All right, great. Thanks very much, everybody. It's always a pleasure to be moderating the discussion with Ryan, Ryan Watts, founder and CEO of Denali, one of the more knowledgeable people I get the pleasure of talking to about neuroscience. I'm going to ask Ryan, I'm sure everyone knows Denali, but I'll maybe just ask Ryan to kind of set the stage with some brief opening remarks, and then we'll do Q&A. Ryan, thank you so much, and take it away, man. Yeah, thanks, Paul. Likewise, I enjoyed speaking with you, and especially at CNS days. This is what it's all about for us. Yeah, you know when we founded Denali, there were two major goals that we wanted to accomplish. The first was to engineer brain delivery, and I think at that time it was both small molecules and large molecules, but we wanted to build a blood-brain barrier platform and a company that had deep expertise in getting medicines across the blood-brain barrier. The second, which is going to be a lifelong goal, I think for many of us, is to defeat degeneration, to make medicines that are effective for especially the big degenerative diseases like Alzheimer's and Parkinson's. We decided to go about this almost in a stepwise approach. We had some early success with our small molecule portfolio, and those programs have started to mature and are in either larger stage studies, some of which we're no longer working on. We also had an opportunity to look at what the competitive landscape looked like in the blood-brain barrier space, specifically around large molecules, antibodies, oligonucleotides. A decade ago, no one had shown that they can get an oligonucleotide across the blood-brain barrier. Enzymes was an area that we're quite interested in. We began to basically invent our own blood-brain barrier platform, which we now call the transport vehicle technology. I think importantly, we knew that the vast majority of work had been done with conventional Fabs, conventional antibody approaches, or Fab fusions, and we wanted a unique technology that allowed for us to modulate the immune system, to have integrated binding for stability, less immunogenicity, and ultimately to have incredible modularity. What came to be is the transport vehicle where we have three basically franchises: the enzyme transport vehicle, the oligonucleotide transport vehicle, and the antibody transport vehicle. As you know, and we're going to get into a lot of detail about some of our lead programs, but basically we now have three clinical- stage, transport vehicle-enabled molecules, and are bringing many more forward, some of which for big indications like Alzheimer's and Parkinson's, which is part of that original goal. I think with that, Paul, that's the introduction and looking forward to diving in. Okay, great. We'll have time to cover a lot of your pipeline, I'm sure, but I wanted to kick off with just a regulatory question on 310. You know, I've been going back and forth with a number of investors lately. I'm trying to understand, you know, why is Denali's stock been weak? It's so hard to decouple anything right now from a tough, punitive macro environment in biotech. That being said, I have a suspicion that Denali has been kind of grouped into a basket of companies that are seen as regulatory flexibility companies, right? There's this underlying concern of, okay, the administration's changing, the FDA's changing, you know, what could all of that mean? You know, if you're talking to investors as, look, I think the 310 phase I/II data are great, but I'm worried about how the FDA might evolve. What can you say that gives us comfort that your regulatory alignment, you know, is really strong and is likely to, I guess, sort of be resilient in the backdrop of whatever is changing at the agency over the next 12 months? Yeah, I think that's a, I think that's probably a fair bucketing. I think let's start there. I think if you look at, for us in particular, the headwinds come when RFK, you know, is basically nominated and the uncertainty around that nomination. I think what's been interesting is, you know, if you look at all the comments around Makary and his, you know, his nomination, there's still a lot of emphasis and focus and support for rare disease. I think John Crowley is a good example, you know, someone who has been a voice for rare disease, but also is a voice in this administration and with his background. What's been actually more fascinating for us is that, you know, we've faced 30 years of headwind in rare disease in CDER in particular. This is the rare disease and medical genetics division where there's been a relatively conservative approach, you know, placebo-controlled trials in monogenic diseases where the cause of the disease is very well known, the biomarkers correlate with clinical benefit. You know, we saw that change, you know, a year ago. That's the positive momentum. You know, frankly, this uncertainty with the FDA, if this had happened two years ago, it probably would have been a great thing because then there would have been an opportunity. We've actually forged a new path in the last year. I think that uncertainty is now that you're on this accelerated approval path and you have support at all layers of the FDA, you know, even, you know, members who have recently left were not actually very involved with the Reagan- Udall Foundation. We're really at the level of the review division. Obviously the rare disease and medical genetics. We've had multiple interactions leading up to, you know, Trump's victory and multiple interactions after. They are consistent and we're consistently focused on, you know, filing the BLA. Frankly, the timing of that is in our hands. We, you know, we are maybe to a fault sort of perfectionists in what we do. We want the very best package. We want the very best data. In fact, I think the data that was presented at World is what will be in that filing. It includes all patients in the 40, you know, 47 patients reaching six months. It's essentially a completed study, which we thought was important and very robust. In fact, the most recent data set looks fantastic on behavior and cognition as it's matured over time. Remember, this is a broad age range as well, you know, two to like 14 years of age. I think, you know, we get it. I mean, that uncertainty, you know, is understandable externally, but our experience internally has been a continued positive interaction with the FDA, responsive, positive, in preparation for this filing and also in preparation for meeting on our Sanfilippo program and defining the accelerated approval path on that program. We, you know, are prepared to launch the end of this year, early next year, but we also get it. I mean, we understand why we're bucketed into the sort of regulatory uncertainty. Yeah. As you've engaged with the FDA since the Reagan- Udall Foundation and since your breakthrough and kind of getting the agency on board with heparan sulfate and the totality of your data, what do you think the one to two kind of key sort of review issues are going to be? You know, I mean, is it really just stress testing the efficacy? Is it more complicated than that? And have you got any indication whether there's going to be an advisory committee? Yeah, it's a good question. We don't know if there'll be an advisory committee. We are prepared and we'll be prepared if that's the case. In fact, would welcome it. I think we're very excited to talk about the data and also lay the foundation for Sanfilippo, Pompe, Gaucher, you know, our IDUA program. I mean, this is really important for the future of the enzyme transport vehicle franchise. One thing that's actually really notable and interesting is that the breakthrough therapy designation, there has to be evidence of clinical benefit. So for us, the excitement receiving that breakthrough therapy designation, it wasn't just that, oh, hey, the biomarkers look great. We've known that for, you know, two years now. It's that the FDA also views the supporting clinical data as, you know, positive, basically, or I'll just say it more carefully, directionally positive. The hearing looks great. You know, I think at World, the investigator who presented the data highlighted that patients or some patients are no longer needing hearing aids. There are really substantial improvements in a number of these patients. That is part of that breakthrough therapy designation. I also just highlighted as far as we know, it is the first breakthrough therapy designation for MPS diseases and certainly the first for blood-brain barrier-enabled technologies, right? To me, that is like a regulatory view that they see this as promising and we hope applies more broadly across our portfolio. Yeah, yeah. Okay. What are you doing right now to prepare to launch the drug? And you know, we talked about this when we had dinner a month and a half ago, right? That you guys have, you know, you're going to be looking at potentially a commercial launch in some of the U.S. and maybe some other territories. You've got multiple other clinical development candidates. You've got this pipeline. Like how do you prosecute in all these things at once? You know, I mean, it feels like you guys could use, you have a lot of money, but it feels like anyone can always use more. Denali can especially use more. Yeah, I mean, we have to be wise about our spend, especially with where we are today. I mean, interestingly, last year, 2024, we spent less than we spent in 2023. Part of that was spinning out our small molecule preclinical assets, creating a separate company. That company launched at the beginning of this year, allowing us to focus entirely on the transport vehicle technology. We raised capital that takes us through 2028. The goal of that was to accelerate and to expand. You know, I think the one thing we do very well is if we set goals, we just go after them, you know, just very robustly and very focused on those goals. You're right, we are doing a lot. I mean, we have a robust pipeline. I think our most important focus right now is that launch preparation. Now, the great thing is it's not a huge therapeutic area and all of the investigators are known, many of which participate in the trial. It doesn't require that we build a huge team to launch, especially in the US. The point that you made, and I want to reiterate, is that we also want to launch in territories that are catalyzed by approval in the US. It's not just preparation around the US. In terms of the other part of the organization that's delivering the next set of INDs and delivering on our earlier clinical portfolio, including, you know, SGSH and progranulin, they're essentially separate teams. That allows us to say, okay, this team, you file, you prepare for launch. This team, you bring the next set of INDs forward. That's been really important. We have, I think one kind of note related to that is that we could file like four INDs in the next six to twelve months. That is unreasonable in terms of just the resource spend. Sequencing those programs or letting the data basically play out the prioritization. We want to bring in another enzyme. We definitely want to bring our first OTV and we want to bring ETV, Abeta. Those are really high priority assets to bring into the clinic as fast as possible. We know that creates the next wave of value. What percent of Elaprase sales patients do you feel like are accessible with just an FDA approval? Yeah, I mean. 50%? Yeah, we haven't, we're not commenting on our modeling of that, right? I think one thing that's worth mentioning is that the vast majority of patients who have been treated with tividenofusp alfa are switching, right? They've been on Elaprase, they switch. We have some, you know, treatment naive patients in the phase I/II. I think we highlighted that data at World when you look at liver volume normalizing, which is important. You know, we want to capture the entire Hunter population, not just neuronopathic, but also non-neuronopathic. Switching will be a major focus. You know, I don't, I don't have a number to share on what that percentage is like, but I think it's important to everyone's modeling of what this drug ends up doing in the U.S. and beyond. How should we, you know, even if we accept that the biology here is de-risked, like the drug works, I mean, heparan sulfate's the disease, it obliterates heparan sulfate. How would you characterize the risk for the phase two, three trial? It's the first time you go up against placebo on, you know, a clinical endpoint, right? Where I feel like from our seat, it's a little bit hard to know exactly how the control arm will perform, you know, variability. I know you guys are sophisticated and thought about all of these things, but you know, if I believe that it's 95% likely that DNL310 works or 99% likely, like what's the probability that a trial like that should work on a cognitive-based primary endpoint? Yeah, that's a great question. I think maybe just one correction, I'm sure it was accidental, but this isn't obviously placebo controlled. Just to add a complexity, it's active comparator controlled, right? Oh, sorry. Yeah, yeah, yeah. You're running the trial. Yeah. Yeah, I get it. Yeah. I think that that's important. On the one hand, what's interesting is if you look at our data, even on peripheral endpoints like urinary gags or, you know, like height, you know, things that would not necessarily be like central nervous system, we debate like hearing is both peripheral and central. We're seeing improvements, right? We're seeing improvement beyond the standard of care. I think part of that is that we believe the standard of care is probably underdosed, right? The way that we model our probability of success comes down to using the natural history that's available, the natural history that we've generated, using, for example, like all the data from IT Elaprase, where there was a very modest effect on the central nervous system and also modest effect on NFL, maybe a 10% reduction where we're seeing, you know, 75%+ reduction in normalization. Like you said, I mean, we're confident that the drug is working at the molecular level. We're confident that we're restoring nervous system function, that we're halting neurodegeneration. Now you need to look at the Vineland and the Bayley, and that data is starting to mature very nicely as well. I think that's the data that we shared at World. Our estimates are based on using these other data and what we would drive is efficacy. I think it's an important note. You may know this already, but when we completed enrollment of the neuronopathic patients, which were 33 patients, we had a number of patients that were essentially waiting to be dosed. We've extended the enrollment. So we're adding additional patients in the neuronopathic. That, of course, when we enroll the last patient, then it's two years from that point for when we'll get the totality of data. You know, we're generally confident that the entire data package looks impressive, especially biomarkers. You know, you want to see the clinical benefit that will then feed into the confidence in these biomarkers going forward. Right. Yeah. Okay. As it relates to Sanfilippo, I mean, the disease is, there's a lot of similarities, right? It's more biased towards neurological. There isn't a standard of care and heparan sulfate is also like at the epicenter of the disease. Why, like why wouldn't you be able to get the same alignment and what is gating to you executing on that? Yeah, I mean, we expect to get the same alignment. I think also there's, you know, a recent gene therapy that's submitted for accelerated approval in Sanfilippo, you know, 3A. I think there is a lot of similarities. Probably the biggest difference is there is no standard of care, which as a result changes the way you think about a phase three trial. This is where I think the FDA has started to evolve significantly. You know, it's very difficult to imagine having a patient be a placebo patient where the neurological decline is so robust and rapid in Sanfilippo, more so than Hunter. That's actually one of the other things. It's very aggressive neurological decline. Our biggest debate right now is what does the confirmatory phase three need to look like? Can it be compared against natural history, which is, by the way, where we were four years ago on Hunter? Yet our sense through the START program, which has allowed us to engage with the FDA and also with Europe, is that there seems to be more openness to this idea of a non-placebo controlled phase three study. That is a risk that, you know, a sponsor would have to take. The other is that you have a placebo where you have this sort of rapid decline. That is probably one of the bigger differences. We expect that the biomarker will most certainly be used as an accelerated approval biomarker. I think that is where we are going with this particular program. What would be the risk you'd be taking as a sponsor by doing a natural history controlled study? I mean, I feel like that feels like an easier trial. Yeah, I think the risk is how do you know definitively that you're providing a clinical benefit? I mean, I think in some ways, you know, I look at the Hunter data and we definitely look at like the hearing data and now the behavioral data and the cognitive data, it looks most certainly like we're having a benefit. Yet you don't have like that definitive comparator. That's essentially the risk you have in those studies. Yeah. Okay. What is the timing there for Sanfilippo? I think you said that, and maybe you just said this, you alluded to this now, but I think you said more explicitly to me in the past, you really want to have the phase three design fully agreed upon before you start the discussion around accelerated approval. Is that right? I feel like some of your peers might, you know, historically be more inclined to kind of put the cart before the horse and just sort of try to go as fast as possible to a filing. Why is this the right strategy? I mean, I think for us the rate limiting step is now we've expanded the phase I/II study, right? We had eight patients in the original phase one, two. We've now added three more cohorts with four patients each. So we're up to 20 patients. We're hoping that, you know, we can do half the size of the study we did for Hunter to sort of get that robust data package that we can submit for accelerated approval. Part of that accelerated approval path is agreeing upon what a confirmatory trial looks like. That is the decision we made. We made that decision last year. We met face to face with the FDA and discussed the confirmatory trial. The next discussion is around the accelerated approval and essentially agreeing upon what that confirmatory trial is. That's just, we think it's the right way to go about it. Those discussions are actually not rate limiting. It's just the maturing of the data that is rate limiting. You know, having the data package that allows you then to file that. You know, that actually doesn't matter as much. What is interesting is that, you know, and we haven't commented very specifically, we're usually kind of more generic and broad about this, but it is, it's enrolling very well. You know, I think the additional cohorts are enrolling well. That's what matters for us in terms of rate limiting to filing. When might we see the data? Is there really downside to showing the data to Wall Street in that it could actually undermine the regulatory process? Again, I just think that's, I'm not saying this is right or wrong, but it is a lot more conservative than peer companies of yours that might be showing us data patient by patient, you know? Yeah, yeah. No, we've been the peer company. You know, we, in the early days with Hunter, it was an example where we showed data like every six months and we all know how that went with the first NFL data. I mean, it's actually kind of amazing when you, and by the way, we haven't actually looked at NFL yet for Sanfilippo because of our experience with Hunter. We want more patients, you know, longer term data. I think what, I'll just share this real quick. Let me just pull this up because I think it's kind of an important context. You know, if we, and I think we learned this lesson in a really interesting way. If we look at these data today versus what we showed in 2020, which was the first heparan sulfate, five patients where we have the ability to normalize in four out of the five patients. We increase the numbers. In 2021, we have five patients where we see NFL and it's right here. Okay. Look at what happened. I mean, just like, I think it's just probably unlucky because younger patients, it actually goes down, you know, more rapidly. What we've learned is that, you know, a maturing data package is very robust. There's no questions about it. We're confident that we have the ability to normalize in Sanfilippo. Now we're just broadening and maturing that data package. The question you ask is, does it front run the FDA? Does it, you know, what are the risks of showing it? Actually to us, the most interesting and important thing to look at is what are our competitors doing? Specifically, you know, in Sanfilippo, you have gene therapy where you do not normalize. There is no NFL data presented on that. We are neck and neck with JCR, who was four years ahead of us in Hunter. You know, we are basically sort of like defining our to-be-marketed dose. We are going to, you know, drive for normalization. These are all the goals we have. We think that that data is only informative to them as it was to us. Like we knew what we needed to engineer. We knew that we needed to drive dose relative to JCR that had, you know, sort of suboptimal heparan sulfate reduction. You know, we're at a point now as a company where we can mature that data, have those regulatory conversations, but not also tip off our competitors. Makes sense. You know, as we think about the transport platform broadly, I still feel like the investment community, myself included, has a hard time comparing programs across companies as it relates to, you know, the antibody construct, affinity, you know, is there any effect or function? Is Is there not? Is it a Fab or is it a mAb? Really what I'm trying to kind of get at is that I feel like this is a space with so much promise, but there's a perception from those, you know, some of those outside Denali that, you know, on these transport programs, and this is a generalization, that there's still some safety risk, right? We see anemia sometimes. We've seen a few stroke events. Are they related to drug? Are Are they not related to drug? I think what I'm kind of trying to say is sort of, again, if you're talking to a prospective Denali investor, what can you say that gives, you know, others comfort, right? That you guys can deliver these products safely and that we're not going to see, you know, some serious hematologic events over time as more people are exposed either with 310, 126, or others. Yeah, those are great, great questions, Paul. There's really, I think I'm kind of unpacking the question. There's two parts to it. It's sort of broadly targeting transferrin receptor as a delivery approach. Has it been de-risked? In other words, like regardless of a Fab, sort of conventional Fab approach or a, you know, Fc engineering approach, that's like question number one. The second question is, how are you different? So, you know, how different are the various platforms? Maybe that's what I'm getting at. Let me address the first one, which is, you know, the general safety. This is something that we've been engaged in now. I think we started working on transferrin receptor. I personally started working on it in 2006, right? So that's 19 years of, I don't feel that old, but it's been a long time. At the time, it was an obscure sort of like backwater idea of using transferrin receptor to cross the blood-brain barrier. The original like technologies are shown here. You know, these are 30 years ago taking a traditional antibody and trying to use it to get across the blood-brain barrier. What we discovered along the way, both, you know, prior to Denali and at Denali, is that the number one risk of targeting transferrin receptor is the fact that it's expressed at very high levels on immature reticulocytes that give rise to red blood cells. If you engage the immune system, you will deplete these reticulocytes and as a result, you'll deplete red blood cells. Now, one of the interesting things about that particular hematological system is that it's extraordinarily robust and it recovers very quickly, right? What we learned in those early studies is that if you make the molecule immune silent, you can basically, you know, you can avoid this robust reticulocyte loss. Now, we went into the clinic with a TREM2 molecule, which reintroduced immune function and we depleted reticulocytes. So, like, we have a lot of data now across many different species. The great thing about, I mean, good and bad, but the good thing about the reticulocyte system and transferrin receptor is that once you deplete these [reticks], they then rebound very quickly and they can restore. That, I think, is manageable. It's monitorable. It's reversible. The two ways you get around it are immune silence and lower affinity. That's been, like, well documented. The other sort of obscure component that you're kind of mentioning, these strokes, I mean, I think as data sets mature from [Dayn] and Avidity and others, the question is, are these like one-off experiences that are related to mechanism or not? The only thing I can say there is it's not obvious. We certainly haven't seen it across, you know, any of our animal studies that there's a mechanistic- related risk around stroke in particular. You know, now we're seeing, you know, hundreds, maybe up to 1,000 patients treated with some type of transferrin receptor molecule. You're going to see these one-off experiences. The other thing is affinity probably matters in that and maybe dose matters. Those are the other things. The second question, I'll be very quick here. The second question is, well, then how are they all different? For us, we had the advantage of, you know, two decades of conventional fab approaches when we founded Denali. No real clinical proof of concept. You know, JCR was moving forward with a traditional antibody. Roche has a brain shuttle. We wanted to engineer a platform that gave us modularity, mostly the ability to not just determine affinity, but also to regulate effector function, which we think is really important. If you look at the Roche data, incredible plaque reduction. It appears to be an immunogenic molecule that is causing some anemia and likely reticulocyte loss. When we make the exact same architecture, we get retic loss. We can engineer around that using this type of technology, which, you know, it's much harder to do with this first version of the technology. Yeah. Yeah. Okay. Great. I know that was an open-ended question. You could have talked for another 20 minutes on it, but that was a succinct way to answer it. Maybe just to finish up and, you know, again, I feel like we didn't really do the rest of the pipeline justice here, but, you know, you've got the Abeta program, you know, a tau, TB, the next enzyme program. You know, what's the general timing for those? And when might we get the first proof of concept from, you know, OTV, for example? Yeah. Our goal is to move one to two programs into the clinic per year starting this year. We have four programs of these six that are actually actively in the IND enabling studies. The others are in manufacturing for IND enabling. Many of these are neck and neck. The data and the resource timing will determine, you know, as we bring each molecule forward. What I can say is that we like to bring a larger enzyme, like an ETV in a larger indication like Pompe or Gaucher. We'd like to bring our first oligonucleotide forward and our ATV Abeta. Those are the highest priority. In other words, we're not going to just bring a bolus of enzymes and then later bring these other molecules forward. That's the timing. We'll share. You know, after filing, then it's, you know, however long depending on what the biomarker is. If it's plaque reduction, if it's CSF tau levels, if it's, you know, glucogen, you know, levels. I mean, there's all different. And those, the great thing is that each of these have their own biomarker that allow us to prove that the molecule's working and that we have the right dose. Yeah. Yep. Great. Thank you very much. Very excited about the next wave of programs here, but also much to do. You know, we got to get ready for launch. We got to get a couple of approvals and build out our U.S. commercial to be ready to really advance these programs. Yeah. Okay. Very good. It is three o'clock. I appreciate it, Ryan. Thank you. It is always a pleasure to talk to you. Thanks, everyone. Thanks for.