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

Hello, everyone. My name is Gena Wang, SMID cap biotech analyst at Barclays. It is my great pleasure to introduce our next presenting company, uniQure. With me on the screen is Matt Kapusta, Chief Executive Officer from uniQure. Matt, do you want to kick off with a brief introduction about -- overview about uniQure?

Yes. Sure. Well, first, Gena, thank you for having us here at the conference. We're delighted to see you over video. So I'm Matt Kapusta, Chief Executive Officer of uniQure. So at a high level, uniQure is one of the leading pioneers in the exciting field of genetic medicine. The company was founded in 1998 and was the sponsor of the first approved gene therapy in the western world, which is a product called Glybera. That was approved in Europe for the treatment of lipoprotein lipase deficiency in 2012. And what I think this opportunity afforded us beyond the experience of bringing a highly innovative treatment to the market is the opportunity to invest very significantly in manufacturing capabilities, which are so part and parcel and critical to the successful development of genetic medicine, in particular, AAV gene therapy. So we are based really across the Atlantic and here in the United States. We have approximately 350 employees with about 200 employees here in Lexington, Massachusetts, here in an 80,000-square foot facility, where we do all of our CGMP manufacturing. We also have a research and technology center of excellence in Amsterdam, where the company was founded in the Netherlands. Our lead program is a hemophilia B gene therapy called AMT-061 or EtranaDez that we are currently in a pivotal study for evaluating that with patients that have severe or moderately severe hemophilia B. And we do plan to have the first data from that study before the end of the year, which will represent not only the first data from a pivotal study of any gene therapy in hemophilia, but it will probably also represent one of the largest data sets ever presented for any gene therapy. So we're very excited about that. We did announce in June that we collaborated with CSL Behring to commercialize EtranaDez across the world. CSL Behring is one of the largest hematology players in the world with commercial operations in more than 80 countries. They are extremely excited about the transformation that EtranaDez can have with patients in hemophilia B, and we look forward to closing that transaction. We have also another very exciting program in Huntington's disease, which represents one of the largest monogenic disorders that is currently being explored in clinical testing. So again, we have a onetime administered AAV gene therapy that is meant to suppress the mutant or pathological gene that we're currently in Phase I/II testing. And then we have a series of other gene therapies targeting largely liver-directed disorders and CNS diseases. And all of this is supported by our state-of-the-art manufacturing and enabling technology platform that, again, has been in development for the greater part of 2 decades. So with that introduction, I'll hand it back over to you, Gena, and we can get into some more details.

Sure. Maybe we'll start with hemophilia B. [ program ]. So I think we did see BioMarin had a complete response letter and they were asking for 2 year end point. And then as we know, there is a history behind it because of the Phase I/II data did not reciprocal -- I mean the Phase III did not -- there were some differences between Phase I, II and Phase III data. So based on your interaction with the regulatory agency, was that very sure? Is that 1-year endpoint will be sufficient for your hemophilia B program? And maybe that's the first question.

Yes. So obviously, there is -- it's difficult for me to comment on BioMarin's program, but I think you did mention one aspect, I think, that is specific to their program, which is potentially some differences in Factor VIII increases that they evidenced in the period of follow-up compared to their Phase I/II study and their pivotal study. I think there are -- in looking at the long-term follow-up data from BioMarin Phase I/II study, I think there were some concerns about the potential for waning of effect in terms of Factor VIII activity over time. And then again, based on what is publicly available, it does appear that BioMarin was pursuing accelerated approval on a fairly limited subset of data from their pivotal study as well as limited follow-up. So those are factors -- we weren't participants in their discussions with the agencies, but there are some notable differences compared to our program thus far. And I think by the design of our protocol and where we are in the study, I think we would anticipate a BLA submission to include 1 year of follow-up data on all 54 patients from our study. And in our interactions with the agencies, there's been no indication whatsoever that, that would not suffice for the registration of EtranaDez. Now having said that, we have not yet conducted our pre-BLA meeting with the agency where we can have that discussion with the benefit of them reviewing the full subset of data. But based on our interactions thus far, that's why I would have to answer that question. And really when you look at the many different hemophilia therapies that have been approved, largely, they are able to get approved based on clinical data. The gold standard of clinical data for hemophilia patients is the control of bleeding. And as I mentioned, I think our study was designed as a noninferiority study. The power to be statistically significant to demonstrate noninferiority based on annualized bleeding after the administration of EtranaDez as compared to prior. And that, in our view, would satisfy how the agency has really approved historical hemophilia products, and we wouldn't see a reason why that would be any different for gene therapy, particularly given that we now have 5 years of follow-up data from our Phase I/II study. Some of that will be presented at ASH. The data that we previously presented has not shown any issues with durability. And we'll also have 2 years of follow-up from our dose confirmation Phase IIb study. So these are all the reasons why I think we feel like we're in a good position from a clinical data standpoint. But as I said, we'll know more after we have our pre-LA (sic) [ pre-BLA ] meeting with the agency early next year.

Okay. Great. And maybe a few more questions regarding hemophilia B. So the -- I hear myself echoing.

I'll go on mute here, okay?

Yes. Okay. So the -- regarding the pivotal trial, was that -- did you use the commercial product? And then also, was -- all the patients had the prophylactic steroid treatment?

Yes. So we did design this study and the material -- the drug product that we provided these patients to utilize the process and the methods that we do plan to commercialize with. So we don't anticipate any material changes to those that, in our view, would impact comparability. The second question was regarding the steroid regimen. Just as a reminder, none of the patients in our study by protocol received prophylactic steroid administration. And that is consistent with the design of the -- not only the Phase I/II study, but also the Phase IIb study. By protocol, if there are elevations of liver enzymes, out of precaution not necessarily out of causality, but out of precaution, the investigators would administer steroids. But we haven't commented on the pivotal study, but that will be information that we certainly will review when we have our data presentation before the end of the year on the HOPE-B study.

Okay. That's very helpful. So that would just like thinking regarding quite some other programs, especially hemophilia A, a lot of variability was attributable to maybe prophy application and then they did see the differences that maybe Spark those -- Spark saw the differences when you give a prophy versus none. So just wondering your thoughts regarding your program, is there anything, the factor or the transgene make a differences?

Yes. I mean all -- it's hard. I mean all we can comment on is our own experience. Normally, the variability in the first 12 weeks after treatment is due to immune responses associated with the specific capsid. And what basically happens is there's a cellular immune response, whereby T cells attack the transduced hepatocytes and that's because fragments of the capsids are presented on the surface of the cell and the T cells believe that they're foreign. And then after attacking it, if they kill hepatocytes, those cells obviously can't express anymore. And that yields itself or manifests itself in a waning of expression or activity. We -- based on the data that we've presented, really across all of our AAV5 gene therapy studies, and we've done like 5 of them even before this pivotal study. We just have not seen those kinds of cellular immune responses that lead to a striking or significant loss of activity within relatively close proximity to administration. So we just don't see it. And as a result, we don't administer steroids. In the Phase I/II study, we did have patients with elevations of liver enzymes. Remember, liver enzymes can be elevated for many, many different reasons. There are other tests that can be done to quantify if there's actually an immune response. Those are not the same thing, elevated liver enzymes and immune responses. In those patients that we had from the Phase I/II study that had elevated liver enzymes, firstly, they were at a relatively low level, below 2x the upper limit of normal. Secondly, there was no confirmed cellular immune response. And thirdly, there was no loss of activity. So it's hard to comment on other programs with maybe different capsids. There might be different situations with them. But as I said, in our program, with AAV5 gene therapy, we just simply haven't seen those similar types of immunological reactions.

Okay. That's very helpful. So I remember in the past, for your hemophilia B program, you did not screen the existing neutralizing antibody. And is that still the case for hemophilia B? Also, do you apply that criteria to the other gene therapy programs?

Yes. So I appreciate you bringing up that point, because it's actually a very important point for this HOPE-B pivotal study. Not only is it the first from a pivotal study in hemophilia and one of the largest data sets, but it's one of the largest data sets where we can pull together a significant amount of data on the impact of pre-existing neutralizing antibodies. As you know, really from virtually all other gene therapy studies, patients that might be environmentally exposed to these naturally occurring AAVs can develop levels of preexisting neutralizing antibodies. And they are not eligible for inclusion into these studies. And if should any of these products go on the market, they likely would be contraindicated for access to those gene therapies. For the first time, we conducted a 54-patient study where we did not screen patients out for pre-existing neutralizing antibodies. So we did measure it. But all those patients received AMT-061. And so we're -- we do look forward to providing some commentary when we present our data to explore the correlation of preexisting neutralizing antibodies to expression and potentially to clinical benefit. To the extent that we're able to demonstrate that patients with high titers of preexisting neutralizing antibodies are able to derive meaningful transduction and clinical benefit, we think that would be one of the first AAV5 -- would be one of the first vectors to do that, and it could benefit really all of our gene therapy -- AAV5 gene therapy programs that we have. We do not currently, in our Huntington's disease program, screen patients out for pre-existing neutralizing antibodies. And what we do know is that whatever preexisting neutralizing antibodies exist systemically, there's a significantly lower amount that exists within the CNS compartment. So that would make it even less of an issue.