So relative to the lead-in phase, the total bleeds overall decreased by 83% and treated bleeds decreased by 91%. Further, 72% of the participants experienced 0 bleeds post dosing compared to only 30% of those during the lead-in phase. And with regard to the treated bleeds, meaning they actually required a Factor IX infusion, 87% of subjects had 0 treated bleeds compared to only 33% during the lead-in phase when they were on standard of care prophylaxis. Let's go to the next slide. Now in the protocol population, which is all 54 subjects, 98% of the patients were able to discontinue prophylaxis and remain prophylaxis-free. This has resulted in a reduction of Factor IX usage from over 290,000 international units per year per patient to about 12,500 international units per year per patient. Next slide. With regards to the safety assessment, 53 patients had 324 adverse events post treatment, of which 37 patients had a total of 88 treatment-related adverse events. The majority, almost 80% of these treatment-related AEs, were mild. 9 patients -- and what we're depicting on the right are the treatment-related AEs that had at least an incidence of at least 5% post treatment. And you can see these include things like flu-like symptoms, headache, the ALT/AST increases, fatigue, nausea, et cetera. There were 9 participants who received steroid -- corticosteroid treatment orally for transaminase elevations as per protocol. We believe that this is a reflection of an immune response to the cells that are processing and then displaying the broken down capsids on the surface of the cell, and they're available for surveillance by the immune system. And the risk of not intervening with the corticosteroids is that the immune cell can mount a cytotoxic immune response against those expressing cells and actually take them out. And that would, of course, lose those expressing cells from contributing to the Factor IX expression. So this has been recognized from the very earliest days of this AAV platform for delivering gene therapy to the liver. The steroids have been shown in previous protocols to be able to normalize the liver enzymes and to salvage the factor expression activity. So in these 9 subjects, all discontinued the steroid course prior to week 26. All of their enzyme elevations returned to normal, and the Factor IX activity was preserved in these 9 individuals in the mild range between 8% and 39%. There were 7 patients who experienced an infusion-related reaction. In 1 individual, this resulted in discontinuation of the infusion. So he only received 10% of the dose. And I mentioned this at the presentation today, my understanding from that event was the patient had symptoms. It was in the early days of doing treatment dosing in patients. There hadn't been a lot of experience in managing the infusion-related reactions at that point. And I believe this patient had some other comorbidities that in the feelings of the investigators at the time, they thought that they had to just abandon the infusion. And so he never got restarted. He never got more than 10% of the dose. In the other 6 individuals who had infusion reaction, it was interrupted in 3. They received some antihistamines and IV corticosteroids. And then their infusion was able to be restarted, and they got the full dose. And in 3, the infusion wasn't interrupted. And in general, the approach to infusion reactions that we now know can be quite successful is simply slowing down the infusion can abate many of the symptoms. And sometimes that's all that's needed. And in some cases, adding the anti-inflammatories, like I mentioned, and the anti-allergy elements can help resolve the symptoms. Notably, no inhibitors to Factor IX have been reported. And what's also important, since we had all the data of the neutralizing antibodies, we were able to look to see, is there any relationship between any of these safety signals and either the levels of neutralizing antibodies or even between those who had neutralizing antibodies versus those who didn't. And we see no relationship in those assessments. Next slide. In conclusion, this is the first report of a Phase III study in patients with hemophilia B and the largest gene therapy trial cohort that's been reported to date. The mean Factor IX activity shows that it significantly increased to near normal levels at 26 weeks post EtranaDez, and this meets the first co-primary endpoint. No need for prophylactic immunosuppression. 52 of the 53 patients received a full dose and responded, and this included patients with pre-existing anti-AAV5 titers up to 678. The patients were all able to discontinue prophylaxis, who had this transduction, and the bleeding was abolished in the majority of patients throughout the 26 weeks. The most common safety findings were transaminase elevations, requiring steroid treatment and infusion-related reactions, and this supports the safety profile that's consistent with the early phase studies. So the final analysis is planned at 1 year. So that will provide the additional co-primary endpoints of the 52-week Factor IX activity and then the opportunity to look at the annualized bleeding rate for the whole cohort over the full 52 weeks, and it would be hoped then that this would support marketing authorization application. Next slide. So I'd like to, first and foremost, acknowledge the participants and their families. A trial like this is a big commitment on their part, and these advances could not happen without them. And secondly, many thanks to the investigators and their teams who really tirelessly care for these patients. And lastly, the uniQure trial team who really have made all of this happen through some extraordinary circumstances over this past year. So thank you for your attention, and I'll be happy to respond to any questions during the Q&A session.

Okay. Great. Thank you, Dr. Pipe. Before we open it up to questions, I'd like to summarize key -- 6 key takeaways from the interim HOPE-B data. First, the HOPE-B study has met its first co-primary endpoint of mean FIX activity of 37% of normal at 26 weeks. Additionally, the FIX increases in this study have been durable thus far with patients maintaining therapeutically relevant activity for up to 18 months. Second, patients experienced a 91% decrease in their number of treated bleeds, in particular, 87% of patients reporting -- reported no treated bleeds during the 26-week period. Third, the usage of FIX replacement therapy in patients declined by 96%, with nearly all patients discontinuing their routine prophylactic factor replacement infusions after treating with EtranaDez. Fourth, the data showed no correlation between preexisting antibodies to AAV5 up to a titer that includes more than 95% of the general population. Specifically, 22 of the 23 patients with previously neutralizing antibodies achieved increases in Factor IX activity that were consistent with patients that had no preexisting antibodies. We believe this confirms the differentiation of AAV5 based gene therapy. Fifth, our study was conducted without the need to prophylactically immunosuppress patients, which we believe has been possible by AAV5's favorable immunogenicity profile. And lastly but not least importantly, EtranaDez was well tolerated with no treatment-related serious adverse events reported, no inhibitor development and no observed correlation between safety and previously neutralizing antibody status. With this, operator, please open the line for analyst questions.

[Operator Instructions] Your first question comes from the line from Paul Matteis from Stifel.

Congrats on the data. I was wondering if you could talk a little bit about the importance of continued durability of expression from the Phase III program. What do you view as the regulatory relevance of that data in light of the valrox setback and increasing focus on durability of hemophilia gene therapies? And then one question for Dr. Pipe. The hemophilia population, I think many on this call have heard that patients may be conservative when they look at new therapies. What do you -- how do you view the adoption curve of gene therapy in hemophilia B within your practice and in other clinicians' practices?

So maybe I'll start off. Thanks for the question, Paul. I think there's a couple of things I would note. One is that in all of our interactions with the agency thus far, we've had no indication that follow-up of more than 52 weeks for these patients would be insufficient for approval of our therapy. And keep in mind that as part of the submission, we would expect to have more than 2 years of follow-up from the Phase IIb dose confirmation study and more than 5 years of follow-up from the patients, the 10 patients in the Phase I/II study. So we think that this will be a comprehensive data set that will obviously include 52 weeks of follow-up on all 54 patients in the pivotal study. We think it's a comprehensive data set that would demonstrate the long-term safety, tolerability and durability of our gene therapy. And keep in mind, I do think -- and Dr. Pipe can certainly chime in to this regard, I do think that there is a level of sophistication with the agencies that while hemophilia A and hemophilia B are both hemophilias, of course, they really are completely 2 different disorders that impact 2 different genes. And that the clinical experience of all the gene therapy studies that have been evaluated in humans for hemophilia B, really, have not shown any long-term waning of effect and pretty remarkable durability. Of course, there's the original St. Jude study, which is now going beyond 8 years and our own data that we presented at ASH now up to 5 years. So that's how I would answer the regulatory piece, and I'll hand it over to Dr. Pipe to provide his comments.

Sure. And one follow-up to that, Matt. I mean you're absolutely right. Hemophilia A and B are similar in name and the clinical expression of their disease. But there is nothing similar between Factor VIII and Factor IX. At a protein level, these are completely different molecules. They have unique challenges in intracellular processing and their secretion efficiency. And so I believe the agency is sophisticated that they know about the differences between these 2 different proteins. And there's a long track record of Factor IX expression in the context of hemophilia B in both animal models as well now in the human clinical trial that has shown the durability that can be expected through this platform of transgene delivery. So I think I'm very confident in the data that we've shown from the Phase III today. I think it's really reassuring. But it's building on a long-term expression data that we have from within this program but also outside of this program in other Factor IX expressions. And then to the specific question about adoption. I think although it's a fair assessment of the hemophilia population to say they're conservative, but this population moves very quickly when there are innovations that impact their health, that impact their quality of life, that impact their ability to live their lives the way they want to. We have seen rapid adoption of new technologies like when the recombinant era first came into being. We've seen rapid adoptions in hemophilia A, with innovative molecules like HEMLIBRA that very quickly established a very large prescribed population in hemophilia A. And patients have been waiting for gene therapy for 20 years. We thought back in the late '90s and early 2000s that we were close to having a therapy that would deliver on the promise of gene therapy. We're a couple of decades behind, but we needed the right platform, and we needed to have the safety and efficacy data to get us there. And I think this is a pivotal program that I think is going to really build confidence in people that this may be what's an appropriate therapy for them. And so I think it's still going to be a personal decision between a clinician and the patient, but this is really strong data.

Our next question comes from the line from Madhu Kumar from Baird.

Yes. So I guess my first very simple question for Dr. Pipe is among the hemophilia B patients you treat now, what fraction of them would you consider for a drug like AMT-061?

So as I was trying to suggest when I was reviewing the demographics, I can tell you that the first hem B patients that I treated with gene therapy was 68 years old, and the youngest patients that I've treated across all the trials at our center was just over 18. I don't see a ideal patient. I think there are advantages for patients across the lifespan. Certainly, for a young early adult, who's hopefully had pretty good prophylaxis all his life, he's got good joint status, the earlier he could do a definitive treatment like this with gene therapy, that's going to just open up opportunities for hem going forward. Patients share this spontaneity that returns to their lives, the ability to live their lives out the way they want to, not having to think about their hemophilia anymore, these are really powerful drivers. And so for those young people, I definitely see the attraction of this therapy. But throughout the rest of the spectrum, we've got middle-aged men who are still struggling with the pathology from their joints. They go through gene therapy, and they recognize, boy, the only thing holding me back now is my arthropathy from my ankle or my knee or my elbow. And so it's driving them actually to want to get joint replacement so that they can get on with their life. And in the latter phase, we've got elderly people who are struggling with their venous access. And really, maybe they have other comorbidities and care challenges. And if we can take hemophilia off the table for them through a transformative treatment like this, it just opens up a lot more opportunities for their overall care. So I see that this has application across the adult life span.

Okay. Great. And then one question both, I guess, for Dr. Pipe and for the company. How do you think about kind of follow-on studies both in the nonadult setting and the pediatric setting given sort of the preclinical data that uniQure has put out there over the last few months or so and also the potential to go after these higher antibody titer patients using some of these new technologies out there like FcRns or IgG proteases or something as a way to really kind of sop up the remaining admittedly small population of people who on an AAV5 NAV basis might not necessarily be a good candidate for 061?

Dr. Pipe, do you want to take that first?

Well, I'll just add my points, but there's good rationale to think this therapy could be effective in adolescents. The main limitation with AAV-mediated liver-directed gene therapy is if you're down at an age where the cellular turnover is very high, there is some risk that you will dilute out the transgenes over time because the majority of the transgenes -- vast majority is episomal. So it's not integrated in the DNA. And so with cell division, you don't copy the episomal transgene, so the daughter cells don't get it. So if you do this approach in very young school age individuals, you are apt to lose expression over time. But we think the bulk of liver growth is probably up through around age 12 or so. So I think some sort of an approach that opens up this therapy to older adolescents and then down into the early teen years, I think, is definitely on the future horizon. And I would hope that we would have the opportunity to do that even with this product potentially.

Yes. The only other comments that I would add to what Steve said is 2 things. One is that while it's early animal data, one of the poster presentations we had at ASH this year was a study that we did in neonatal rodents that we followed into maturity. And we were able to demonstrate no loss of activity despite their maturity and growth. If you were to ask a lot of the clinicians in the initial days, the early days of gene therapy, how long this would last, a lot of them probably said 1 or 2 years. Again, the oldest follow-up [Technical Difficulty] up to a decade now. And there are some theories as to why there might be longer durability, but more data is going to need to be seen to fully understand it. The second thing I would say is that for AAV5, we have demonstrated in nonhuman primates the ability to actually redose using common technologies. And one of the advantages, the other side of being able to treat patients with preexisting neutralizing antibodies is that there is a window that we clearly can see is now perhaps up to 700 titer that if we can reduce their titer after the initial dose to that level using these off-the-shelf technologies, we might be able to re-administer to the extent that there is a waning of effect. So I think we do have great interest trying to expand. Obviously, this will be something that we'll have to do in collaboration with CSL. But we have great interest collectively, looking into treating patients earlier because I think most clinicians would agree that the earlier you can intervene medically and prevent the buildup of arthropathy, the better the prognosis is for those patients.

Great. And I'll say this is an exciting HOPE-B, and I realize that. And you guys should be really proud of the work here to kind of be a big step towards the -- I know it's a hyperbolic term, but the cure of hemophilia B.

Thank you, Madhu.

Your next question comes from the line from Robyn Karnauskas from Truist Securities.

And I reiterate what my colleague just said. So I think you just touched on it a little bit, on retreatment. So what -- do you have a sense of how high the antibody titers are over time after patients get therapy, so we have a sense of maybe what percentage might be able to be retreated without any other ways to lower the antibody? And then the second question is for patients who already have titers of AAV5, is there anything you've seen digging through the science of the data that suggest they may need steroid use? If there's any other correlation between either side effects or knees or levels over time at all that you're starting to see? Or I mean -- there's 2 questions there.

Yes. The first question, when you -- it's one thing when you're exposed environmentally to AAV5, the titers, as we've seen now across most of the patients that have preexisting titers, is relatively low. We're talking under 500. When you do an intravenous administration of AAV5 gene therapy, the titers do increase significantly in all patients. And so I think it's normal and expected in all gene therapy studies. Now what we did in these nonhuman primates is we would infuse them with an AAV5 reporter gene. And so we would mimic the substantial increase in titers that you would expect with an in vivo intravenous administration and then use immunoabsorption technology to reduce their titer down to a level where it's no longer neutralizing or inhibits transduction. So we've shown proof of concept that we can do that, and we do think that, that is something that can be applicable in the clinical setting. With respect to your second question, I think Dr. -- and I don't want to put words in Dr. Pipe's mouth, but I think he has covered this in the prepared remarks or his presentation, where there was no correlation of any safety findings or adverse event profile in the follow-up thus far in patients that had preexisting neutralizing antibodies versus those that haven't.

I guess a follow-up for Dr. Pipe. So how important is -- are patients aware that even though for Factor IX we see very long duration of expression? And how much does the fact they may have to be retreated over time weigh in their decision as to when they get therapy?

Well, I mean I can understand that concern, but we don't have any piece of data from any AAV-mediated liver-directed gene therapy for hemophilia B that suggests anybody needs to be retreated. So I certainly don't -- I don't -- when I'm consenting patients for participation in these trials, I certainly don't promise them retreatment. And if this was commercially available today, I would also not hold that out to them that this may only last for a little while, but it's okay, by then, we'll have technology that can be -- you can get retreated. Our patients really want something that is going to last for them for hopefully a lifetime. Now I do believe that they are willing to conceive that there's not very many things in life that lasts for a lifetime. But I hope that there is such a level of durability from this treatment. And I think based on the early Phase I/II data, what we've seen with other trials in hem B, a decade or more is pretty substantial and would really be transformative for a patient at any time in their adult life. And I do have confidence that over a decade, we can have some innovations that would probably be able to satisfy some small percentage of patients who did lose activity over time. So that's my perspective as it is now. I think I want to be able to present my patients a degree of confidence that this is going to be a transformative therapy for them for a long, long time.

[Operator Instructions] Your next question comes from the line from Joseph Schwartz from SVB Leerink.

Congratulations as well. I was wondering, can you talk about the patients that responded to a lesser degree? And are there any patterns there of interest, even if they're not this positive that you can share? For example, it looks like one of them at least had a transaminase elevation based on the range of expression that was reported for the 9 patients in that group. Were there others in that range? Or any other defining characteristics that might be interesting to note?

Sure. Yes. I'll try to get -- give you a little bit of color there. The nonresponders are limited to the patient who had the super high titer and then the one patient that only got 10% dose. So we had no response -- no nonresponders in the patients who got full dose transduction and who are through the NAb titers up through 678. If we look at the bracket of those who ended up with levels of 5% to 10%, both of those individuals had -- were transaminase elevations, and that's where their factor level was salvaged after the corticosteroid treatment. If we look at the next bracket of 10% to 20%, I think it's 4 out of the 6 had transaminase elevations, and that's where their Factor IX level was stabilized. And then after that, now you're in the 20%-plus range, vast majority of those individuals did not have the transaminase. So if I were to say what's the biggest risk for where your Factor IX level settles out with this treatment, it really is whether you get the transaminase immune reaction or not. And I hope that we'll be able to do a deep dive into the data and the experience from those 9 subjects, maybe we'll learn something about the timing of how the steroids are initiated. And there may be some things that we can carry forward into hopefully a commercial phase that will maybe even be able to salvage those Factor IX activity levels at even a much higher range. So hopefully, that gives you a little bit more color about what's happening with those few patients at the lower bounds.

Yes, absolutely. That's super helpful, Dr. Pipe. And maybe one for the company. What is your understanding of whether the FDA or EMA has any critical thresholds that they want to see of EtranaDez, any proportion of patients above in terms of expression or bleeding and then how this data compares in that regard? How much cushion is there when we look forward to the 52 weeks based on this data?

Yes. Thanks, Joe. I think that the study design, now includes co-primary endpoints that include annualized bleeding rates after the administration of EtranaDez compared to -- prior to administration while patients were on high-dose Factor IX replacement therapy. The study is powered to demonstrate noninferiority on a bleeding standpoint. And we do believe that, that is -- that has traditionally been the gold standard. It is the traditional way that these products have been approved, and we think that is a standard that the agency will view as something that would justify approval, determine based on 52 weeks of follow-up data. And if you could demonstrate that, the exact threshold, whether that's 22% or 38%, becomes less relevant because you're really looking at, again, the gold standard of clinical outcomes for these patients.

Your next question comes from the line from Jim Birchenough from Wells Fargo Securities.

This is Yanan dialing in for Jim. And congrats on the data. I just wanted to dig maybe a little deeper into the bleeding data. If you look at the bleeding event that occurred post dosing and compare that with the patients' factor levels, is the pattern consistent with expectation? Because I think you mentioned for nonhemophilia levels of Factor IX, you should really have no spontaneous bleeding. And for the mild range Factor IX, you should see very rare spontaneous bleeding. So is the data consistent with this expectation? And does that indicate whether the gene therapy-expressed Factor IX behave essentially the same as endogenous Factor IX?

That's a great question. I will say that the bleed analysis as part of the secondary endpoint still needs a full analysis. So what we're presenting here are just the numbers. We don't yet have the correlation with individual patients and factor levels, et cetera. I think you can take from this data that the Factor IX is behaving as promised based on activity. I think our experience with the individual patients that I follow at my center versus the broader breakdown here, it's behaving exactly as I would expect for the relative levels. And I do have one individual who's at the lower end of the Factor IX expression. And so I do have that perspective as well, that we're still seeing benefit even though they're just into the mild range. So I don't see any concern about using the hyperactive Factor IX variant that it's not giving us the right assessment of the Factor IX activity and its protective benefit. I think what people are probably going to want to see eventually, and I hope we'll be able to generate that data for them, is for those individuals who are close to the normal range or well into the normal range, did we completely abolish spontaneous bleeding, traumatic bleeding, that sort of thing? And I think that data will be forthcoming. We just don't have that full analysis right now.

Yes. And I'll just say just something -- 2 things really quickly. One is in the data that was presented, spontaneous -- the propensity for spontaneous bleed is really why many of these patients were on prophylaxis to begin with. This group of patients had 37 bleeds -- spontaneous bleeds in the lead-in period that require treatment. And all these patients subsequently in the 26 weeks after had 3 spontaneous bleeds. And again, we'll do the full analysis of that when we have the 52-week data. The second point I would make is that if you look even at the Phase I/II study, these patients had, in the high-dose cohort, roughly 5% to 10% of Factor IX activity. And in the last 52 weeks that we evaluated, they really didn't bleed at all. So I think that substantiates some of the commentary that Dr. Pipe was making.

Got it. And if I can squeeze a very quick question, corticosteroid impact on Factor IX activity. I hear what you said about patients even after corticosteroids still remained in the mild range. But could you give more detail on generally what is the percent reduction before and after corticosteroids and whether that experience is consistent with the prior gene therapy experience in hem B patients?

Yes. I would just tell you my personal experience is that these patients are similar as the observations in other trials. By the time you see the transaminase elevation, sometimes the Factor IX activity will not change at all. And it will just be sustained, but transaminase is resolved on steroids, and there's no loss of Factor IX activity. And then in other cases, for reasons we don't have a handle on, their Factor IX does decline and sometimes the decline can be pretty substantial. I think the nice thing about this trial data set, which was a large cohort of patients, is that it was only 9 subjects that had to go through this, and all of them managed to maintain their Factor IX in the mild range. And so they're getting at least a good benefit from this treatment, even though they had that adverse event. So I don't think there's anything that's predictable once a patient shows that transaminase elevation. They all just need to move forward with the protocol. And we have -- hopefully, they're going to settle out as we observed in the clinical trial program.

[Operator Instructions] The next question comes from Danielle Brill from Raymond James.

Congrats on the data. I actually have a follow-up to the prior question, and it pertains to your Phase IIb updated data. It looked like the patient who experienced spontaneous bleeds that required treatment actually had FIX levels well above the nonhemophilic range. I was wondering if you could provide a little bit more color on this patient and how we should think about that.

I don't know -- you want to, Eileen, answer that, is that okay?

Sure. I'll take that. So this patient had levels of about 50% sustained after treatment. He was a patient that had a lot of joint morbidity coming into the trial and underwent 2 hip surgeries on separate occasions. So in this particular case, it was a spontaneous bleed reported in the leg muscle, that he self-administered a single infusion of Factor IX to treat. And that was considered a precaution to ensure that there was no adverse effects from that bleeding.

Yes. I mean this is an important thing to know. I remember meeting the patients that actually had a liver transplant. And so they had absolutely 100% normal levels of Factor IX activity. And they would tell me that because sometimes a joint damage can be so bad that they might still bleed. So it depends on a number of these comorbidities, as Eileen mentioned.

The next question comes from the line from Martin Auster from Credit Suisse.

This is Matt Terwelp on for Marty. Have you measured factor expression levels using the chromogenic assay? And if so, I'm curious what relationship you saw between the one-stage and chromogenic assays. And also have regulators indicate a preference for which technique they prefer?

Yes, we have measured both Factor IX activity using both the chromogenic assay and the one-stage clotting assay. The differences between the 2, we've characterized, we understand, and they're consistent with what has been reported by others. And we have had a discussion with the agencies regarding this, and they are comfortable with the one-stage clotting, which has been historically used for decades now.

The next question comes from the line from Salveen Richter from Goldman Sachs.

Could you give us more clarity on the bleed rates? And I don't know if you do have this, but at 26 weeks, what the breakdown was between spontaneous and traumatic? And when you assess that, how are you thinking about the ABR rate at 52 weeks here?

Dr. Pipe, do you want to address that?

Yes. So just to remind people the numbers because this slide wasn't up for very long, but if you still have your deck there. So in the lead-in phase, when these gentlemen were all on regular prophylaxis, 123 total bleeds, 107 of which were treated. We looked at the breakdown there, 42 spontaneous bleeds, 66 traumatic and 15 other. If we look within the spontaneous, 88% of those required treatment. If you look at the traumatic bleeds, 83% required treatment. So then in the post transduction, 21 total bleeds post transduction, only 7 spontaneous bleeds but only 3 that require treatment, 11 traumatic bleeds, 5 of which required treatment, and then we have 3 others. So I think we even see a shift in the perceptions of the patients. This is what I would take from this data. So less than half of the bleeds that they're having, either spontaneous or traumatic, are they making a decision that they think it needs to be treated. So this could be some of the nuance of doing a clinical trial, where we give them these diaries, and we tell them we want to hear absolutely everything that's going on with them. So I think the data is what it is. I think the overall reductions are exactly to be expected. And just to give you an anecdote, one of my patients was fishing in the summer post-transduction, and he got his rod snagged, and he was jerking his line. And the rigging came up and hit him in the face, and he got a bruise and a fat lip. And he came and tell me like the next day. So that was recorded as a bleed, and he didn't treat for it. And honestly, I would have had the same bruise and I would have had the same fat lip if it has happened to me, too. So I think in the context of this data, expecting bleeds of 0 in 100% of the population is not reality. But the fact that we had a drop to -- or if you like, an increase to 87% of the patients who experienced 0 treated bleeds, I think, is entirely in keeping with the Factor IX levels that we observed in the cohort.

The next question comes from the line from Joseph Thome from Cowen and Company.

Congratulations on the progress. I have one on the infusion-related reactions that we saw. I know you indicated it wasn't related to any sort of preexisting antibody. But are there any other comorbidities in the patients that saw the infusion reactions that would indicate maybe what types of patients would have infusion reactions? And is this essentially a nonissue that maybe can be remedied with just physician education upon launch?

So as far as I've -- as we have reviewed the data to date, there doesn't appear to be any predictors of these infusion reactions. And we did specifically look for correlation with neutralizing antibodies and did not find that. It has been observed, in my experience, in all the clinical trial of using AAV, including other vector serotypes, both in hemophilia A and B, we do see these infusion reactions. We're prepared for them. We have protocols for how to approach them. In general, it is dose-dependent. So the higher the dose of vector being delivered, the more likely you are to see these, and it's also related, it seems, to the rate of the infusion. So what is being manifest by these reactions, I don't think I know particularly. There is an aspect of innate immunity that might be getting activated because of the viral particle load. So that's a reasonable hypothesis. But the fact that in the vast majority of these, you can get through it by just slowing down the infusion and in the few that are having exacerbation of their allergy symptoms, they do respond to antihistamines and corticosteroids if needed. So again, the one patient who didn't get the full dose, I think that's unfortunate. Almost certainly, there were extenuating circumstances that prevented them from being able to complete the infusion. But I think that people will be prepared for this, and hopefully, they will have a good strategy for how to deliver this and make sure the patients get full dose.

Your next question comes from the line from Luca Issi from RBC.

Congrats on the progress. Great news for patients, first of all. Had a question for either the company or Dr. Pipe. Wondering if you can comment on the competitive landscape here, given Pfizer and Freeline are in the mix as well. And maybe ask a little bit more directly, do you expect that the higher Factor IX activity that Freeline has shown will drive a superior clinical profile?

Yes. Maybe I'll start off, and Dr. Pipe, you can chime in. I think as opposed to commenting individually on the other programs, I think the way that we look at it is, we view EtranaDez really optimizes 3 critical factors. The first one is efficacy; the second one is safety; and the third one is patient access. And I think that we've designed this target product profile to provide at the low end enough comfort that patients will have a high-enough increase in Factor IX activity that they will be able to discontinue their prophylactic replacement infusions, and we think that we'll be able to do that durably. And at the high end, we are not increasing Factor IX to such an extent where it potentially can pose a thrombosis risk. And if you look at the overwhelming majority of patients, as I think Dr. Pipe said, you have 80% of patients that are over 20%. And really all but those exceptional cases, you had patients in the mild range. So I think we've really accomplished establishing that target product profile. We're doing it without administering prophylactically steroids, and we think that we have the potential to provide this clinical benefit to all or nearly all patients. So I think when you look at those factors and you compare them to these competitive programs, we do think that we have the potential to be best-in-class.

Yes, I would agree. I think there is some risk. If you're only going to accept the lower bound as normal, the interpatient variability is not going to go away with the AAV platform. So to think that you can thread the needle in a very narrow window of Factor IX expression, I think, is just unreasonable. So as you shoot higher and higher to have patients at the lowest outcome only be in the normal range, the risk then becomes, on the other side, is that you're going to have patients who are going to be at a very high level of Factor IX and potential consequences from that.

The next question comes from the line from Suji Jeong from Jefferies.

I have a question for the company. And do you think the FDA or EMA will require companion diagnostics for the neutralizing antibody as part of the approval? Or have you had such a discussion with the agency?

Yes. I think we are -- as I think we've mentioned, we are planning to have a pre-BLA meeting with the agency early next year, where we can provide them the bolus of this data and evaluate it. But we have had discussions with both the device side of the agency as well as the biologics side of the agency and very good interactions with them. I can tell you just from our perspective, and I think Dr. Pipe you can chime in on this, when you have 22 or 23 patients that have been able to discontinue their prophylaxis, that have seen meaningful, clinically-relevant increases in Factor IX activity and meaningful clinical outcomes, and you have one patient that you really just can't draw a line through because it's one patient, I think it really does substantiate, in our view, that this is something where it would be very difficult to establish a cutoff and where that cutoff is, and that -- we would argue that we would not require an approved, an FDA-approved companion diagnostic. Dr. Pipe can chime in as to whether or not clinicians would be interested in evaluating this. But I do think that this is something that is better spent looking at it post approval, collecting more information and then evaluating whether a cutoff is appropriate after the fact.

Yes, I would agree. I don't think we have enough data to establish an upper threshold cutoff. And we'll have to see what the agency recommendations are. There are other ways to do these neutralizing antibody tests that could still be available to clinicians without it being an FDA-approved assay, I suppose.

The next question comes from the line from Difei Yang from Mizuho Securities.

Just a quick one for Dr. Pipe. With regards to thrombosis, at what level of Factor IX level that you would have started to get concerned or started thinking about there could be such an event?

Well, with most of the clotting factor levels, it's a continuum of risk factors. So there's no particular threshold where you would say you're not at risk and then you are at risk. The normal population range, if you go out 2, 3 standard deviations, you have patients that can be upwards to 150% on Factor IX. So what level would people start to get concerned? Yes. I think when you're well above 150% and you're at a sustained level, that would carry risk. I think it also has to be balanced by -- as with most people in thrombotic risk. It's not just a single independent risk factor, but it's viewed in the overall evaluation of the risk based on other comorbidities, et cetera. So that risk could be very different in a 75-year-old versus an 18-year old.

The next question comes from the line from Kristen Kluska from Cantor Fitzgerald.

Congrats on all of the results that you presented at ASH over these last few days. So Dr. Pipe, during the presentation at ASH earlier today, you made some comments highlighting that liver health could potentially be the primary determinant whether a patient could be deemed suitable or not for gene therapy like this. So if this therapy is approved, what are going to be the key criteria to look at in your view to determine whether someone's liver is healthy enough to receive this therapy? And then of your patients in general, what percent do you think could be eligible based on this liver health status?

Sure. Well, as you probably know, the biggest challenge to liver health in the hemophilia population has been hepatitis C. HIV obviously exacerbates that, but HIV has had pretty good controlling therapeutics now for a number of years. But the hepatitis C pathology was stealth in a lot of patients over a long period of time, and it manifested later in life after 10-plus years. We do know now that you can abrogate some of that pathology by doing the definitive hepatitis C eradication treatment. So some patients' liver parameters will actually improve somewhat after hepatitis C eradication. So I think in the U.S. population, in particular, the vast majority of individuals have now had the opportunity to have their hepatitis C eradicated. So that really bodes well for the future because it means that whatever the status of liver health is in our current population is probably not going to get worse due to that reason. But there's also just North American lifestyle and steatosis, fatty liver, just not healthy lifestyle also contributes to liver health. So we did have some cutoffs based on parameters such as liver enzymes, such as these external assessments of liver health like fibro scans, which are detecting the -- it's an indirect measure of fibrosis of the liver. These were part of the clinical trial program, and it's a few of the reasons why patients were excluded after screening. So I think there's even more reason now to get our patients concerned about their liver health because we are doing a treatment platform which is targeting their liver. So it just makes sense, they should have the best liver condition possible to make it eligible for them. So yes, so we work hard with our younger patients. We want to keep them active. We want to keep them eating healthy. And a therapy like this that allows a patient to maintain an active healthy lifestyle, I think, is really going to be a benefit for the future for them as well.

Your next question comes from the line from Vincent Chen from Bernstein.

One for Dr. Pipe. Curious how you -- as we see more gene therapies come to market over time, how do you think you're going to ultimately choose between different hemophilia gene therapy options? I guess what matters in your decision-making? Is it a matter of the length of total experience with the product, personal experience, average factor levels achieved, consistency, bleeding rates, responders versus nonresponders? What would you look at to compare? And I guess the answer is that you'll present patients with the options and then ask them to choose. And I guess what would you do if they turn around and said, "Dr. Pipe, what would you do if you were me?"

Yes. No. It's a great question. I think we've been doing that in our clinics for a number of years now. The explosion of new products for both hemophilia A and B in the last 5 years is really unbelievable. We've had to embrace all the different methodologies for extended half-life molecules, and we had a complete paradigm shift for treatment for hemophilia A with HEMLIBRA. So we have been doing this kind of risk/benefit interaction in our clinics. And the way we do it is we talk about these therapies well before they were approved. I spend some of my time in our clinic interactions with most of our patients talking about what's in the pipeline, what's being developed, recent clinical trial results. We do talk about how can you make sure that you are -- that you remain eligible for these treatments should they become available. So then once they are approved, we go through that risk/benefit analysis of that particular therapy. And we do make decisions about what's going to be right for you right now in the stage of life that you're at. So I don't have every one of my patients with hemophilia A on HEMLIBRA. But I have a number of them, and I have them at different stages of life because it was the right decision for them at that stage of life. And I think that's going to play out true for gene therapy. Now from a pediatrician's perspective, we spend all of their pediatric lifespan with us worried about maintaining pristine joints. That's the goal, to get them to the adult clinics with healthy joints. So if we now have a therapy that has an option to sustain joint health over the long term and allow them to live their life the way they want to, we're -- I think that's a huge weight on the benefit side that I'm going to want them to consider. I do accept that there are unknown risks with gene therapy, and those are unknowns that we may not know for 40 and 50 years. They can't possibly wait for those results to make those decisions now. I think we have enough safety and efficacy data that it's informed the Phase III trials. And if the Phase III trials pan out the way I think the early data from HOPE-B is, I think this is going to be something that all clinicians can sit down and at least go through that assessment of patients. As far as the little bit of specifics that you said, I mean, am I going to make a decision not to offer it to a patient because 2% or 5% of the patients were nonresponders? I don't think so. I mean there might be a patient that says, "No, I can't. I can't take that risk." But what about the fact that if I can tell them that 80% of the patients are going to hit at least 20% or higher, and the likelihood of you having any more joint bleeds is extremely low, that's going to be a very persuasive data point to share with them.

Your last question comes from the line from Patrick Trucchio from H.C. Wainwright.

Congrats on the data. I have a follow-up on the unique neutralizing antibody profile of the AAV5 vector. I'm wondering if you could tell us what proportion of hem B patients would be expected to present with a titer of NAbs above 678. And how we should think about the efficacy and safety demonstrated in HOPE-B and the presence of NAbs in the context of other hem B programs and in the context of a potential commercialization, specifically how the profile could be reflected on the label?

Yes. What I can tell you is we've done our analysis in hundreds of healthy volunteer patients in South America, Europe and the United States. And I think we can say with relative confidence that less than 5% of patients would have neutralizing antibody titer probably over 100 to 500. And so I think we can get the -- really the overwhelming majority. And if you look at Dr. Pipe said, the one patient at 1,000 to 3,000 because we don't know the cutoff is at 1 to 680, right, because that was just the second highest patient. At 1,000 to 3,000, it's less than 1%. So I think this is a big deal. I think the -- one of the things that we said around our Phase IIb study was that 2 of the 3 patients that we treated in the dose confirmation study had previously failed other gene therapy studies because they were precluded because of their preexisting neutralizing antibodies. And we do know that using our sensitive test that we had north of 40%, and that's not inconsistent with screening failure rates from other AAV studies that have precluded patients with previously neutralizing antibodies from being dosed. So I think this is a big deal. It's a big deal to go through all that education and the discussions with your family and to decide that you're going to go through a gene therapy and get entered into a study and then realize that you now have screened out because you have a low titer preexisting neutralizing antibody. So I think it's a big deal to the patients. And I think it's a big deal for the commercial opportunity that we can treat potentially all patients or nearly all patients and provide them a transformational clinical benefit. In terms of what the label is, I'll leave that for the discussions with the agencies. We'll certainly have a lot more detailed discussions with them in our pre-BLA meeting, and we'll certainly provide updates on that.

Thank you. We have no further questions. With that, I will hand back to Matt for closing remarks.

Okay. Thanks, operator. Just in case anybody wants to revisit the slides that were presented by Dr. Pipe, they're now posted on our website, and so feel free to access them there. As I mentioned earlier, we're extremely enthusiastic about these initial data from the HOPE-B study, which we believe demonstrates the potential for gene therapy to transform hemophilia treatment standards and help patients realize a life full of potential and free from the burden of hemophilia. In this regard, we believe EtranaDez has the potential to be the first hemophilia gene therapy to reach the market in the world and possess a best-in-class profile that optimizes 3 critical variables: one, patient safety; two, durable clinical outcomes; and three, broad patient access. I want to take a minute to thank Dr. Pipe for his participation on today's call and his many contributions to the EtranaDez clinical development program and to express my sincere gratitude to the dozens of patients, physicians and uniQure employees who have worked tirelessly over the years with a singular goal of bringing this potentially transformative therapy to patients living with hemophilia B. We anticipate announcing the 52-week factor activity levels and annualized bleeding rates, which are the other 2 co-primary endpoints in the HOPE-B study in the second quarter of 2021 and to submit filings for regulatory approval of EtranaDez in the second half of the year. We look forward to providing further updates on our progress in the coming months. Thanks again, everybody, for staying late and joining us on tonight's call. We look forward to speaking again soon. Thank you.

That does conclude the conference for today. Thank you all for participating. You may now disconnect.