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

[Audio Gap] And maybe share with us kind of the strategic vision. The company has kind of, I think, really starting to define itself in this past couple of years here and going forward. Maybe speak from that perspective. And We'll jump into the programs from there?

Yes. Yes, I appreciate that. First, let me just thank you, Marty, and Credit Suisse for having us here at the conference. We're delighted to attend. And I'm also here with Dr. Ricardo Dolmetsch who's our President of R&D as well, who will be helping me answer some of the questions that you might have. Just in terms of a brief introduction, so uniQure which was founded in 1998, in our view, is 1 of the pioneers within what has been a fast emerging space of gene therapy. Back in 2012, uniQure was able to get the first approved gene therapy in the Western world, a product called Glybera. And on the back of that, we were able to make very significant investments in our platform, which, in our view, has been such an important part of the success that we've had and what we believe will be our success going forward. We were able to parlay that success with Glybera into the development of an exciting hemophilia B gene therapy, which is currently in pivotal stage clinical trial. We expect data before the end of this year, initial data on all 54 patients in the pivotal study and look towards filing a BLA submission next year. We have another very exciting program in Huntington's disease, which is a very significant clinical unmet need that impacts somewhere around 60,000 or 70,000 identified patients in the United States and Europe. We are the first onetime gene therapy product candidate to be in clinical testing and are currently undergoing a randomized controlled Phase I/II study. And really, these programs represent 2 key areas for us, which are liver-directed gene therapy disorders as well as neuroscience, which we think is a very significant opportunity within adult and pediatric neurology. We have a program that leverages a lot of our insight to know-how in technology, that we're in late-stage preclinical and IND-enabling studies in a disease called Spinocerebellar ataxia type 3. And we look forward to that being the next IND that we would submit an additional clinical program. And we have a number of other exciting liver- and CNS-oriented gene therapies that we look forward to very much talking about in the first half of this year. We entered into a collaboration on our hemophilia B program with CSL that is in practice of antitrust regulatory review. And we think that this is a really fantastic strategic deal and so much that it provides us with a really strong player in the hemophilia space with more than 3 decades of experience to commercialize that product and to expand it into as many patients as possible around the world as fast as possible. And we're also very excited about deploying the capital from that transaction in aggressively expanding our pipeline towards CNS and liver-directed diseases as well as in continuing to invest in our manufacturing platform as we really work to migrate gene therapy applications in larger genetically defined indications. So look forward to talking about these items in more detail today.

Sure. Let's start talking about 61 for hemophilia B. And maybe just to talk a little bit about the clinical program, just frame where that is. Obviously, data is expected pretty -- in the very near term. I think most of the questions and interactions we've had lately with investors have been more around what you see as kind of necessary to kind of have a successful regulatory outcome post data, but let's talk about kind of the trial, what the outcomes that you're targeting are and what you think kind of the threshold of the bar is here to kind of support success in the next steps in approval?

Sure. Ricardo, you want to address that one?

Absolutely, yes. So for AMT-061, this is -- we're delivering Factor IX, and we essentially have 2 main outcomes. So one, of course, is Factor IX levels. And we have been -- we have a Phase I/II study where we have shown that we can get significant Factor IX activity. And then in addition to that, we -- our second endpoint or the second thing we're measuring, of course, is annualized bleeding rate, which is an important aspect of hemophilia to the absolutely clinically important outcome. And we're well on track to measure that after 26 weeks. And then we will continue that study and we will report. And then we will report on that data soon. And then we will also bin later, next year in March or so, we will have, it will be a year since the enrollment of the first patient in our Phase III, and we will have the -- we will have the full data set.

Sure. So the annualized bleeding rate sort of speaks for itself, right, in terms of what that median ABR, mean ABR looks like. Do you have any sort of -- kind of an efficacy bar or a framework for how to think about what the Factor IX levels are? And obviously, you showed a fairly consistent profile in that small sample size in Phase I. But what are you looking for from the Phase III? And is there any sort of inputs or guidance from the regulatory side about what they might be looking for from Factor IX? Or is it really a focus on the ABRs?

Yes. Maybe I could just chime in here. So we've said now since we moved into this next-generation program with AMT-061 that we expected to get average increases in Factor IX activity into the range of 30% to 50%. And that level of increase of Factor IX activity is either functionally curative or in what's considered the normalized range of factor activity. The overwhelming majority of patients that have Factor IX activity at those levels won't be susceptible to bleeds, and will certainly not require ongoing prophylactic infusions of replacement therapy. There certainly is going to be some interpatient variability. But I think, generally, we've tried to target a level of activity that we think provide substantial benefit for patients and allows the health care economic system to avoid the cost of theater support and provision of drugs and replacement therapy for those patients. And it allows us to target that, understanding some of the variability and to ensure that we don't have patients that are experiencing super physiological levels of Factor IX activity that could provide a risk of thrombosis. And also on the downside, enabling all or nearly all patients to endure clinical benefit associated with the therapy. So we think we found a sweet spot in our Phase IIb study. We had 3 patients that were all within the 30% to 50% range. At ASH and around ASH, we'll have a few sets of data that we'll be presenting. One is going to be up to 5 years of follow-up on the original Phase I/II study, which the last update we provided was in December when we showed very substantial durability. We're going to have now 2 years of follow-up data from our Phase IIb study. And then as Ricardo mentioned, it will be the first look at 26-week factor activity from all 54 patients in our pivotal study of AMT-061.

Are you expecting that initial presentation of the Phase III 26, we'll get it to be at ASH?

So we -- the abstracts were submitted prior to our locking of the database. So what we've committed is that we will have an investor interaction before the end of the year.

Got it. Okay. So 1 of the things, Matt, that we've talked about in the past was kind of what do you do in something like Heme B where you don't have a global hematology franchise? It's a fairly small population in any given territory. And what do you do about that commercially? And as you highlighted in your kind of -- the initial remarks, you struck a partnership with the CSL who's one of the global leaders in hemophilia. Can you talk about kind of, I guess, some of the kind of pro, cons as you were thinking about the decision of what to do with hemophilia? And also kind of what is this -- like how are you thinking about the long-term with uniQure and other? What does this mean for things like SCA3 or Huntington disease? How do you think about the commercial advisability for uniQure in some of those settings that maybe have larger populations or maybe are more focused in terms of -- or less competitive?

Yes. So let me start off by saying that we poured in a tremendous amount of analysis and research and time into this decision, and we didn't take it lightly. And that the decision that we made for AMT-061 is very specific to this particular product and this particular market, which is a relatively mature market in a rather competitive space with very large entrenched players. We are really excited about the opportunity for gene therapy in hemophilia. We, as well as CSL, do believe that this is going to transform care for patients with hemophilia. And of course, AMT-061 now represents potentially the first approved gene therapy for any hemophilia. So it is really an exciting opportunity at the potential to enable these patients, which have to take weekly or biweekly infusions of replacement therapy. They have to deal with peaks and troughs of factor activity level that often lead to breakthrough bleeding irrespective of being on high-dose and expensive replacement therapy, and we can replace that with a onetime administered 30-minute IV infusion that based on our clinical data, suggests that there's going to be significant durability. So it really is a very exciting opportunity, but it is one where we think that, to get this therapy out around the world as fast as possible, in this particular market, we're better suited partnering with one of the large players versus investing very significantly and heavily in a commercial infrastructure that is highly specialized within the hemophilia space. That decision will be very different, for example, in the area of CNS, where we think there's multiple opportunities that we can pursue and that we can leverage, a lot of those investments across a strategic call point in a number of indications that we can apply gene therapy to. So we don't think our mission of becoming a fully integrated biopharma company has changed. We just think that this is the appropriate way to maximize the value of this hemophilia B opportunity and then to redeploy the funds that we receive in this collaboration into substantially and aggressively expanding our pipeline and continuing to build out our manufacturing capabilities.

Okay. So let's -- maybe let's pivot over to talk about AMT-130 gene therapy for Huntington's disease. Maybe to start, we could start with framing kind of where you're at in this clinical trial. It's obviously -- it's a pretty innovative study, as you indicated, it's the first gene therapy in clinic for Huntington's disease. And there's -- it's also as far as I know, the first brain directed gene therapy that's been administered. So if you could -- or 1 of the first, I guess. But if you could maybe frame what you're doing there, what the objectives are and where you're at in terms of the clinical trial right now?

Sure. So AMT-130 is a -- we're delivering a microRNA that targets the fire farm region of the Huntingtin gene. So it reduces the expression of both the poly to expand the gene as well as the wild-type also reduces the expression of exon 1, which is important. It is an -- in the AAV5 backbone, it's being administered directly into the striatum surgically. So we know that it gets to the right cells. It also spreads to cortex. So it covers the important regions of the brain pretty well. We have, thus far, enrolled 4 patients in the study. The SMB gave us the go-ahead to enroll the second 2 patients in the study, which tells us that it is safe. Of course, it is a placebo-controlled trial. So we -- it is still blinded. After we get the go ahead for the DSMB sometime early next year, we will then proceed to enroll the next 6 patients, 4 on the drug, 2 on placebo. And then after that, we will then look for additional feedback from the DSMB to see whether we can enroll the second cohort, which is -- in which patients are going to be exposed to a higher level of the drug. Yes.

Yes. So Huntington's is an area of substantial unmet need, no disease-modifying therapies, not much in the way of symptomatic control either. Maybe if you could speak a little bit to kind of the magnitude of the opportunity, the kind of the need here. And then as we think about how to intervene, this is kind of this first wave of disease-modifying efforts to address Huntington's are focusing on lowering of the HTT protein. Can we talk about kind of what do we know and what are we going to learn from these early clinical studies, be it gene therapy or ASO approaches about kind of the safety and efficacy of that and speak from that perspective?

Absolutely. So Huntington's is 1 of the first genetically-refined neurodegenerative diseases for which we actually identified the gene, and it is really quite common. There are at least 100,000 patients in the U.S. And this means that it's a large opportunity there. It is a devastating disease that affects both adults and young adults. It -- so what do we know? So it is an expansion of a triplet that -- so 3 nucleotides that are expanded in the genome that encode for glutamine. So -- and this, in turn, causes the protein to aggregate and become toxic. And I think we have learned over time -- and if you have more than 40 repeats, it is -- you have the disease. I think what we've learned over time is that it is -- what we've learned over time is that it is -- is that the protein is -- the protein causes the disease by -- sorry, let me just go back. So -- yes. And so what we've done over the course of this sort of study is we've developed a microRNA that downregulates the mRNA that encodes the protein. And so we are in the midst of studying this now. Yes. Let me just stop there.

Okay. So we know that there's mutant protein production and the objective of the program then is to kind of -- to broadly decrease the expression of HTT protein. How much lowering are you targeting? And kind of how confident about -- are you in your ability to kind of control how much you're able to reduce the HTT protein?

Absolutely. So yes, sorry, about that. Yes. No, no. So we're targeting 70% reduction in the striatum and 50% reduction in cortex. And the reason for targeting 70% reduction is that we believe that, that is going to be efficacious based on our studies in preclinical models. The -- we think that -- so our microRNA reduces the expression both of the mutant protein as well as the wild-type protein. And so that, in turn -- and so we think that, that will be safe because we know that we don't want to reduce the total expression of the wild-type protein too much. We -- yes, so that's the approach.

And so what drives the toxicity? Is it just -- it's the mutant Huntington protein? Is it the polyglutamine that's kind of overexpressed? Is it -- do we know exactly what the driver of the toxicity is? Or is it kind of just a little bit nebulous at this point, but we know that kind of generally knocking down the HTT expression should encompass what we're trying to do to kind of bump the neuronal toxicity?

Yes. So the genetics are very clear, right? So the expanded polyglutamine is completely penetrant. So if you have the expanded domain, you will get the disease. The question is what actually causes cell death. So I don't think it is entirely clear. It is clear that when the mutant protein is produced, it aggregates and it is thought that, that aggregation in term of triggers probably an inflammatory response that ultimately kills the neurons. But the expanded protein also seems to bind to proteins inside cells that can cause those cells to die. So I would say, as for many aggregation and many diseases caused by protein aggregation, we don't exactly understand the exact mechanism of cell death. What we do know is that if you eliminate it, you can substantially reduce cell death, at least, in good clinical models. And so we hope that, that will also be true in patients. And I mean, I think the vision really is that we're going to convert a disease, an incurable neurodegenerative disease into a disease that is treatable surgically, and that is really the opportunity here.

One more mechanistic question. I just -- there's also -- there's these Exon 1 fragments, right, in Huntington's disease where they're kind of truncated versions of the HTT protein. What's the importance of that? And are you able to address that with your gene therapy? And what do we know about kind of ratio of these exon 1 fragments versus full Huntington protein production? And is that predictable?

Yes. So a few years ago, it was discovered that -- so just for everybody who's listening. So the polyglutamine expansion is in exon 1 of the protein. And a few years ago, it was discovered that there is incomplete splicing of exon 1 to the rest of Huntington. So you get, in patients as well as in the animal models, full-length Huntington that has this long polyglutamine stretch, but you also get just the exon 1 protein that has just the polyglutamines, and it is unusually toxic. It's -- I don't think anybody really understands what fraction of the Huntington is improperly spliced. It is clear that the longer the expansion, the more you get exon 1. What is clear is that both exon 1 and the full-length polyglutamine protein are both toxic. So we have targeted a region that encompasses both exon 1 and the full length protein. So with our microRNA, we should see a reduction of both the exon 1 fragment as well as the full-length protein. Not -- of course, not everybody has done that. Many people who developed their therapies before this was known targeted a different region of the gene.