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

Good afternoon, everyone. I'm Salveen Richter, biotechnology analyst at Goldman Sachs, and I'm pleased to welcome uniQure. And with us we have Matt Kapusta, CEO of the company.

With that, Matt, thank you for joining us. And to start here, maybe we could talk about the overall strategy for the company here. You've out-licensed the development and commercialization of your lead product or your lead gene therapy product, Phase III EtranaDez in hemophilia B, to CSL Behring. And could you just remind us as to your forward strategy for the overall portfolio, though, focus on neurology and liver disease? And how you're even thinking about BD in that context?

Yes. Sure. Well, thanks for having us, Salveen. Yes, so uniQure's mission still is to be a fully integrated gene therapy leader, including the commercialization. I think we made strategic decisions that you and I have talked about previously that we're really focused on the best go-to-market strategy within the specialized field of hemophilia. And we're very pleased to be partnering with CSL in that regard. We think they have fantastic commercial capabilities. We really believe in EtranaDez and the potential to transform care for these patients with hemophilia B. And so we think that's the right strategy. But that's a strategy specifically for hemophilia. I think we feel very differently about the opportunity set within neurology and potentially other rare diseases. So we're right now very focused on building a leading portfolio of gene therapies to harness the power of our platform that we've really been in the process of developing and optimizing for more than 20 years. So we -- as part of the strategy in the transaction with CSL, we did $2 billion collaboration. We're fortunate enough to have a very strong cash position with approximately $700 million and a line of sight to about $300 million of near-term milestones associated with regulatory submissions and first commercial sale, the potential for another $1.3 billion in milestones. And then, of course, royalties on net sales up to the 20% range. So that puts us in a position where we have really ample capital to try to leverage this platform to invest significantly on aggressively expanding the pipeline focused on those areas as well as in building the platform. And so we have an R&D Day coming up on the 22nd of June. It's in a couple of weeks, where we'll outline that strategy, and we'll also disclose some new programs within those areas that we've been working on. We'll provide updates on some of the other elements of our pipeline, including Fabry and spinocerebellar ataxia. We'll cover the Huntington's program. We'll also cover hemophilia B and some of the investments that we're making across our enabling tools or technology suite to develop these differentiated therapeutics that we're excited about as well as expansion in our state-of-the-art manufacturing platform scale and capacity.

Matt, that was very comprehensive. Maybe to start with one of the programs that we're going to start -- we're going to see data for the first time in the second half and in Huntington's. While we know the data will be from the first 4 patients that have been treated and largely focused on safety and tolerability, could you discuss the key biomarkers that you expect to present and what you're hoping to see and how much follow-up we're also going to get from these 2 sets of patients?

Yes. So as you pointed out, this is the first of what we hope is going to be really a pretty long and significant train of data that comes from the study beginning at the end of this year. And so we have a comprehensive Phase I/II program that includes an ongoing U.S. study, which is a randomized controlled, blinded study taking place in a number of centers in the U.S., and we just announced an open-label study that will take place in Europe. And in totality, they cover 41 patients, of which 31 will be treated, and there's 10 control patients that will undergo imitation surgery to serve as a comparison. So this initial data release will include 4 patients, 2 of which are treated, 2 of which will receive or have received imitation surgery, they're rolling off their blind in the second half of the year, and they will have approximately 12 months of follow-up data that we'll have. So it's a very small sample set, and we're largely looking at these initial patients really as a -- to serve as supportive for the safety of the procedure. The -- we're obviously going to be evaluating and collecting information on a number of biomarkers, safety and potentially efficacy-related biomarkers. Those generally include chemistry biomarkers that are assessed and evaluated from specimens of cerebral spinal fluid, and then there's other markers of inflammation and immunogenicity that are tested with blood samples. They also include volumetric imaging biomarkers that are largely looking at various structures of the brain that can be impacted by atrophy. And typically, those impacted by atrophy will shrink in terms of their volume. We're very, very interested in this particular biomarker because this is a -- it's a leading indicator of disease progression and pathology that tends to be highly correlated, in particular, with motorial function. So we're very interested in collecting that information to see what that tells us. And of course, this is information about specifically what is going on inside the brands of these particular patients. It's one of the few pieces of information that can tell us that. There's also functional imaging biomarkers that we can assess through magnetic resonance spectroscopy. That can also tell us about what's going on in the brain in terms of metabolic function of neurons and gliosis associated with neuronal function. And then, of course, there's the functional parameters where we look specifically at quantified motor scoring, which, as the name suggests, really looks at a comprehensive panel of motor function for those patients as well as the standard United -- Unified Huntington's Disease Rating Scale, which is really a composite that includes not only motor function but also behavioral, psychiatric and emotional scoring. I think the most interesting and what we'll probably focus on are the biomarkers. The functional -- the clinical functional outcomes will likely take longer follow-up, probably in the order of maybe 18 or 24 months. 12 months is probably the minimum that you might be able to detect something going on with some of the biomarkers. But we'll be looking at, as I mentioned before, volumetric imaging of the brain as well as neurofilament light and the presence of mutant protein in the cerebrospinal fluid.

Great. And I mean, it's early days, but what could a pass-through approval look like for this drug?

Well, I guess, as of yesterday, I think it does suggest and open the door for the potential for accelerated approval within this disease. This is a very significant high unmet need, where there really is no disease-modifying treatments. I think that we don't necessarily view mutant protein in the cerebrospinal fluid as a fantastic surrogate biomarker because I think as one of the recently large studies has foretold, the understanding between that particular biomarker and disease progression or clinical outcomes is really not very well understood. But we do think that this is very comparable to Alzheimer's disease in so much that it's a devastating disease, as I mentioned, without really treatment alternatives. And there is the potential, we think, on some of the better-characterized biomarkers such as neurofilament light and volumetric and functional imaging to potentially create a pathway to have a discussion with the agency around accelerated approval or registrational approach. One of the reasons why we designed this study as a blinded -- double-blinded, placebo-controlled study is that the FDA very clearly indicated a strong recommendation to do so even in a first-in-man study and suggested that it actually could lead to more expedited development pathway. So it all depends on the data in the end, but I do think there is an avenue and a pathway to, at the very least, have a discussion about registrational strategy, potentially accelerating approval if we're able to elucidate strong signals of efficacy.

And maybe just your thoughts here on -- given the Roche-Ionis discontinuation of their Phase III study for their ASO in Huntington's, are there any -- I guess, what are your thoughts on the program approach versus yours and whether there were any read-throughs yet?

Yes. It's certainly not our study, but we can -- I can provide you some perspectives. Of course, there's probably a lot more questions than answers. But we've been very consistent with the perspective about our approach compared to the others out there. It is really not a given, right? I mean, one of the most important things in any disease is biodistribution, right? I mean, you need to know that your drug is getting into the disease tissue, right? If you don't have that, I mean, you could have the greatest construct and it could be perfectly suited, but you're not going to affect the disease and the clinical outcomes if you can't get drug there. What we know about Huntington's is it is a deep brain disorder, it can impact in later stage of disease other areas of the brain, but that is where you need to get drug if you're going to have a meaningful clinical impact on these patients. Because the antisense oligo modality needs to be repetitively administered, the administration is intrathecal in the lower lumbar. And so the drug really needs to travel against the natural flow of cerebrospinal fluid and really the only testing that's been done is in animal models, even the non-human primate animal models are the size of small children. And then, of course, there's the experience in spinal muscular atrophy. But again, those are small children, where, in some cases, the blood-brain barrier isn't really formed. Huntington's impacts 40-, 50-, 60-year-old adults, very, very different anatomy. And we've always been somewhat skeptical of the ability to get drug penetrated into the deep brain. So our view is that, that is a really plausible explanation as to why efficacy may not have been elucidated from the study. Our view as well -- because a lot has been talked about the safety and toxicology, our view is that a nonselective mechanism of suppressing Huntington is safe. We can talk about that later. And that there is also a plausible explanation of potential toxicity associated with a class effect of antisense oligos. If you look at the Phase I/II data for Roche and Ionis, this is -- the potential tox signals associated with prolonged elevations in neurofilament light and increases in ventricular dilation were evidenced even in the Phase I/II study that was published in the New England Journal of Medicine back in May of 2019, and this was seen even at low doses. So it does suggest that if you're finding these things with relatively short-term follow-up at low doses, there might be something associated with the construct. And then, of course, we've noted cases of hydrocephalus from the Roche Phase III study. And I do believe there's also cases that have been evidenced in commercialization of Spinraza. So there's a number of -- it's a cloudy picture, but I think there's a number of factors that point to things other than the mechanism of action here. And we certainly believe in our approach, which is a direct administration into those disease areas of the brain. And we've studied for 6 years the safety and tolerability of our treatment and feel very strong and confident that it is safe and well tolerant.

We can dig a little bit into your confidence why a nonselective knockdown of the Huntington gene is the right approach and, I guess, how you're thinking that the animal data translates to the human data sets here.

Yes. So there's a number of things that we'd look at. Of course, what we do is we test these things in animals, and we do that ourselves. But we're not the only ones that have tested this. There's probably been upwards of 15 different independent studies done in various disease animal models. And I'm not aware of a single study that demonstrates a concern about safety and toxicity with suppression of wild-type protein up to around 75%. The studies that have generally suggested that there's tox, these are complete knockout models. These are models for animals that are bread without this particular gene. So they're born without any Huntington protein whatsoever. And what we do know about Huntington protein is that it is vital for developing central nervous systems. Of course, Huntington's patients are -- these are adults, mature adults that have fully developed central nervous systems. And so the in vivo animal data really does support pretty significant -- safety and significant suppression of wild-type protein, as I said, up to 75%. Remember, in our approach, we're aiming for typically a 25% to 75% suppression in specific areas of the brain. We're not getting full knockdown. We're not even getting that level of knockdown in every cell of the brain or systemically. The other piece of evidence is that there are documented case reports of completely healthy individuals that are born with a single allele deletion, and so these people were born with about 50% normal levels of Huntington protein, and they've developed completely normally and are asymptomatic. I think the issue in the end is what does it take, right? I mean, I think there's nothing wrong with the approach of just knocking or suppressing the mutant allele. I think the question is, can it be done and can it be done within a therapeutic window. In the course of our research, we did evaluate that. What we found is that it's possible to do, but that the doses that are required to do so are very significant. And so there's potential tox associated with the dose and that even at some of those high doses, the selectivity of those constructs become debatable. So that's really what it's about.

Perfect. And then moving to hemophilia B here, what have your key learnings been following the listing of the clinical hold here as you looked at that diagnosis of HCC? And how to think about just your -- the platform as a whole?