We're going to get started with our next session. I'm Andrew Tsai, Senior Biotech Analyst at Jefferies, and it's my pleasure to have the Denali team with me today. To my direct right, Ryan Watts, CEO, and to his right, Alex Schuth, CFO. Welcome, both of you. That's great to be here. Thanks, Andrew. Maybe we can spend a couple of minutes for those less familiar with the Denali story, talk about what you're working on, what you're trying to achieve, milestones that we can expect over the next 12 to 24 months, and then we go from there. Yeah, great. Great to be here in London. Thanks for the invitation. Exciting time at Denali, exciting time in the tissue distribution, blood-brain barrier field, especially as we've been working on this for over, I guess, now two decades across multiple companies. What you're seeing is, I think, the beginning of the next class of medicines using transferrin receptor for tissue distribution to brain, to muscle, to bone. I think it's a very unique opportunity to open up a new class of medicines using transferrin receptor and other receptors to cross the blood-brain barrier. Just as a bit of background, we've invented the transport vehicle technology with the goal of doing two things. One is to cross the blood-brain barrier, and the second is to defeat degeneration. We believe in our first program, our Hunter program, we have achieved both, both at the biomarker level and now as we start to see these patients who have been on medicine now over four or five years really have substantial benefit in hearing and cognition and behavior. We are the first to submit a BLA using the transferrin receptor technology, of course, in the U.S. We have a program that is under review right now. This is Tividenofusp alfa, formerly known as DNL-310. We have another program on the heels of that in Sanfilippo as well. I think really exciting in the last quarter, we just filed our first regulatory filing for an Alzheimer's medicine, getting the oligonucleotide across the blood-brain barrier using, again, the transferrin receptor technology or the transport vehicle technology. In terms of milestones, I think as we go through each program, we'll discuss them. It's worth mentioning that our ETV franchise is growing beyond Hunter, Sanfilippo with a regulatory filing and IND filing for Pompe. This is ETV:GAA. Of course, we see this near-term potential in our Alzheimer's portfolio with Tau, but also with Aβ. Again, preparing for our first commercial launch, bringing multiple medicines forward. We had guided towards one to two new INDs this year. We ended up filing two and bringing these programs into the clinic. The same will be next year. We expect another Alzheimer's medicine, our Aβ program, and then one or two others. I guess with that, we'll dive into questions. Okay, sounds good. We'll tackle these one by one. You are hosting an R&D Day, I think December 4th. Can you give us a teaser of what you plan to share? Is it something across the pipeline, or are you focused on one or two assets? Any color would be helpful. Yeah, great. There are really three major themes for R&D Day. This is on December 4th in New York. The first is around engineering brain and whole body delivery. The details around transferrin receptor delivery, around transport vehicle delivery. The second is laying the foundation for our ETV franchise, specifically the first commercial launch, the next product going into details. Obviously, we'll have, I think, a guest speaker talking about the opportunity in lysosomal storage diseases and in Pompe and then focusing on Tivi and that launch. I think the last piece will be around Alzheimer's disease. Obviously, there are many opportunities we can pursue with the transport vehicle technology, but it just happens to be that the most present one now is Tau and Aβ. We will focus on that. I think woven into all of this are principles of engineering that set the transport vehicle apart from many of these other conventional Fab-based approaches. Great, thanks. Let's shift gears to Tivi, which has a PDUFA April 2026. Can you give us a sense of how big the Hunter's market is in terms of US versus ex-US patients? What is the peak sales opportunity for your product? Yeah, I'll address that. I mean, first, we're super excited to be at the start line to start commercializing Tivi to launch our first drug. We hear tremendous enthusiasm from families and physicians who believe that the drug is clearly differentiated from the standard of care, being able to treat the whole body, including the brain, to have the broad tissue distribution. With respect to the market opportunity, the best benchmark here is the standard of care, EloPrase. EloPrase has been on the market since 2006. Annual sales are between $650 million-$700 million. With respect to the global distribution, it's about one-third in the U.S., one-third in Europe, and one-third in the rest of the world. Understood. Let's just say this was approved. This is technically an accelerated approval. When you launch, how will you be marketing this relative to EloPrase? You do not necessarily have generated the confirmatory data that is going on to tell physicians we are superior to EloPrase. Where is the low-hanging fruit when you launch exactly? Yeah, so the phase I-II data, which is the basis for accelerated approval, is actually a very robust study. The primary endpoint here was reduction normalization of heparan sulfate, which is the substrate of the enzyme that is missing in these children with Hunter syndrome. Heparan sulfate is very well understood by physicians. It's actually measured routinely in clinical practice to measure the treatment effect of EloPrase. In addition to normalization of heparan sulfate, we've also shown normalization of neurofilament. Neurofilament is now an established marker of neuronal damage. By normalizing neurofilament, damage is essentially halted in the brains of these children. The third piece is that we have very encouraging clinical data with respect to behavior, cognition, and improvement in hearing. While this is in an open-label study, I think it does provide the robust package to show superiority to standard of care. Understood. I'll just add one other point, which is it's recognized that there's significant room for improvement in patients that are treated with EloPrase, both I think in dose and in biomarkers. The majority of patients treated in our phase I-II study actually are switching from EloPrase to Tivi. We get a good insight into what their biomarker profile is prior to treating with Tivi. I think, as Alex already highlighted, as our behavior, cognition, and specifically our hearing data matures and other aspects, we're seeing pretty significant improvement. Okay, so how do you envision the launch curve to look like in the U.S., let's just say in the first year or so? Yeah, that's a great question. We will talk more about that at the investor day in December. In general, launches in rare diseases based on the mechanics of a launch of getting treatment patients on drug and then really working through the reimbursement typically follow an S-shape adoption. With respect to the first year 2026, we probably expect modest revenues. The real measure to look at with respect to the enthusiasm of the uptake is the number of patients that start treatment within the year. That's what we will look at as a metric for our commercial team and to see if we're on the right track. Can you give us a sense of pricing bookends? How much does EloPrase cost, for instance? Yeah, so EloPrase on a whole-acquisition cost price is about $500,000 per patient per year. That's about for a 30-kilogram patient. Based on the clinical profile that we have, we do believe that a premium price is supported for Tivi. We do have our field payer team in place, and that team has now spoken with the vast majority of payers, and we do feel that that is understood and supported. Great. In the meantime, back to the PDUFA, technically got extended by the FDA. Long story short, it seems like it is more of an administrative benign issue than anything. Have you resolved that, and where are you? Has the FDA visited your manufacturing sites, for instance? Yeah, so as you can imagine, these BLAs are extraordinarily large and complicated. I think what was interesting in this particular example is that through part of the usual request for information process it was identified that there was a clerical error in the molecular weight calculation for Tivi in a public database. Actually, there are two separate public databases, and one has the correct molecular weight, one does not. The one that does not was used for population PK analysis by a separate group. Essentially, it is a relatively easy fix. It is about a 5% difference, and there are no changes to the conclusions in terms of exposure or pharmacodynamic or associated safety. We think that will be a very quick fix. I think logistically it makes sense. I mean, the FDA has ability, especially late in the cycle. Our CMC evaluation is ongoing. We actually completed our late cycle meeting. Even with this delay, a lot of progress, and we see the FDA very engaged. What are the remaining questions? Are you in labeling discussions, for instance? Yeah, the label negotiations have begun. I think I'd just say stay tuned. I think we're in a good spot. Obviously, the trial is designed to capture the vast majority of patients. We have both neuronopathic and non-neuronopathic patients in that study. We're excited to be at this point. Also, concerned with the major amendment that that would be delayed, but that's actually ongoing now, both label negotiations and the completion of the late cycle meeting. Great. Back to the launch, you mentioned modest, expect modest in 2026. You'll be tracking patient signups and so forth. How many sales reps do you ultimately need to launch this? Yeah, it's very, the team is in place, both the field sales team, the MSL team, and then the support team. We will be ready to launch essentially on day one after we get the green light. It's a very small and focused team. In terms of the field sales, it's low double-digit individuals that are in field sales. The reason here is that in Hunter syndrome, essentially all patients are already identified because they are already on EloPrase, and all treating physicians are known as well. From a commercialization perspective, that has the advantage that we can easily approach those and start the engagement and the education. I see. Before, I guess it's a nice segue to Sanfilippo. Can you leverage the existing sales force for Sanfilippo's launch eventually? Yeah, 100%. Sanfilippo patients are, Sanfilippo is MPS IIIA, Hunter syndrome is MPS II. In many cases early on, it's even a differential diagnosis in clinical practice. The same physicians that treat Hunter also treat MPS IIIA or Sanfilippo. There are a lot of synergies between these two programs, obviously commercial, but then also from a clinical development and regulatory perspective where we are using the same biomarkers and again, the accelerated approval pathway. Great. Moving on to Sanfilippo then, you've shared some initial data on an initial set of patients. I think you completed enrollment in 20 patients in November, or actually this month. You'll be sharing an update at World in February 2026. When exactly do you plan to file for this application for accelerated approval, and when could this launch relative to Hunter's? Yeah, so just backing up a little bit, we provided early guidance on the data cut at the very beginning that we saw robust reduction in CSF heparan sulfate. That was at 24 weeks with roughly the first eight patients. We then made the decision at that time. Actually, when we started the Sanfilippo program, it wasn't clear that there was an accelerated approval path for Tivi. It was a small phase I-II that would then immediately go to a phase III. Basically, with progress with Tivi, we've expanded the phase I-II now to approximately 20 patients, completing that enrollment actually in September. In the most recent, I think in the Q2, we gave an update that at 49 weeks we see sustained robust reduction of CSF heparan sulfate. Now with the 20 patients enrolled, they're really focused on two things. One is completing that 49-week data in September of next year and then preparing for filing thereafter. That would be the data cut, not giving an exact date on filing. What's notable about this particular filing is that we are manufacturing the Sanfilippo product ourselves. We've been using Lonza for Tivi. Our products going forward are manufactured now at Denali. That will be our first filing out of our own facility, including producing commercial product. We're very excited about that. The World data cut will obviously not include all 20 patients, seeing that the trial had just completed enrollment in September, but it will be essentially an interim look at the Sanfilippo data and then the final data set next September. I guess some point after September as we complete the data, I actually think the rate limiting step here will be nailing down manufacturing to be prepared to launch. That being said, we've seen a significant reduction in cost in doing our own manufacturing. Got it. Got it. One step back, big picture, what is the peak sales potential of Sanfilippo relative to Hunter's? Yeah, so from an epidemiology perspective, Sanfilippo is about the same size, maybe a bit smaller than Hunter. On the other hand, there is no standard of care, which might lead to more flexibility on pricing. So roughly we consider those two opportunities about similar in size and together $1 billion plus. Together billion dollar plus worldwide? Yeah. Got it. When you file for an accelerated approval, is it contingent upon biomarker reduction of heparan sulfate only, or does the FDA want to see functional trends on top of that? Yeah, so it's actually a very interesting question, and it's nuanced. The idea is that these surrogate endpoints are reasonably likely to predict clinical benefit. That comes from the totality of the data in the MPS field where we see that momentum with Tivi. Technically speaking, accelerated approval is actually on the biomarker, not on the clinical data. That clinical data matures obviously over time. I think we've invested heavily in the Hunter program that informs subsequent MPSs. We'll be going after multiple MPSs. Obviously, the next one is MPS IIIA, Sanfilippo. The actual filing is really focused on the biomarker data, and then you have ultimately the clinical data as the follow-up for the full approval. I see. By the time you submit for accelerated approval, the confirmatory study would have been underway. Is that correct? That's absolutely correct. That's been the focus. Interestingly, our focus with the FDA, this particular program has STAR designation. We have a lot of engagement with the FDA on the Sanfilippo program. Before we address the AAA path, we address the phase III design. Most of the conversation with the FDA is what does the phase III design need to look like? We turn to the AAA path where we define these 20 patients as being sufficient for accelerated approval. Now we've turned back to the phase III design and kicking that particular study off. I think what's unique about Sanfilippo relative to Hunter is there is no standard of care. When we were negotiating the phase III design for Hunter, we were pushing towards using natural history as opposed to an active comparator. Of course, the COMPASS study is not that. It's an active comparator study. For Sanfilippo, there is a lot of momentum both in the U.S. and in Europe to use natural history as opposed to placebo because there is no standard of care. It's sort of a one-way direction in Sanfilippo in terms of these patients declining very rapidly. It's likely that that phase III will look very different than the COMPASS trial and will most likely use natural history data and similar clinical endpoints such as CSF heparan sulfate in either the Vineland or Bayley or Kaufman. I see. Very helpful. In terms of the ex-U.S. strategy for both programs, Hunter and Sanfilippo, how do you go about this? Do they require confirmatory studies or can they leverage, or can you leverage, the U.S. approval? Yeah, so we believe that about 60% to two-thirds of the global market can be accessed leveraging the phase I-II data. With accelerated approval in the U.S., we can almost immediately start to commercialize in a handful of countries that follow the U.S., the Middle East, for example, and some others. There are countries, the U.K., Japan, some Latin American countries where we can also file for a conditional marketing approval or something like an accelerated approval pathway based on the phase I-II. The ongoing COMPASS study, which is the confirmatory phase II-III trial, will, that's our base case, be needed for approval in Western Europe for the EMA. That's for Hunter, to be clear. That's for Hunter, right? Is it your intention to launch ex-US yourself? Our intention is to commercialize in the U.S. and in Western Europe. We have a small site in Zurich, which right now focuses on clinical operations to run our studies, but can also then be the hub to commercialize in Western Europe. Beyond that, we are building up a network of distributors to make sure that any patient that could benefit from our drug has the ability to do so. Understood. Okay. I think in the last five minutes, maybe we dig into your other earlier stage programs, but not too earlier stage per se. Maybe I noticed you did not mention the LRRK2 program for Parkinson's, but one question, you do have a data readout mid-2026 looking at Parkinson's patients pretty broadly, not necessarily with the LRRK2 mutation. What gives you guys the confidence you will show positive, strong efficacy data? Yeah, I'll take that one as well. LRRK2 or mutations in LRRK2 are one of the strongest genetic risk factors in Parkinson's disease. It's a gain of function mutation. Individuals with that mutation have overactive LRRK2. What that does is it impairs lysosomal function. Inhibiting LRRK2 improves, it boosts lysosomal function, which is understood to be a central pathology of Parkinson's disease. The therapeutic hypothesis here is you boost lysosomal function by inhibiting LRRK2. The study that is ongoing is called the LUMA study. It's in partnership with Biogen. It's a collaboration that we started in 2020. It's a fairly large and very well-designed phase II-B study, 650 patients with a clinical endpoint UPDRS, 48-week treatment duration. It will be a very good testing of the hypothesis if LRRK2 inhibition has a clinical benefit. We're excited about the scientific rationale and the design of the study. In the end, we'll have to await the data. Let's just say it did succeed. Would you need to start another study? Yeah, so it was prospectively designed to be potentially registrational. In the base case, it would be one of the two phase III studies. There would be a second phase III study which would need to be run. In the wildly positive scenario, one could imagine Biogen taking the path to potentially registering or seeking approval, but the base case is that a second study would be needed. Great. Moving on to your Alzheimer's, maybe starting with the MAPT that you filed an IND to start phase I maybe next year. Can you talk about your differentiation for your asset compared to the others out there? Yeah. In August of 2024, we published our first study that we basically had achieved the ability to get oligonucleotides across the blood-brain barrier. This is a new class within a class of medicine. I started at the very beginning talking about how transferrin receptor and these technologies will get medicines across the BBB. It was in about 2021 that we showed for the first time that we could get oligonucleotides. That includes antisense oligos, siRNAs, other types of oligonucleotides across the blood-brain barrier. We had a very comprehensive study that was published in 2024. MAPT is the first target we're going after using this, what we call the OTV or the oligonucleotide transport vehicle. That particular study is going to focus directly, we're going to go directly into patients. The goal there is to look at tau reduction in cerebrospinal fluid and tau PET, the ability to reverse tau pathology. I think there's some precedent out there with using ASOs intrathecally delivered. This will allow us to have even and broad distribution throughout the CNS. Just a broader comment around this class of medicines. Historically, antibodies have been tested as stopping the spreading of tau pathology. This is actually quite different than oligonucleotides that reduce the expression of tau. What we've seen is basically there is a, I'd say, I won't call it obscure, but less prevalent hypothesis that tau spreads from cell to cell. The great thing about going with oligonucleotides is that it's sort of agnostic to spreading or cell autonomous effect on tau pathology. In other words, lowering tau in that way would reduce both spreading, but also cell autonomously reduce tau pathology. Very helpful. When could we get phase I data in actual patients? It's great to hear this. Yeah, we'll talk more about the design at the R&D day in December, but I don't think we're guiding exactly on when that data is. There's going to be a whole dose escalation. It will depend on what dose is required to drive the pharmacodynamic effect. Okay. We'll stay patient. Maybe last question on, you do have another phase I-II in FTD dementia. There was a recent failure from Elector. What is your comment or why your study could be different? I'll try to keep this brief. We've talked a lot about Hunter and Sanfilippo for progranulin and specifically FTD granulin mutation carriers. We're taking a very similar approach we took for Hunter and Sanfilippo. It's basically progranulin like a replacement therapy. It's an ERT for this disease. We basically take full progranulin, put it on the transport vehicle, get it across the blood-brain barrier. We see a very robust effect in the animal models using this technology. This is fundamentally different than blocking a natural receptor and then driving, let's say, redistribution of progranulin. In fact, it might be considered the exact opposite. Rather than basically using the natural receptor, using progranulin, using the transport vehicle to drive progranulin uptake into cells rather than reducing its uptake in cells. We've obviously are enthusiastic about the program. We had a Cell paper that described the mechanism of progranulin in the lysosome and the associated biomarkers. Those biomarkers that are explained in that paper will be the type of biomarkers we're ultimately looking at in human and FTD granulin mutation carriers. I think with the recent failure, our enrollment has actually gone up substantially. As that other study stopped, other studies stopped enrolling. Initially, it was very challenging for us to enroll, but we've now fully enrolled B2 and have moved actually relatively quickly on B3, which is just a dose escalation in this phase I- B, phase II study. Okay. I think that's all the time we have, but look forward to more progress soon. Thank you. Thanks, everyone, for coming.