Ladies and gentlemen, thank you for standing by, and welcome to today's top-line data from HOPE-B pivotal trial of etranacogene dezaparvovec in hemophilia B. At this time, all participants are in a listen-only mode. There will be a presentation followed by a question and answer session. We would like to ask you to only ask one question and one follow-up question. 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, thank you for joining us as we review the initial clinical data from the HOPE-B pivotal study of etranacogene dezaparvovec, 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 etranacogene dezaparvovec. The presentations on etranacogene dezaparvovec that were delivered at the Virtual ASH Meeting are available on the investor page of uniQure's corporate website under Investor Downloads.
Today's webcast presentation will be available on our website at the conclusion of this event. Please know 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 ending 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 Cantor. 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 one of six 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 criterion for other AAV gene therapy product candidates in clinical testing. HOPE-B began enrolling patients a little more than two years ago.
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 a 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 Dolmetsch ?
Thanks, Matt Kapusta. Good afternoon to everyone. As Matt Kapusta stated, we're very pleased with the initial data from the HOPE-B pivotal trial, which Dr. Steven Pipe will review shortly. I would like to highlight that we have also presented new clinical data on etranacogene dezaparvovec from the ongoing phase IIb study that shows that a single administration of etranacogene dezaparvovec is well-tolerated and leads to sustained factor IX activity of 41% at 52 weeks. Two years after dosing, all three patients are free from factor IX replacement therapy, and two of the three patients have had no bleeding events. A single bleed was reported in one 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 five years into the study, AMT-060 shows steady long-term continued durability, including stable Factor IX expression, approved disease phenotype, and substantial reductions in bleeding and factor consumption. These clinical data, together with the HOPE-B pivotal data, speak to the strength of the uniQure platform, and we plan to include 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 five uniQure trials conducted in nearly 80 patients with hemophilia B and other indications. These data also reflect the strength of our proprietary in-house commercial-scale manufacturing capabilities and our use of an insect cell baculovirus process that has now been shown to be safe and effective, and that 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 etranacogene dezaparvovec and the principal investigator of the HOPE-B pivotal study. Dr. Steven Pipe , thank you so much for being with us today.
Thank you, and good afternoon, everyone. It's my pleasure to be a part of this afternoon's event and to go through the initial data from the HOPE-B study. If you could advance to the initial slide here, I want to go over the goals of this program. Severe hemophilia is characterized by a lifetime risk for spontaneous bleeding, primarily into 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 of Factor IX concentrates. The goal of gene therapy for hem B is to deliver a one-time 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. 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 six to eight-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 four and a half to five 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 was evaluated in the three participants who participated in that phase IIb study. They're continuing to show a mean factor IX activity now two years out from dosing of 44%, again, and 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, this is the largest cohort of gene therapy for hemophilia that's been reported 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. The individuals had to have previously been on continuous prophylaxis for at least two 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 to date, preexisting anti-AAV neutralizing antibodies were assessed, but they were not used as an exclusion criteria. The participants were evaluated in a lead-in phase of 26 weeks to assess bleeding events occurring during standard of care continuous routine Factor IX prophylaxis. Participants were then dosed at two times 10 to the thirteenth genome copies per kilogram as a single approximately one-hour infusion. Then, they were followed weekly for 12 weeks, then monthly through the first year, and then continuing every six months in the long-term follow-up, which will be through year five. Next slide. The study has three co-primary endpoints to evaluate efficacy and durability.
A central one-stage Factor IX clotting assay is reported at 26 weeks after dosing, 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. 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. This is showing the patient disposition of the trial participants.
75 patients were screened. There were eight screen failures, but this is mostly for failure to sign the informed consent form, or they were 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 were deemed to be ineligible after we had an evaluation of their liver health using scoring tools such as the FibroScan. Some were 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. 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 one of the efficacy endpoint assessments. I am going to describe in the safety assessment that one participant only received 10% of the scheduled dose.
Next slide. The participants in this study were a mean age of 41 and a half 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. Notably, 42.6% of participants had neutralizing antibodies directed to the AAV5 capsid. There was a max titer observed in one 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 were on Factor IX prophylaxis. 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 and a half 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 lifespan. The percentage of patients with 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.
To have that matched with the 42.6% who had the neutralizing antibodies to AAV, again, matching population seroprevalence studies that have been done previously. 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. Here we're showing the Factor IX activity of all the participants up through 26 weeks post-dosing. Now, the activity levels were censored in the first two weeks to account for residual Factor IX activity from the Factor IX prophylaxis prior to dosing. 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. The expression was robust by three 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, and I think it's pretty informative. Over 80% of the patients have achieved the Factor IX activity of at least 20% at six months, but further, 68% of the participants are at least 30% or higher, and 38% have Factor IX levels that are in the non-hemophilic 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. In red, this indicates the nine 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. These results show similar Factor IX expression continuing beyond week 26, with one 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. What we're showing here are those who received the full dose of vector. Patients with undetectable neutralizing antibodies are all plotted, stacked on top of each other at seven on the horizontal axis, because that was the threshold of the assay. 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 one participant who had a titer of over 3,200 who did not respond, and he's outside this graphic scale.
Overall, what these results show is it confirms the observations in the preceding phase I/II study of AMT-060 and the phase IIb study with this enhanced vector, that there was 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 through 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 one non-responder 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 may be 1% or so of patients who are going to have titers at that level.
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. 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? 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 themself a Factor IX treatment.
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. 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 zero bleeds post-dosing, compared to only 30% of those during the lead-in phase. With regard to the treated bleeds, meaning they actually required a Factor IX infusion, 87% of subjects had zero treated bleeds, compared to only 33% during the lead-in phase when they were on standard care prophylaxis. Let's go to the next slide. 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. Nine 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. You can see these include things like flu-like symptoms, headache, the ALT, AST increases, fatigue, nausea, et cetera. There were nine participants who received 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. 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. That would, of course, lose those expressing cells from contributing to the Factor IX expression. 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. In these nine 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 nine individuals in the mild range, between 8% and 39%. There were seven patients who experienced an infusion-related reaction. In one individual, this resulted in discontinuation of the infusion, so he only received 10% of the dose. 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. 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. He never got restarted. He never got more than 10% of the dose.
In the other six individuals who had infusion reactions, it was interrupted in three. They received some antihistamines and IV corticosteroids, and then their infusion was able to be restarted, and they got the full dose. In three, the infusion wasn't interrupted. 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. 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.
What was 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's significantly increased to near normal levels at 26 weeks post etranacogene dezaparvovec, 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 preexisting anti-AAV5 titers up through 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 a safety profile that's consistent with the early phase study. The final analysis is planned at one year, 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. It would be hoped then that this would support a marketing authorization application. Next slide. 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.
Secondly, many thanks to the investigators and their teams who really tirelessly care for these patients. Lastly, the uniQure trial team, who really have made all of this happen through some extraordinary circumstances over this past year. 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. Steven Pipe . Before we open it up to questions, I'd like to summarize six key takeaways from the interim HOPE-B data. First, the HOPE-B study has met its first co-primary endpoint with mean FIX activity of 37% of normal at 26 weeks. Additionally, the FIX increases in the study have been durable thus far, with patients maintaining therapeutically relevant activity for up to 18 months. Second, the patients experienced a 91% decrease in their number of treated bleeds. In particular, 87% of patients 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 treatment with etranacogene dezaparvovec.
Fourth, the data show no correlation between pre-existing antibodies to AAV5 up to a titer that includes more than 95% of the general population. Specifically, 22 of the 23 patients with preexisting 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 is made possible by AAV5's favorable immunogenicity profile. Lastly, but not least importantly, etranacogene dezaparvovec was well-tolerated with no treatment-related serious adverse events reported, no inhibitor development, and no observed correlation between safety and preexisting neutralizing antibody status. With this, operator, please open the line for analyst questions.
Thank you. Ladies and gentleman, just a quick reminder, if you would like to ask a question, please press star and one on your telephone keypad and wait for your name to be announced. Please be advised only to ask one question and one followup question. Your first question comes from the line from Paul Matteis from Stifel. Your line is now open, please ask the question.
Great. Thanks so much for taking my question. 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 BioMarin setback and increasing focus on durability of hemophilia gene therapies? and then one question for Dr. Steven Pipe . The hemophilia population, I think many on this call have heard that patients may be conservative when they look at new therapies. How do you view the adoption curve of gene therapy in hemophilia B within your practice and in other clinicians' practices? Thanks so much.
Maybe I'll start off. Thanks for the question, Paul Matteis . I think there's a couple things I would note. One is that in all of our interactions with the agencies 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. Keep in mind that as part of this submission, we would expect to have more than two years of follow-up from the phase IIb dose confirmation study and more than five years of follow-up from the patients, the 10 patients, in the phase I/II study. We think that this will be a comprehensive dataset that will obviously include 52 weeks of follow-up on all 54 patients in the pivotal study. We think it's a comprehensive dataset that would demonstrate the long-term safety and tolerability and durability of our gene therapy.
Keep in mind, I do think, and Dr. Steven 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 two different disorders that impact two 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 eight years, and our own data that we presented at ASH now up to five years. That's how I would answer the regulatory piece, and I'll hand it over to Dr. Steven Pipe to provide his comments.
Sure. One follow-up to that, Matt Kapusta. 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. I believe the agency is sophisticated, that they know about the differences between these two different proteins. 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. I think I'm very confident in the data that we've shown from the phase III to date. I think it's really reassuring.
It's building on long-term expression data that we have from within this program, but also outside of this program in other factor IX expressions. 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've seen rapid adoptions 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. Patients have been waiting for gene therapy for 20 years.
We thought back in the late 1990s 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. 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. I think it's still going to be a personal decision between a clinician and the patients, but this is really strong data.
Great. Thanks very much.
Thank you. Our next question comes from the line from Madhu Kumar from Baird. Your line is now open.
Yeah. I guess my first very simple question for Dr. Steven Pipe is, among the hemophilia B patients you treat now, what fraction of them would you consider for a drug like AMT-061?
As I was trying to suggest when I was reviewing the demographics, I can tell you that the first hem B patient that I treated with gene therapy was 68 years old and the youngest patient that I've treated across all the trials at our center was just over 18. I don't see an 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 him going forward. Patients share this spontaneity that returns to their lives, the ability to, you know, live their lives out the way they want to, not having to think about their hemophilia anymore. These are really powerful drivers.
for those young people, I definitely see the attraction of this therapy. 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." It's driving them actually to want to get joint replacements so that they can get on with their life. 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. 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. I see that this has application across the adult lifespan.
Okay, great. Then, one question both, I guess, for Dr. Steven Pipe and for the company. How do you think about follow-on studies, both in the non-adult setting and the pediatric setting, given sort of preclinical data that uniQure has put out there over the last few months or so? Also the potential to go after these higher antibody titer patients using some of these new technologies out there, like FcRn 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 NAb basis might not necessarily be a good candidate for 61.
Do you guys want me to start?
I don't know, Dr. Steven Pipe do you want to take that first?
Well, I'll just add my point that 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. It's not integrated in the DNA. With cell division, you don't copy the episomal transgene, so the daughter cells don't get it. If you do this approach in very young school-age individuals, you are apt to lose expression over time. We think the bulk of the liver growth is probably up through around age 12 or 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. I would hope that we would have the opportunity to do that even with this product potentially.
Yeah. The only other comments that I would add to what Steven Pipe said is two 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 one or two years. Again, the oldest follow-up is up to a decade now. 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 non-human primates the ability to actually redose using common technologies. One of the advantages, the other side of being able to treat patients with pre-existing 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 readminister it to the extent that there is a waning effect. I think we do have great interest of trying to expand.
Obviously, this will be something that we'll have to do in collaboration with CSL, but we have great interest collectively in 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. Thanks. I'll say, this is going to sound hokey. I realize that 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 a cure of hemophilia.
Thank you, Madhu Kumar.
Thank you. Your next question comes from the line from Robyn Karnauskas from Truist Securities. Your line is open.
Hi, guys. Thank you for the question, and I reiterate what my colleague just said. I think you just touched on it a little bit on retreatment. Do you have a sense of how high the antibody titers are over time after patients get therapy? We have a sense of maybe what percentage might be able to be retreated without any other ways to lower the antibody. 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 suggests they may need steroid use, or there's any other correlation between either side effects or needs or levels over time at all that you're starting to see? I mean, there's two questions there. Thank you.
Yeah. The first question, it's one thing when you're exposed environmentally to AAV5. The titers, as we see 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. That's normal and expected in all gene therapy studies. Now, what we did in these non-human primates is we would infuse them with an AAV5 reporter gene. We would mimic the substantial increase in titer that you would expect with an in vivo intravenous administration and then use an immunoadsorption technology to reduce their titer down to a level where it's no longer neutralizing or inhibits transduction.
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. Steven Pipe , and I don't want to put words in Dr. Steven Pipe 's mouth, but I think he had 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 pre-existing neutralizing antibodies versus those that haven't.
I guess a follow-up for Dr. Steven Pipe . 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. I certainly don't, when I'm consenting patients for participation in these trials, I certainly don't promise them retreatment. 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 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 concede that there's not very many things in life that last for a lifetime, but I hope that there is such a level of durability from this treatment.
I think based on the early phase I, II data, what we've seen with other trials in hemophilia B, a decade or more is pretty substantial and would really be transformative for a patient at any time in their adult life. 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. That's my perspective as it is now. 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 time.
Great. Thank you.
Thank you. Ladies and gentlemen, may I please ask you, in order to give everyone the opportunity to ask their question, to please stick to only one question? Your next question comes from the line from Joseph Schwartz from SVB Leerink. Your line is now open.
Hi. Thanks very much, and 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 nine patients in that group. Were there others in that range, or any other defining characteristics that might be-
Yeah
interesting to note?
Sure. Yeah. I'll try to give you a little bit of color there. The non-responders are limited to the patient who had the super high titer, and then the one patient who only got 10% dose. We had no non-responders 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%-10%, both of those individuals had transaminase elevations, and that's where their Factor level was salvaged after the corticosteroid treatment. If you look at the next bracket of 10%-20%, I think it's four out of the six had transaminase elevations, and that's where their Factor IX level was stabilized. After that, now you're in the 20%+ range, vast majority of those individuals did not have the transaminase.
If I was 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. I hope that we'll be able to do a deep dive into the data and the experience from those nine 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. Hopefully, that gives you a little bit more color about what's happening with those few patients at the lower bounds.
Yeah, absolutely. That's super helpful. Thanks, Dr. Steven Pipe . Maybe one for the company. What is your understanding of whether the FDA or EMA has any critical thresholds that they want to see etranacogene dezaparvovec keep 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?
Thanks, Joseph Schwartz . I think that the study design, and now includes co-primary endpoints that include annualized bleeding rates after the administration of etranacogene dezaparvovec compared to prior to administration while patients were on high-dose Factor IX replacement therapy. The study is powered to demonstrate non-inferiority on a bleeding standpoint. We do believe that has traditionally been the gold standard. It is the traditional way that these products have been improved, and we think that is a standard that the agency will view as something that would justify approval, determined based on 52 weeks of follow-up data. If you can 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.
Makes sense. Thanks for taking my questions.
Thank you. Your next question comes from the line from Jim Birchenough from Wells Fargo Securities. Your line is open.
Hi. Thanks for taking the question. This is Yanan dialing in for Jim Birchenough . 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 patient's factor levels, is the pattern consistent with expectation? Because I think you mentioned for non-hemophiliac levels of Factor IX, you should really have no spontaneous bleeding. For the mild range Factor IX, you should see very rare spontaneous bleeding. 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? Thanks.
No, it's a great question. I will say that the bleed analysis as part of the secondary endpoint still needs a full analysis. 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. I do have one individual who's at the lower end of the Factor IX expression. I do have that perspective as well that we're still seeing benefit even though they're just into the mild range.
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? I think that data will be forthcoming, and we just don't have that full analysis right now.
I'll just say just two things really quickly. One is, in the data that was presented, the propensity for spontaneous bleed is really why many of these patients are on prophylaxis to begin with. This group of patients had 37 spontaneous bleeds in the lead-in period that required treatment. All these patients subsequently in the 26 weeks after had three spontaneous bleeds. 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. In the last 52 weeks that we evaluated, they really didn't bleed at all. I think that substantiates some of the commentary that Steven Pipe was making.
Got it. Thanks. If I can squeeze a very quick question on corticosteroid impact on Factor IX activity. I hear what you said about patients even after corticosteroids still remained in the mild range. 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 hemophilia B patients? Thanks.
I would just tell you my personal experience is that these patients are similar as to observations in other trials. By the time you see the transaminase elevation, sometimes the Factor IX activity will not change at all. It'll just be sustained. The transaminase is resolved on steroids, and there's no loss of Factor IX activity. 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 with only nine subjects that had to go through this, all of them managed to maintain their Factor IX in the mild range. They're getting at least a good benefit from this treatment, even though they had that adverse event.
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. Hopefully they're going to settle out as we observed in the clinical trial program.
Great. Very helpful. Thank you so much.
Thank you. Ladies and gentlemen, please may I remind you to only ask one question and no follow-ups anymore in order to give everyone a chance to ask a question. Thank you. The next question comes from Danielle Brill from Raymond James. Your line is open. Danielle Brill, your line is open.
Hi, guys. Good evening. Thank you for the question and 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 a spontaneous bleed that required treatment actually had FIX levels well above the non-hemophilic range. I was wondering if you could provide a little bit more color on this patient and how we should think about that. Thanks.
I don't know. Do you want Eileen Sawyer answer that? Is that okay?
Sure, I'll take that. 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 two hip surgeries on separate occasions.
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. That was considered a precaution to ensure that there was no adverse effects from that bleeding.
Yeah. This is an important thing to know. I remember meeting a patient that actually had a liver transplant, they had absolutely 100% normal levels of Factor IX activity. They would tell me that because sometimes joint damage can be so bad that they might still bleed. It depends on a number of these comorbidities, as Eileen mentioned.
Got it. That's helpful. Thank you.
Next question.
Thank you. The next question comes from the line from Martin Auster from Credit Suisse. Your line is open.
Hi, this is Matt [Turropp ] on from Marty. Thanks for taking the question. Have you measured factor expression levels using the chromogenic assay? If so, I'm curious what relationship you saw between the one-stage and chromogenic assays, and also have regulators indicated a preference for which technique they prefer? Thanks a lot.
Yeah, we have measured both Factor IX activity using both the chromogenic assay and the one-stage clotting assay. The differences between the two we've characterized, we understand, and they're consistent with what has been reported by others. 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.
Great. Thanks a lot.
Thank you. The next question comes from the line from Salveen Richter from Goldman Sachs. Your line is open.
Thanks for taking my question. Could you give us more clarity on the bleed rates? 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. Steven Pipe, do you want to address that?
Yeah. Just to remind people the numbers, because this slide wasn't up for very long. If you still have your decks there. In the lead-in phase, when these gentlemen were all on regular prophylaxis, 123 total bleeds, 107 of which were treated. We look at the breakdown there. 42 spontaneous bleeds, 66 traumatic, and 15 others. If we look within the spontaneous, 88% of those required treatment. If we look at the traumatic bleeds, 83% required treatment. Then, in the post-transduction, 21 total bleeds post-transduction. Only seven spontaneous bleeds, but only three that required treatment. 11 traumatic bleeds, five of which required treatment and then we have three others. I think we even see a shift in the perceptions of the patients. This is what I would take from this data.
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. 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. I think the data is what it is. I think the overall reductions are exactly to be expected. 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. He came and saw me the next day. That was recorded as a bleed and he didn't treat for it.
Honestly, I would've had the same bruise and I would've had the same fat lip if it had happened to me, too. I think, in the context of this data, expecting bleeds of zero in 100% of the population is not reality. The fact that we had a drop to, or if you like, an increase to 87% of the patients who experienced zero treated bleeds, I think is entirely in keeping with the Factor IX levels that we observed in the cohort.
Thank you.
Thank you. The next question comes from the line from Joseph Thome from Cowen and Company. Your line is open.
Hi there. Thank you for taking my question and 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 non-issue that maybe can be remedied with just physician education upon launch? Thanks.
As far as we have reviewed the data to date, there doesn't appear to be any predictors of these infusion reactions. 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 trials 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. The higher the dose of vector being delivered, the more likely you are to see these. It's also related, it seems, to the rate of the infusion. What is being manifested 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. That's a reasonable hypothesis.
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. 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. 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.
Great. Thank you.
Thank you. Your next question comes from the line from Luca Issi from RBC. Your line is open.
Oh, fantastic. Thank you for taking my question, and congrats on the progress. Great news for patients, first of all. Maybe a question for either the company or Dr. Steven Pipe. Wondering if you can comment on the competitive landscape here, given that Pfizer and Freeline are in the mix as well. Maybe asked a little bit more directly, do you expect that the higher Factor IX activity that Freeline has shown will drive a superior clinical profile? Thank you.
Yeah, maybe I'll start off, and Dr. Steven 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 three critical factors. The first one is efficacy, the second one is safety, and the third one is patient access. 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. We think that we'll be able to do that durably. At the high end, we are not increasing factor IX to such an extent where it potentially can pose a thrombosis risk.
If you look at the overwhelming majority of patients, as I think Dr. Steven 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. 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. 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.
Yeah, I would agree. I think there is some risk. If you're only going to accept the lower bound as normal, the inter-patient variability is not going to go away with the AAV platform. To think that you can thread the needle in a very narrow window of Factor IX expression, I think is just unreasonable. 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.
Terrific. Thank you.
Thank you. The next question comes from the line from Suji Jeong from Jefferies. Your line is open.
Hi. Thanks for taking my question. I have a question for the company. Do you think the FDA or EMA will require companion diagnostic for the neutralizing antibody as part of approval, or have you had such discussion with the agency? Thank you.
Yeah, 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. We have had discussions with both the device side of the agency as well as the biologic side of the agency, and very good interactions with them. I can tell you just from our perspective, and I think Dr. Steven Pipe chimed in on this. When you have 22 of 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'd be very difficult to establish a cutoff and where that cutoff is. That, we would argue that we would not require an FDA-approved companion diagnostic. Dr. Steven 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.
Yeah. I would agree. I don't think we have enough data to establish an upper threshold cutoff. 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 a FDA-approved assay, I suppose.
Great. Thank you.
Thank you. The next question comes from the line from Difei Yang from Mizuho Securities. Your line is open.
Good afternoon. Thanks for taking my question. Just a quick one for Dr. Steven Pipe . With regards to thrombosis, at what level of Factor IX level that you would started to get concerned or started thinking about there could be such an event? Thanks.
With most the clotting factor levels, it's a continuum of a risk factor. 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 two, three standard deviations, you have patients that can be upwards to 150% on Factor IX. At what level would people start to get concerned? When you're well above 150%, and you're at 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 their risk based on other comorbidities, et cetera. That risk could be very different in a 75-year-old versus an 18-year-old.
Thank you.
Thank you. The next question comes from the line from Kristen Kluska from Cantor Fitzgerald. Your line is open.
Hi, good afternoon, everybody, and congrats on all of the results that you presented at ASH over these last few days. Dr. Steven 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 a gene therapy like this. 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? Thank you.
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. 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+ years. We do know now that you can abrogate some of that pathology by doing the definitive hepatitis C eradication treatment. Some patients' liver parameters will actually improve somewhat after hepatitis C eradication. I think in the U.S. population particular, the vast majority of individuals have now had the opportunity to have their hepatitis C eradicated.
That really bodes well for the future because it means that whatever the status of liver health is in our current population, it's probably not going to get worse due to that reason. There's also just North American lifestyle. Steatosis, fatty liver, just not healthy lifestyle also contributes to liver health. We did have some cutoffs based on parameters such as liver enzymes, such as these external assessments of liver health like FibroScans, which are detecting the 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. 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. It just makes sense.
They should have the best liver condition possible to make it eligible for them. Yeah. We work hard with our younger patients. We want to keep them active. We want to keep them eating healthy. 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.
Great. Thank you.
Thank you. Your next question comes from the line from Vincent Chen from Bernstein. Your line is open.
Thank you very much for taking the question. One for Dr. Steven Pipe . I'm curious. 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 to 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 non-responders? What would you look at to compare? I guess if the answer is that you'll present patients with the options and then ask them to choose, then I guess, what would you do if they turn around and said, "Dr. Pipe, what would you do if you were me?
Yeah, 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 five years is really unbelievable. We've had to embrace all the different methodologies for extended half-life molecules. We had a complete paradigm shift for treatment for hemophilia A with HEMLIBRA. We have been doing this kind of risk-benefit interaction in our clinics. 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 remain eligible for these treatments should they become available.
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. 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. 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.
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, 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 with patients.
As far as the little bit of specifics that you said. Am I going to make a decision not to offer it to a patient because 2% or 5% of the patients were non-responders? I don't think so. There might be a patient who says, "No, I can't take that risk." 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.
Great. Thank you very much for taking the questions, and congrats on the progress.
Thank you. Your last question comes from the line from Patrick Trucchio from H.C. Wainwright. Your line is now open.
Hi, good afternoon. Congrats on the data. I have a follow-up on the uniQure 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 in 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.
Yeah. 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. I think we can say with relative confidence that less than 5% of patients would have neutralizing antibody titer probably over one to 500. I think we can get really the overwhelming majority. If you look, as Dr. Steven Pipe said, at the one patient at one to 3,000 because we don't know the cutoff is at one to 680 really because that was just the second highest patient. At one to 3,000, it's less than 1%. I think this is a big deal. One of the things that we said around our phase IIb study
Was that two of the three 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. 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 preexisting neutralizing antibodies from being dosed. 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 decide that you're going to go through gene therapy and get entered into a study, and then realize that you now have screened out because you have a low titer of preexisting neutralizing antibodies.
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.
That's helpful. Thank you very much.
Thank you. We have no further questions. With that, I will hand back to Matt Kapusta for closing remarks.
Thanks, operator. Just in case anybody wants to revisit the slides that were presented by Dr. Steven 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 etranacogene dezaparvovec has the potential to be the first hemophilia gene therapy to reach market in the world and possess a best-in-class profile that optimizes three critical variables: one, patient safety, two, durable clinical outcomes, and three, broad patient access.
I want to take a minute to thank Dr. Steven Pipe for his participation on today's call and his many contributions to the etranacogene dezaparvovec 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 two co-primary endpoints in the HOPE-B study in the second quarter of 2021, and to submit filings for regulatory approval of etranacogene dezaparvovec 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.