Biotech analyst here at RBC Capital Markets, and today is our great privilege to have uniQure with us for a fireside chat. Representing the company, we have Matt Kapusta, Chief Executive Officer. Matt, thanks so much for joining us. How are you doing today?
Great. Thanks for having us here, Luca.
That's great, that's great. We have a long list of questions here, but maybe before I ask about some of the specifics, it would be great if you can give us a little bit of an overview of what progress has the organization made over the last few months, and maybe most importantly, what's ahead here for uniQure?
Yeah, sure. So, we've outlined three strategic imperatives for this year. The first one starting with Huntington's disease, and to clarify the road ahead, so we can get into that in more detail, but we are on track to initiate interactions with the FDA this quarter. We're gonna have some additional data coming out, where we're starting to get into a really chunky time of the follow-up. So we've got 30 patients where, we're now gonna have up to 3 years of follow-up with, more than 2/3 of those patients with a minimum of 2 years. So I think that's gonna be an important update for us. The second one is we have three additional clinical studies that are all poised to initiate enrollment in the coming months.
So that includes temporal lobe epilepsy, Fabry disease, and ALS. And we are working very hard to expedite enrollment as rapidly as possible. And then the third is conserving capital. And we announced last week with our Q1 business update that we have an ongoing review of our operations with an objective to identify meaningful cost savings, and we expect to complete that review in the third quarter or in the middle of the year.
Got it. Got it. Super helpful. Maybe since you mentioned the third point, I mean, obviously, you have already have gone through a few round of cost optimization. What's different this time? What are you looking at specifically between R&D and SG&A? How should we think about potential additional efficiency from here?
Yeah, I mean, the bottom line is we're a business. I mean, we're in the business focused on patients. So we have a mission, and we're serious about our mission, and we center the company around patients. But in the end, we need to be sustainable. And, you know, when you're in the biotech space, things evolve, and we need to evolve with it, and that's my job. So, you know, we've had, for a variety of reasons, both environmental and company-specific, a decline in our valuation where, you know, we have to ensure that we can get to our value-achieving or value-creating milestones.
We have a very high cost of capital, and, you know, we have to make sure that we're focusing our spend on critical activities that can drive value, and on things that are, potentially longer term or more ancillary, we have to be very thoughtful.
Got it. Got it. Very helpful. Maybe if I can go into Huntington here for a minute. You already mentioned the upcoming interaction with the FDA. Walk us through how you're gonna pitch your current data to the FDA, and how do you get them to focus on your functional data and not on your target engagement data?
Yeah. So let me take out my FDA pitch right now and go through with you. No, but... Well, let me answer the second question first. I don't think you need to convince really anybody, but particularly the regulators, to look at clinical outcomes. Clinical outcomes are what matters to the regulatory agencies, and it's, in the end, what matters to patients. You know, we, of course, in the gene therapy space, talk a lot about biomarkers, right? And biomarkers are absolutely important. The problem is that in Huntington's disease, you know, there really is no validated biomarker. This isn't hemophilia, right? And so the other issue is that it's a relatively slow-progressing disease.
So, you know, we think that in the end, if we can demonstrate a meaningful slowing of the progression of the disease, that that is extremely valuable therapeutically for patients. And one of the very unique benefits of being a one-time administered gene therapy is that we can actually collect long-term outcomes from an early phase I/II study. That's very complicated to do for other therapies that have to be chronically administered in an early study for a discrete period of time. So I think that, you know, in the end, while it is not a prospectively defined study, that if we're able to demonstrate at some future point in time, some statistical impact on the progression of disease, that's pretty important data, that I think the regulatory agencies would want to understand and want to evaluate.
Got it. Got it. Super helpful. Do you have any sense of whether senior leadership of the FDA is gonna be involved in this meeting that you'll have for Huntington? Obviously, Peter Marks is out there making the rounds, obviously, talking about DMD and somebody on unmet medical need. Could Huntington be next?
Yeah, I won't get into, like, specific meetings and who's gonna attend in a particular meeting, but, you know, for those that are following the evolution of CBER, and particularly cell and gene therapy, you probably know by now that, you know, the FDA has really leaned into emphasizing partnership with sponsors to try to get prospective therapies to patients that suffer from extremely high debilitating, high unmet needs, debilitating diseases where there's no disease-modifying treatments available. I think Peter's been vocal and articulate in saying that they even understand that they may make mistakes, and that those mistakes, in their mind's eye, are worth it.
So I mean, you know, we—I do look at Huntington's, and, and I had the privilege of meeting with a major advocate of Huntington's, who has the disease herself. This is—I don't think we have to convince anybody that this is a highly devastating disease. It's really its own special kind of hell. And that I think that, you know, the FDA is going to be constructive in trying to consider the challenges of constructing clinical development and trial protocols, the challenges in being able to demonstrate placebo-controlled, you know, traditional data, and I think they will be opening to listening to potential alternatives.
Got it. Got it, helpful. What's the go-no-go decision here, based on the conversation, obviously, that you will have with the FDA? I'm assuming that if the FDA comes back and tells you to run a trial similar to the one that Roche and Ionis has had to run, obviously, very, very large trial, 700 patients and placebo-controlled, that's probably gonna be no-go. One, is that fair? If that is fair, what would be go?
Yeah, and I think it's really important to define go, no-go. And the reason why I say this is because, in one sense, you could argue the only no-go is if there's a real safety issue in our data. And what I mean by that is that for us to continue to collect long-term outcomes from our phase I/II study, well, number one, we're obligated ethically to do that, continue to follow the patients for five years. But if we continue to see encouraging data from the study, there's very little investment for us to continue to follow these patients and collect the data. So... And we all know that the FDA can say one thing now, and if the data continues to demonstrate strength with long-term follow-up, they can change their mind, right? And in the end, there's very little investment.
Now, in terms of go, no-go for phase III study, I think we've been very clear externally that, you know, we do not plan to initiate a phase III study by ourselves. Because a phase III study, by definition, is going to be large, most likely is going to require, you know, multiple years and be expensive. And, you know, without a partner, that's something that's gonna be very challenging for us to do.
Got it, got it. Super helpful. Obviously, in addition to the conversations with the regulators... Well, maybe one more on that front. How are you planning to communicate the outcome of that interactions with the FDA to the street?
Yeah, we've tried to be very clear that, you know, we don't intend to give, you know, meeting-by-meeting updates on, you know, the details of the conversation. We think what's most constructive for external consumption is that when we have, you know, meaningful clarity, that is when we'll provide an update, and we think that, you know, that would be the most sensible way forward. We do expect that there'll probably need to be multiple meetings. That's very par for the course. We do believe that we have the potential to get that meaningful clarity by the end of the year, and we've committed to providing an update at that point in time.
We will. When we have our data update in the middle of the year, we'll give perhaps some perspective on the planning or the process, but unless we have, you know, meaningful clarity, we'll likely not get into those details.
Got it. That is super helpful. And maybe, obviously, the data is upcoming, mid-2024. Can you just talk about what are you going to show us in that data outcome in mid-2024? And I think importantly, I always reflect on the fact that obviously Huntington’s is a slowly progressive disease, right? There’s not, you know, there. Sometimes investors make a comparison with other diseases that are not as slow progressive as Huntington’s. So, like, in that context, how should we think about what’s the real signal here that you’re hoping to see?
Yeah, so, and you're absolutely right. I mean, if you believe in the thesis, you know, if you believe in genetics, Huntington's is a monogenic disorder, and you believe that it's really, there is potential in modifying the disease, it does require patience. And, you know, that's just the nature of a slow-progressing disease. I do think it's one of those things that if we crack, it could be one of the largest opportunities that exist today, in the rare disease space. In terms of what we plan on presenting, in the middle of the year, we plan on having, generally speaking, most of the kind of data that we've been presenting historically, and I think we've tried to be very transparent, given the importance of this study in the Huntington's disease community.
So that will include safety data, biomarker data, and then a battery of functional and clinical outcomes data. One of the things that we're spending a lot of time on is to try to make the natural history data that we presented in the past as robust as we possibly can. So we've put a lot of energy into that, to try to make it as equivalent as we possibly can to the kinds of patients that we enroll in our study. And so that's something that I think we'll likely talk more about in the next data update. So yeah, that's what I would expect. One thing I just want to make clear is we will not have mutant huntingtin data. And we mentioned this, this is not new.
We mentioned this, at the end of last year, that we're now, because of just variability in that assay, batching that, once a year, and so that won't be available in the middle-of-the-year update.
Will you present that data at some future date, or?
Yeah, we likely will present it. I mean, we obviously collect it because we think it's, you know, it's part of our protocol. We've obviously got into a whole host of reasons why it's a very complicated assay that, given our administration deep into the brain, where that's actually measured in the lower lumbar, that, you know, we don't think it's a particularly good biomarker, in addition to, data produced from the tominersen study that showed, you know, showed different correlations between lowering mutant huntingtin. So nevertheless, you know, we'll always try to err on the side of being transparent, but we don't think it's a particularly good biomarker, nor do we think it's really an approvable biomarker.
Got it. Super helpful. Maybe where do you stand in the never-ending debate on allele specificity in Huntington and whether it is important to have an allele-specific approach or not? Obviously, you don't, but, you know, there are obviously, I would argue there's literature on both sides that argue for, for both the importance versus not. What's your latest thinking on that debate?
Yeah, I mean, we obviously, you know, everybody's got their narrative, right? But I can tell you what, what we know is the data that we see. There's a tremendous amount of independent research on this, and, you know, we also, you know, speak to key opinion leaders in the space. What I'm not here to tell you is that if, if it were simply being able to snap your fingers, and I could just ensure 100% specificity in lowering the mutant allele, everybody would do it, right? There, there is no disease-causing impact associated with wild-type mutant huntingtin protein. The problem is that, number one, it is very difficult technically to do. It often requires considerably high doses. Those higher doses can potentially be toxic.
And what we've seen, because we've looked into this, is that there's really no such thing as 100% pure specificity, and you wind up actually getting, with high doses, lowering of the wild-type allele anyway. When you have an allele-specific approach, you have to go haplotype by haplotype, so you can't develop a therapy that really is universal for all Huntington's patients. And I think most importantly is there's this very significant amount of data that suggests that in adult humans with developed brains that are having a lowering of wild-type protein in the 25%-75% range in select areas of the brain, that that's just simply not deleterious. In fact, there are reported case studies of people being born with just a single allele. They have just 50% levels of wild-type protein, and they're completely asymptomatic.
So I mean, we believe what we believe. The data that does suggest otherwise is usually pointed at complete knockout models. These are every cell in the body is completely vacant of wild-type protein, or it's in neonatal models, where they do have developing brains, where wild-type huntingtin actually serves a role that's different than adult humans. So that's our perspective on the situation.
Got it. Got it, super helpful. Maybe in the last few minutes, let's talk about Fabry first, if I may. Maybe just walk us through why you're excited about that program, and maybe some of the timelines associated with it. And then also, I find it in Fabry, there's a little bit of a dichotomy there between what AVROBIO said versus what Sangamo have said in terms of what could be a registrational trial. It looks like Avro claimed that they had to run a trial head-to-head versus Fabrazyme versus Sangamo saying that that's not required. So walk us through your thinking on Fabry.
Yeah, sure. I mean, just the upshot is, you know, we believe, and we've confirmed this with our own market research, that there is a meaningful unmet need. We know enzyme replacement has been around, and there's been some innovation in that space, but, there's a lot left to be desired, and there's significant pathology associated with the current medications that patients with Fabry disease have to endure. We have a gene therapy that, again, is poised to enter into the clinic. We're really focused on enrolling a modest number of patients. There's validated biomarkers that we think we can collect data to confirm our target product profile thesis very quickly and with very discrete, modest spending, and to make a no-go, go decision next year.
This is a product construct that leverages a lot of our know-how and understanding of Hemgenix. Hemgenix is an approved product. We believe that AAV5 is the premier liver-directed AAV vector because it has, by far, the least immunogenic profile. It's got a pristine safety data set with long-term follow-up data, and we ultimately think that that's going to be most important for Fabry patients. We know with AAV5 that we can treat patients and have a therapeutic effect, irrespective of pre-existing neutralizing antibodies and we're using a highly potent liver-specific promoter that we hope will generate super physiological levels of GLA activity. So, that's our view. I think it's very difficult to compare what AVROBIO heard from the FDA to what Sangamo heard from the FDA.
I mean, I don't like to comment on conversations others had, but it's two completely different points of time and two completely different modalities, one being, a lentiviral, ex vivo approach, and the other one being, you know, a traditional AAV approach. So, I, I think it's difficult to say, but we do believe that there is potentially a path forward without a head-to-head.
Without a head-to-head. Okay. Okay, that's helpful. Maybe on epilepsy program, walk us through your thinking.
Yeah, I mean, look, epilepsy is, again, I think it has the potential to be one of the largest gene therapy opportunities that is currently being worked on. It is a condition that millions of patients have around the world. Temporal lobe epilepsy is the most common form of epilepsy. We have leveraged years and years of research that's been done on a particular kainate receptor. This kainate receptor has been well-characterized as being a critical component of the neuroexcitatory pathway. The whole thesis is that if we can inject a one-time administration, focal amount of therapy into the lesion of the brain that is emanating this neuroexcitatory behavior and suppress that pathway, that we can potentially meaningfully impact the frequency of seizures in patients that are refractory to standard anti-seizure medication. So that is really the goal.
The problem is that patients that, for whatever the reason is, cannot control their seizures with standard anti-seizure medication, really have very few alternatives.
Sure.
It's typically laser ablation or actually removing a particular lobe in the brain. Both are invasive, and patients don't desire it. What we represent is potentially a relatively straightforward, potentially outpatient procedure that preserves the area of the brain and enables them to continue to have these other options as alternatives, should whatever reason, you know, the gene therapy not work. The other thing we like about it is that in terms of a clinical proof of concept, we can evaluate clinical outcomes very quickly. So we can look at seizure frequency, we can probably look at that with a minimum of four months of follow-up, and with a, you know, critical mass of patients, begin to understand the potential therapeutic effect of AMT-260. So there's a lot that we really like about, epilepsy.
Got it. Super helpful. Maybe if I can ask a question on gene therapy more broadly, I know you're not gonna be able to comment on the specific of the launch of your hemophilia B product, obviously, partner with CSL, but maybe just a big picture, lots of approval in gene therapy recently. However, we only have one commercial successful product so far, which is Zolgensma, right? I mean, we can talk about BioMarin, we can talk some other players, and what is holding back the commercial success of gene therapy more broadly? And maybe in the context of that answer, it would be great if you can give us some color on the ongoing launch for hemophilia B.
Yeah, I think that people have to step back and understand that gene therapy is truly a paradigm change. It's a paradigm change for patients, it's a paradigm change for clinicians, and most certainly, it is a paradigm change for payers. So the practical answer to your question is that I do think... You know, this notion of trying to place a value on a one-time administered therapy that is gonna have long-term effect is very complicated. It's complicated in Europe, and it can be complicated even in the hemophilia space. It can take many, many months for a payer to negotiate with the hemophilia treatment center, the specific reimbursement, even when they've made a decision to cover the product.
I really do think that, and I do believe this, while I'm not in the trenches with CSL, that there is real meaningful underlying demand for hemophilia B. There is recognition of the strong data set. There's a growing backlog, and I do think it's gonna be a matter of time, but it's going to take time. But the other thing to keep in the back of your head is that, you know, the unmet need does matter.
Sure.
It doesn't mean that there's not potential in areas of lower unmet need. It just means that areas of lower unmet need may simply take more time to build the market. When you have a very, very high unmet need, and your child's life and, you know, is depending on it, you know, the amount of time it takes to, you know, to drive and ramp a product is just gonna be shorter.
Sure, sure. Certainly, SMA and DMD, very different diseases than hemophilia A or B-
That's right.
or some of the others. So that's, that's actually very helpful. Lots more questions, but no more time. Matt, appreciate you joining us here at RBC. Thanks, everyone, for listening, and best of luck for the rest of your conference. So thanks again.
Thanks, Luca.
Thanks again, Matt. Appreciate it. Yeah, thank you.