Great. Good morning, everyone. Thank you so much for joining us. It's a pleasure to have the Denali team here with us. We have Ryan Watts, CEO, and Alex Schuth, CFO. To start here, the recent approval of Avalaya and Hunter syndrome serves as Denali's first commercial launch and the first from the transport vehicle platform. In this context, can you frame the outlook for your vertical specifically, the blood-brain barrier vertical, your key priorities, and the catalyst outlook as we look to the next 12 to 18 months?
Maybe before I talk about the future, I'll just have a comment or two about the past. We've been working on blood-brain barrier technologies for almost exactly 20 years. And in fact, it was 20 years ago that the first medicine was approved for Hunter syndrome, either soul face. And so for us, it's been a journey of inventing a platform, I think really pioneering this space for over two decades. And the last two or three months have been extraordinary for us. It's really exciting to be able to launch our first medicine, to have the first FDA-approved blood-brain barrier-enabled technology with Avilea. And it's been an exciting time. And I think an important point is this now becomes a new area of biotherapeutics where the competition is rising, which is great news. In biotech, whenever anything works, everyone jumps in, and so we're happy to be leading the way with transfer and receptor and with the transport vehicle technology. Of course, this is just the beginning as well. And so talking about the next really 6 to 12 months, in addition to everything related to the launch, which is, of course, our focus of the commercial team, we also have the next enzyme replacement therapy, which is for San Filippo, where we'll complete the 49-week portion of that study in September, basically get the data ready, ideally present it world, and then submit the BLA in 2027. What's exciting about that product is we're actually going to do the commercial manufacturing ourselves. Our original, with Ablea, we've worked with CDMOs. Now we're going to be manufacturing for San Filippo, and we think this is the beginning of many enzyme replacement therapies. The next will be in Pompeii, where we're enrolling that study now, also looking at data in 2027. And then at the end of this year, we've sort of categorically put our progranulin program into the enzyme replacement therapy because it's very similar to enzyme replacement therapies, but we'll have our first look at the word B3, the sort of the highest dose for that study. That's coming up soon. Now, I think what's happened for us is that we often get asked the question, why not just be an enzyme replacement therapy company? You know the technology works. You have your first launch, a lot of enthusiasm around that, and in the community to bring forward other programs. But actually, we founded the company to ideally treat neurodegenerative diseases as well, like Alzheimer's and Parkinson's. So we'll have our first two data readouts in Alzheimer's disease also in the next 12 to 18 months. One is an oligonucleotide that knocks down the gene that codes for tau, and the other is an A-beta antibody, which we published last year in August 2025 in Science around our mechanism of basically removing amyloid plaque, which we hope is safer and ideally sub-Q dosing. And so that's also what's on the horizon. And I know we'll go into each of those aspects, but a very exciting time at Denali. Definitely.
Perhaps we can just start on the Hunter syndrome program here. So given the first commercial patients have been treated, and could you just speak to early launch dynamics to date, including the conversion rate from start forms to active patients, and how the medical exemption process and reimbursement has evolved since approval?
I have to remind myself that it's been about 10 weeks or so since approval, and I think what happened first is, you know, let's get the drug into channel. We were able to do that within two weeks, obviously with the label, and then in three and a half weeks, our first patient was dosed in the commercial setting, and this is not a patient that's, you know, switching over from trials, so it's really exciting. It actually wasn't at one of our trial sites, and now we have multiple patients who have been dosed on the commercial product. And so it's very early days to understand the dynamic of conversion from start forms to approval and getting the first dose, the first infusion. But what we can say is that it's exceeded our expectations in terms of the enthusiasm from the field, and we're seeing really positive trends on time from start form to infusion.
And what is the mix of treatment naive to newly diagnosed patients and those on prior standard of care? And has there been any pushback on patients or physicians on the need to return to clinic to initiate treatment?
I mean, the vast majority of patients, especially early on, are going to be switched. If you think about it, there's 500 patients in the U.S. I think almost all patients are on Ida-Sulfase, or the vast majority, unless it's sort of like end of life. And so that dynamic, what's happened in the field is there's just real enthusiasm about the possibility of treating neurologic manifestations in addition to the fundamental treatment of the disease. We also saw, you know, our peripheral biomarkers were better than what has been shown for standard of care. And so we haven't seen, you know, really barriers to that. I think, again, the field is driving that enthusiasm. So most of the patients that are on drug now, our commercial patients, have switched. from idrosulfate, a handful will be newly diagnosed, and that will just happen over time.
The drug is priced at a premium to previous standard of care, Eliprase. And so as you engage with payers, what has feedback been around pricing and weight-based dose, the weight-based
dose model? I'll hand that to Alex. Yeah, I'll take that one. So the pricing does reflect the clinical profile. So what we've shown in the clinical studies is that we are able to normalize the key biomarkers, hiperonsulfate, and also neurofilaments. And it is the one, the first and the only drug that treats the whole body, including the brain, and that is appreciated by payers. So we have not encountered pushback on the price by payers. It has not been a barrier to access at this point. It's priced by weight. The weight-based model is very well understood. It's standard in enzyme replacement therapy. So we feel very good about the price.
And have your expectations for modest revenue this year changed as the payers come online and as you kind of watch the trends that are playing out just given, I think you've guided to kind of the whole year needed in order to get that payer dynamic settled before you see that inflection in revenue more in 27?
Yeah, so this is, as Ryan said, we're very pleased about how the launch is going. We're very pleased about the interest, about the engagement, about the enthusiasm in this product and also what's coming in the pipeline. What is expected in a rare disease launch, especially in a buy and build setting, is that prescription activity will outpace revenues in the early stages of the launch. And that's exactly what we're seeing right here. 2026 is the setup year. This is why we guide towards the modest revenue, and this is why we use the illustration of the S-shaped curve, right? We think 26 is the setup year. 27 will be the inflection year. We think in 27, once patients are on drug for a number, for a period of time, but especially once all the payer engagements, once the payer policies are in place. We have guided that, or we've stated that it's about 50-50 with respect to the payer mix. And it will take about six months or so for commercial insurance, Medicaid. So that's when we then expect.
And what is the status of the European filing?
Yeah, I'll go on, I mean, European filing, but also really international. So the international market is very important. About two-thirds of the overall hunter market is internationally. And ultimately, our goal is to capture that full market and make sure that every patient that can benefit from Avlea will have the opportunity to do so. So we're very actively engaged internationally. In some instances, we can work with accelerated or conditional approval settings. We can work with pharmaceutical product certification, which will allow us to capture part of the international market before COMPAS reads out. So that's with the current data set in hand. Now, specifically with respect to Europe, we will need to wait until COMPAS reads out. So COMPAS was fully enrolled by the end of last year. It's a two-year endpoint, so we expect the date by the 7th, and then file in Europe.
On the confirmatory study, which includes patients up to 26 years of age, what is your current target for filing a supplemental BLA here to expand the label to include the adult Hunter syndrome patients?
I think there was two reactions to the approval of Avala. The first was enormous enthusiasm that there's finally a medicine that can treat the central nervous system, but the other was disappointment that the drug wasn't immediately made available to adults. And so obviously that's one of the important focus for us. What's interesting is once you're on drug, you stay on drug. So it's not like as you transition to adult, you then come off Avala and go on idosulfase. And so that's important and clearly articulated in the label. The COMPAS study is a little bit more than 60 patients split into two cohorts, cohort A, which focuses mainly on neurologic manifestations, and then cohort B, which has a broader age range, including adult. And so the key there, that's more peripheral, and we're looking for equivalency, and frankly, ultimately, we should see data that's superior to standard of care, but it's power to show sort of equivalency on biomarkers, things like liver and spleen volume and six-minute walk. So the goal is that totality of that data will put us in a position to go to Europe, which is the main focus of Compass, at least Germany, France, some of the countries that won't really recognize an accelerated path, but also to really focus on expanding the label.
Just maybe broadening out on the transport vehicle platform here, following the preliminary Phase 1-2 data that was presented from DNL-126 and San Filippo Syndrome at the World Symposium. How has your dialogue with the FDA evolved here regarding the use of heparin sulfate as a surrogate endpoint for the BLA filing, and does the 2027 filing remain on track at this point?
I thought this might be the first fireside chat where we don't get a question about the FDA. It's been an incredible journey for the last two or three years. You'll recall two or three years ago we were talking about the inconsistency between CBER and CEDAR, with CBER, I think, being much more aggressive on biomarkers as a potential path to accelerate approval. And then in some ways, obviously, that switched as everything panned out over the last nine to 12 months. And I think what's really been important for us is that the review team has been the same over that three years. And so the evolution of thinking about biomarkers has been with the same people who have seen, for example, the Reagan-Udolph Foundation presentation now over two years or so ago that articulated why CSF heparin sulfate should be a surrogate endpoint reasonably likely to predict clinical benefit. And that was the foundation of that mindset shift. Those are all the same individuals. So those that were recently, you know, concerned about it were the ones who then understood, agreed, and then understood that the approval of Ablea is setting. And so our engagement with the FDA on Dino 126 has remained consistent. You know, obviously setting a high bar, we saw on average 80% reduction of CSF heparin sulfate in Sanfilippo with the ability to normalize. What's different about Sanfilippo is that all patients are treatment naive. And so basically you have to build tolerance. And when you do, you're able to see this robust reduction of heparin sulfate. And the other thing that's like this very distinct about Sanfilippo over Hunter is it is a very aggressive degenerative disease. Patients will often have pretty significant volumetric loss even before we begin dosing. And so early is going to be really important. But our engagement with the FDA remains consistent. We've always sort of, I would say the way we've approached it is around the review team. The review division is the most important relationship and interactions that we have for our medicine. And given there's no
standard of care therapy on the market for San Filippo here. How do you think the launch trajectory will play out versus Hunter's?
Yeah, I think that's, as I pointed out, no standard of care. It's not a switch dynamic. I think the other point is you need to find these patients and diagnose them. They often are diagnosed in the same center. So from a positive point of view, it's the same physicians. We'll have the same commercial team. All the interactions are similar. The NPS Society has been very involved with both Hunter, San Filippo, Herler Shea. That part, I think that dynamic is going to be fantastic because you see the momentum of Ablea, which will then feed into 126. But there is no standard of care, so I think it's important to continue to push for newborn screening. As I mentioned before, because of the rapidity of how quickly this disease degenerates, finding patients really early is ultimately going to be key to have the most robust clinical benefit. So, you know, similar patient numbers, ultimately. So we see the combination of Ablea and 126 as probably a billion-plus opportunity worldwide with just those two products, and that's just the beginning of the enzyme transport vehicle franchise.
Can you just remind us what the rationale was for Takeda's decision to end the collaboration on 593 in the Frontal Temporal Dementia Program.
Yeah, I'll take that one. So Takeda made a strategic portfolio prioritization decision in the broader context of their restructuring of the rare disease and the neurology portfolio. Takeda had been a great partner for nine years since we started the partnership, but now we take the program forward ourselves. It's very strong biology. It's a very direct mechanism substituting progranulin, which is missing or lacking in these patients with that form of frontotemporal dementia. The study is ongoing. It's fully enrolled now, and we expect the data by the end.
And what specific biomarker thresholds are we looking for with that data read?
Yes, so I think, as Alex mentioned, this form of FTD is a mutation in granulin. These are heterozygous carriers, so they have one copy loss of function. We published a paper in 2021 in Cell categorizing a set of biomarkers that we think may be relevant that are downstream of this loss of function. And so there are lysosomal-related biomarkers like glucosophingosine and a number of BMP and other biomarkers. Those are the proximal biomarkers. The distal biomarkers are the traditional degenerative biomarkers like NFL and GFAP. And so for us, we're interested in both proximal and distal. And our experience in Hunter syndrome and in San Filippo is that you hit the proximal first, you establish dose, and then over time, assuming that this is disease-modifying, you should expect the ability to reduce the distal biomarkers like NFL. And so that's what we're looking for early on here, is early data trying to understand the proximal biomarker and dose that will then drive ultimately what we believe will be the clinical benefit, which is then obviously looking at biomarkers like NFL. I think one challenge you have here is because it's a single copy loss of function, the signal to noise in your biomarkers is not the same as what you see in Hunter and San Filippo, where those are complete loss of function. Heparin sulfate is elevated tenfold, where glucosophingosine is elevated 25%, 30%, not even twofold. And so that's a dynamic that we'll have to be prepared for, and especially as we sort a select dose, and I think the ultimate goal would be to pin a decision on the distal biomarkers like NFL with longer-term data. And that's the other thing we've learned quite a bit from Hunter is that we have a fantastic medicine, but it took time to basically normalize NFL.
Following Biogen's recent data from its tau-targeted ASO in Alzheimer's, we're going to see the the full data, I guess, or whatever data we can mid-year at the Alzheimer's Conference in London, but they commented on, you know, demonstrating a slowing clinical decline in tau reductions, but they did not show a clear dose response. Maybe help us understand what you believe is the read-through to your own programs here.
I mean, taken at face value, this could be historic. There's really only one drug target in Alzheimer's that has shown clinical benefit, which is A-beta. This would be the second. And if you look at the totality of the data, at least as articulated in the press release, what it tells you is reducing tau in slow cognitive decline. And that would then represent the second Alzheimer's target that has clinical validation. I think it's, as usual, complicated to read into dose response. I think added complexity with their particular program is that intrathecal delivery introduces a significant amount of heterogeneity in brain biodistribution. And so it'll be very interesting to look at the data and understand how many patients were in each of the dose cohorts. If I understood correctly, there were three dose cohorts. But it's possible, for example, that the lower dose had fewer patients and then maybe more subject to heterogeneity. But I think the take-home message is reducing tau appears to result in a clinical benefit, in a cognitive benefit. And I think that's historic, actually, because now it's like, how do we improve A-beta? How do we improve tau? We have a real opportunity. And I think then enter our approach, which is the transport vehicle that allows you to have much more consistency from patient to patient in terms of biodistribution. We saw this in our non-human primate studies. We did intrathecal delivery and compared it to the oligotransport vehicle. And with intrathecal, our monkeys, some had decent brain exposure and some had very little. So you had always had great spinal cord exposure because these are lumbar delivery, but you had very significant heterogeneity in how much it gets into the brain. With the oligotransport vehicle, where you're delivering across capillaries, you have an even distribution, and it was consistent from monkey to monkey. And so I think that's just part of the dynamic, and I think we've seen it in the A-beta field as well, is that as these new technologies, these brain shuttles, and in our case specifically the transport vehicle, enter, you have now this ability to very rapidly reduce amyloid about three times faster at maybe one-fifth the dose.
So I think it's very exciting.
It's very exciting to see another target that may be clinically validated in Alzheimer's.
And remind us on the timelines for your program here.
Yeah, so we're targeting 2027 for the first biomarker data. We're enrolling now rapidly the Alzheimer's patient study. it's a multiple dose out of the gates for OTV MAP-T, the key here is obviously to see tau reduction and understand the dose that drives tau reduction, and then I think everything will follow, the tau imaging PET and then ultimately running a study large enough to look at clinical benefit. Again, timing of intervention matters, and we'll also be at AAIC, very excited to be there, we'll be presenting there. I think the thesis that I like to articulate is that amyloid is a trigger, tau is an executioner, and then you have all these other contributors to disease that are these microglial targets. They probably contribute in the inability to remove amyloid, but if you look at the data, it's pretty consistent that amyloid's at the top of the cascade, but tau, I mean, I think ultimately is driving neuronal loss, and so I think they're both obviously very interesting targets.
You also have the beta amyloid program that's moving forward. Can you just walk us through the learnings that have played out with the programs that are approved also in the clinic and how that translates to your program?
So both OTV-MAP-T, which is our tau reducer, and then ATV-A-beta as the rest of our portfolio uses the transport vehicle. So it's transferum receptor to get across the blood-brain barrier. And what we've learned about A-beta in particular, there's room for improvement. I mean, one, it used to be thought very simply, you remove amyloid, you cause vasogenic edema, or what is now termed ARIA. But now that's disconnected. You can remove amyloid much more rapidly and have less ARIA. And it's probably around the biodistribution, similar to what we were just discussing with intrathecal for oligonucleotides. In the case of antibodies for A-beta, when you deliver using the transport vehicle technology, you don't have extraordinarily high concentrations in these perivascular spaces that cause breakdown of the blood-brain barrier and vasogenic edema. Instead, you get this even distribution throughout brain, and we show that in our science publication in August of last year, how that is differentiated. The other important point is we can preserve the effector function. We can preserve the immunological function of the antibody when bound to amyloid plaque, But when bound to transferrum receptor, we can silence it. And that is through a unique engineering insight where we create a mutation on the FC that makes it silent when bound to transferrum receptor. That is distinct and I think is unique to the architecture of the transport vehicle. And so our expectation is a safer profile. The binding to transferrum receptor is integrated, so less immunogenicity than what I think is being seen for other brain shuttles. and then ultimately sub-Q dosing where you have rapid plaque reduction and less ARIA.
And what are the key metrics from the initial Phase I trial in Pompe disease that we should look to understand how that's working out, specifically as we look to understand the impact on muscle and bone?
Yeah, so shifting gears now back to the enzyme transport vehicle. Here we're delivering GAA. There's a series of medicines in Pompe that are enzyme replacement therapies for Pompeii, what we're seeing is that there's not fantastic delivery in particular to skeletal muscles. So even with standard of care, there's still a significant unmet need. I think major advances in cardiac, obviously overall survival is better for IOPD, but a real unmet need. And the question is why, and we've, you know, as we engage with, by the way, the same investigators in Hunter and San Filippo are also many of these investigators are seeing Pompeii patients. And the general thesis is that standard enzyme replacement therapy for Pompeii relies on this mannose fixed phosphate receptor in muscle, which apparently is not highly expressed. And so there's not great distribution of muscle. And so what we see is a very substantial differentiation with any of the standard of care in Pompeii when you use the transport vehicle. This is now enhanced delivery to muscle. Obviously, we'll have delivery to CNS, which standard enzymes don't have. So that's going to be important. That would be more in IOPD. But what we're looking at in these early studies, so Pompe is enrolling now, 2027 data as well. And the goal there are these glycogen products to show that we've got the right dose, organ engagement, and then rely on the biology where we have improvement in muscle delivery, which should ultimately lead to clinical differentiation.
Great. And just on the small molecule pipeline here, so following the announcement that the Phase 2B study in idiopathic Parkinson's did not meet its primary endpoint, were there any analyzable trends that you can talk to that played out in these LARC-2 patients?
I'll take LARC-2. And as you mentioned, the LARC-2 inhibitor was part of our legacy portfolio of small molecules, so completely separate from the transport vehicle. As you mentioned,
which was timed to confirm worsening part two and three and importantly in
the idiopathic Parkinson's population. So essentially the all comers Parkinson's population. The study was well designed it was well executed the molecule performed as expected we saw very strong target engagement and acceptable safety but I think we have to conclude that LARP2 inhibition is not the path at least in idiopathic Parkinson's. Now importantly we have another study ongoing in parallel of the Beacon study, which is purely focused on LARC-2 carriers. So that is 50 LARC-2 carriers. Biomarker study, we expect to see those data by the end of the year. In Luma, the number of LARC-2 carriers was too small to really look for a signal in the subset. There were only about 10 LARC-2 carriers out of these 650 stations. So that really does not give us any.
Alex, another question for you here. You've been busy in terms, you know, all along since the genesis of this company, with partnering and business development strategy. Maybe talk to the types of deals that make sense for you from here.
Yeah, absolutely. Thank you for that question. Partnering business development is a key part of our strategy. We have a track record. We set up collaborations early in the phase of Denali until about half of our portfolio was partnered. Then there was a period when we prioritized wholly owned programs and advancing those. And now we're at the state where essentially our portfolio is almost entirely wholly owned. So that opens up a lot of new partnering opportunities. The blood-brain barrier field has been very active in the last two years. Ten years ago, we were essentially the only ones, but now we see a lot of activity. There's a lot of interest from large pharma. There are a number of smaller companies as well. We've been engaged in many of those conversations. but right now we're very well financed we ended q1 with just over a billion dollars in cash so we have the ability to really advance the program to the right moment in time of when we would do it I think really to highlight we are one of the few companies to have a wholly owned Alzheimer's portfolio as we just discussed right there is a beta there is tau there is a lot of preclinical expertise on in on additional mechanisms which at some point will be a very obvious partnering opportunity. We can definitely generate clinical proof of concept, high-quality clinical proof of concept in patients, and that's probably the time when
we would... On one of the points you made, the space has been really busy around blood-brain barriers, and you have some of these larger companies working on their own programs. How do you think about yours, just given the validity here through the commercial assets that are coming out, and the defensibility and differentiation of it versus what's playing out in the competitive landscape.
The idea of crossing the blood-brain barrier using transferum receptor was first proposed in the late 1980s. So this is like the typical story of biotech and discovery and iteration. The industrialization from that academic proposal has been a journey. We started on that journey, as I mentioned, 20 years ago in 2006. That was prior to founding Denali. And what we did is we just made every existing platform that was out there to say, do any of these cross the blubbering barrier in therapeutic concentrations?
And 20 years ago, the answer to that was actually no. There was no existing platform that we had actually tried that was working.
And so began the process of the industrialization. The question is, what was wrong? And I think the first challenge was that most of them, most of the technologies were getting trapped in the blood vessel. You were not getting therapeutic concentrations across the BBB. So now I think, you know, of the 20-plus competitors that we count, there's probably 30 that have bona fide blood-brain barrier platforms, 97% of them, well, 95% of them or 90% of them are all using the original sort of conventional FAB approach. So it's an antibody approach. It's a FAB fusion. And when we founded Denali 11 years ago, we wanted to build a platform that was highly modular, that didn't give up an arm of the antibody, or didn't have to, you know, in an unnatural way, attach an arm of the antibody, but integrate the binding into the FC, similar to the FCRN or FC gamma, and that began the engineering quest to build that in. And we knew that because we'd already seen the first-generation brain shuttles that were out there. We had already five, ten years of experience, and we knew the limitations, which was stability, immunogenicity. That's the challenge with a lot of these fab fusions, and that was actually in the original publications. And so we built the transport vehicle in a way that we integrated the binding into the FC. And it is now still the only molecule that does that, very distinct from the conventional fabs. And as you point out, it's now the only molecule that is FDA approved, will have commercial validation as well, and that allows us now to create an entire portfolio. Now, we had a decision 10 years ago, and Alex mentions the partnering strategy. Our decision was not to create a technology to enable the world, but to create a technology to enable our medicines and then find a way to collaborate on medicines, not on the platform. But there are other BBB technologies and strategies where the strategy is to out-license the platform. But those, again, are the conventional fab approaches. And so the transport vehicle is definitely distinct in the way that we engineered it, also had the advantage of a decade worth of experience before building it.
Great. Well, with that, Ryan and Alex, thank you so much. We appreciate your time today. Thank you so much.