Denali Therapeutics Inc. (DNLI) Earnings Call Transcript & Summary

Our Investor Day. We've been excited to share an update. I think often, I'm sitting in a fireside chat with many of you. So it's great to see her faces here. We're going to go into some depth today about what we're doing at Denali. And I think it's a unique opportunity for us to really set the stage for what the future looks like for Denali but then dive into some questions. We also have some really important guests with us, which I'll introduce later from the lysosomal storage disease community. So these are our forward-looking statements, and let's dive in. Let's start with the key messages. So our purpose at Denali is to deliver the power of biotherapeutics to the whole body, including the brain. This is a little different than what we've said maybe in the last 5 or 6 years. And what we've realized from our own clinical data is that the transport vehicle technology not only crosses the blood-brain barrier, but enhances delivery to other parts of the body.including hard-to-reach tissues. And so we've really seen now an evolution in transferrin receptor-enabled biotherapeutics, and we like to believe that we help lead this revolution. Our ultimate goal is, of course, to transform the life of people living with serious diseases. And this is also a little bit different from what we've said in the past where it was focused primarily on neuro degeneration, but we believe we can open up now muscle disease and other areas with the transport vehicle technology. There are 4 key messages for today, and these are really important. And in fact, the presentation is broken up into these messages, and I'll share them in the introduction as well. The first is that we have a best-in-class blood-brain barrier platform or transferrin receptor-enabled technology, which we call the transport vehicle. We recognize that brain shuttles are now front and center. And I think again, a decade ago, it was just an idea. Now there are clinical data that really prove that we can get medicines into the brain and hard REITs tissues. The second point is that we're ready to capture $1 billion plus opportunity in enzyme replacement therapies with the ETV franchise. And so for the first time, we'll lay out our commercial plans and very excited to do so and also bring the patient community here and have a discussion around the opportunity around enzymes, which, of course, has been multiple decades since new medicines have been launched in this area. So there's a huge unmet need. We have a deep pipeline across high-value therapeutic areas. And we thought today rather than focus on everything we're doing, we're going to focus on Alzheimer's and really the second half of the Investor Day in part because we believe the transport vehicle is set to transform Alzheimer's. So on the one hand, we have this great opportunity with enzyme replacement therapies, but also in an area that's really starting to break open is Alzheimer's disease, mainly enabled by biomarkers, but now the first approvals in this space that the transport vehicle technology is really set to enhance these medicines. And then we'll end with a discussion around efficient execution and capital allocation. And this is important because we know the transport vehicle works, how can we now expand and bring many programs forward, but do it faster and cheaper. And I think that's a key to our approach. So here is the transport vehicle technology. I'll spend a little bit of time and then in the second half, Joe will go into some detail. I think the #1 question we get is, how is the transport vehicle different from all the other transparent receptor-enabled technologies. And so we want to spend time in the second half articulating that. But I want to introduce, I think, the most important concept, which is we have the ability now to deliver enzymes oligonucleotides and antibodies across the blood-brain barrier and hard-to-reach tissues. And again, the focus we'll start with is on our enzyme technology. So here is our broad portfolio. There are really 2 areas. The lysosomal storage disorders and then common neurodegenerative diseases. And I want to give a quick update, which we shared this morning in our press release and in our 8-K. Let me start with tividenofusp alfa. So very excited to announce that we signed a deal with Royalty Pharma which could be worth up to $275 million. $200 million is unlocked by the approval of Tivi with a capped royalty. We have details in the press release. In addition to that, I want to give you an important update. So when we -- in 2019, we received rare disease pediatric designation or rare pediatric disease designation for Tivi, which we believe made us eligible for the PRV -- when we filed the BLA, we did not file the request for the PRV. And so unfortunately, in our discussions with the FDA, the FDA has said based on this timing gap, we may not be eligible for the PRV. So we're in discussions with the FDA that's been very productive discussions. Our primary focus is basically getting the medicine approved. Our primary focus is timing more than anything else. Separately and important update, the third update related to Tivi, so Royalty Pharma, PRB and the third update is that we've completed our late-cycle meeting with the FDA, and we're deep in label negotiations. And so although we've had a delay to the PDUFA date, we're seeing significant progress and engagement with the FDA. And that's been actually really fantastic back and forth. And the focus now is really getting to the finish line and launching Tivi. The second important update this morning is that we received a clinical hold on our Pompe program. This is ETV GAA. And I want to really highlight what happened with this particular program. So based on hypersensitivity in mice, the FDA has suggested protocol changes through the FDA, we obviously haven't started our clinical study yet. The team immediately turned around those protocol changes. They've been resubmitted and we believe that they will address the questions on this clinical hold. But again, this is well known for Pompe and specifically for GAA, I think part of this is really a question of timing and the time to review and make associated protocol changes. Both of those are highlighted by the way, in the 8-K. So let's talk about what the future looks like for Denali. So I think the first is what we call the D3 strategy, discover, develop, deliver. And I think importantly, we have been fueled by discovery from the beginning. And I think pioneering the field of blood-brain barrier delivery with the transport vehicle and with transparent receptor. We spent the last 5 years validating the transport vehicle and submitting our first BLA, which, of course, we're very excited by that, and we'll expect many more to come. And now it's about delivery. As I mentioned before, we'll focus today on our commercial launch for Tivi and broadly how we're approaching commercial for the enzyme transport vehicle. And so it's exciting to see that transition for Denali. And so it's really by 3. So let me explain what that means. So this was actually the first time we're presenting 3-year goals. And I'll start with, I think, 1 of the most important goals, which is to really build 2 brands for Tivity 126, that will lay the foundation for Denali going forward. Now next will be 5 clinical proof of concept. And I think on the horizon, the near-term horizon is Alzheimer's disease, and proving that the transport vehicle will deliver the best-in-class molecules for A-beta and for tau and then continue to bring programs forward in an efficient way. So 4 to 6 new clinical stage programs over the next 2 to 3 years. And I think this year is an example where we filed 2 regulatory filings, bringing 2 more programs forward with tau and GA. So ultimately, we want to deliver both near-term value by launching medicines but also create this long-term portfolio of clinical stage and ultimately, commercial products. This is what will happen in the next 3 years. So let's talk a little bit more about the transport vehicle just so we set the stage for today's discussion. So we invented this transport vehicle about 9 years ago, and we've proven it over the last 5 years that it works for enzymes. And the way that it works is we bind to a natural receptor known as transfer receptor. Now there are many different brain shuttle receptors but the most validated receptor is transferrin receptor. And in our efforts, we've looked at all these other receptors as well. And we believe that transparent receptor remains the most promising approach to get across the blood-brain barrier. As I highlighted before, and part of this is through our own clinical experience, and as I'll share on the next slide, it's not just about delivery to the brain, it's also enhancing delivery to other tissues. And so here is an example, and this is -- we've shared this at least the center images before. So what you're looking at is a standard antibody compared to a transport vehicle-enabled molecule on the right-hand side. And in the center is the brain. So obviously, you can see a really big difference between a standard antibody, which is perivascular versus a transport vehicle-enabled molecule, which gives you this even distribution throughout the mouse brain. But what I wanted to show here is whole body distribution on either the bottom left or the bottom right. And what we've noticed is that we get great distribution to bone and muscle in addition to brain. And part of this is where transparent receptor is located. So we believe this technology now opens up other therapeutic areas. And I think Pompe is a great example of that, where we can enhance delivery to muscle and hopefully either have less frequent dosing or lower doses but even at the same dose, much better distribution into muscle. Now if we look at the clinical data, I think importantly, we've shared many, many times the heparan sulfate reduction in cerebrospinal fluid, which is representative of brain. So I think this is really robust. Obviously, normalization of heparan sulfate -- but what I think we often miss is the fact that we also get more robust reduction in urine and in plasma. And so what we see is, again, distribution throughout the body to enhance delivery of enzymes. And this will be important as we think about the opportunity for enzyme replacement therapies even for ERTs that are not necessarily targeting the brain but rather the whole body. So what is the transport vehicle. Basically, what we've done is we've engineered the Fc portion of an and we've engineered it to bind to transfer receptor. So there's no unnatural linkages, which is basically what we'll talk about in some depth is a competitive landscape. What have we shown? So we have the first potential FDA approval for a TFR-enabled therapeutic Five clinical stage programs. We've demonstrated the ability to correct neuro filament, which we think is a key biomarker across many diseases. This is, of course, is in Hunter syndrome. We have more than preclinical stage programs using this TV technology, over 200 subjects dosed to date over 11,000 doses given with the TV and a number of publications and patents. I'm not going to go into a lot of detail here, but Joe later on today will talk about modularity, brain uptake, safety and architecture, including comparisons with other basically conventional fab approaches, which are shown on this slide. So what you see, the vast majority of other companies that are approaching this technology are using fabs and making fab fusions either using leak or chemistry or other dynamics in terms of bringing this fab. And we'll show you some of the differences between an integrated binding site versus these conventional fab approaches. I think also important is just the overall clinical experience and how much -- how many patients not only have been dosed, but how many doses have been given and the number of clinical stage programs. So the TV is now the most clinically validated BBB technology, and I've already highlighted this before, you can see here some of the competitive landscape, which we'll discuss in detail later. So let's talk about the 2 franchises and where they stand. Let's start with the ETV franchise. So we believe that the launch in Hunter and San Filippo gives us a combined market opportunity of about $1 billion. I think most importantly, and we're going to discuss in detail is how transformative these medicines can be -- and what do we do when we're successful, we're able to reinvest and really build a broader franchise for the TVs. There are over 30,000 individuals living with lysosomal storage disorders. Of course, these are single enzyme deficiencies. And so when we thought about the first place to go with the transport vehicle technology. We wanted to go somewhere where the biology risk was low. We know what's causing the disease and then we can basically solve that with the transport vehicle technology. 2/3 of lysosomal storage diseases patients have CNS manifestations. And I think as we mentioned, I'll just make one other really important point, which is there's about a 90% historical success rate with enzyme replacement therapies, which is very different than, let's say, even cancer or the Alzheimer's space. So we see this as a long-term foundation for Denali to build this franchise. And as a result, we've invested not only in the ability to launch this medicine commercially, but also to manufacture these medicines. And we'll have a -- we'll be able to spend a little bit of time about talking about our manufacturing capabilities. In terms of the longer-term potential, although this is now becoming much more near term with OTV entering the clinic and very soon. ATVA beta at the first half of next year also entering the clinic we can now take advantage of the transport vehicle to deliver genetic medicines like oligonucleotides or variations of antibodies. And this just highlights and we'll go into some detail around our ATV A beta program, but also our OTV MAPT program using these technologies. And I think it's very exciting to see the Alzheimer's field evolve and utilize these technologies. So let's talk about today's agenda. So we'll start first with the enzyme transport vehicle. And I have the pleasure of introducing Barbara Burton, who, I guess, when I met Barbara for the first time at the family conferences, she is basically one of the most well-known physicians treating lysosomal storage disease for a number of years. In fact, I think Barbara won the Lifetime Achievement Award at the last MPS conference in Chicago. We'll hear first from Dr. Burton. She'll set the stage on the opportunity around these diseases. And then we'll hear from Peter Chin and Katy Pang around our clinical data and our commercial approach. And then we'll end by talking about the ETV franchise. We will also have a panel discussion with Jason Madison, who I'll introduce in a moment, and Dr. Kim Stevens, who is our major advocates and also Jason is living with Hunter syndrome.and has been -- become a close friend and colleague and our efforts around Hunter syndrome. So with that, I'm going to hand it now over to Dr. Burton.

All right. Good morning, and thank you for the introduction. So I'm going to focus for the next few minutes on clinical aspects of 3 of the lysosomal disorders of interest to Denali, of course, MPS II, but also MPS III and Pompe disease. And as you know, these are all lysosomal storage disorder part of a family of more than 50 disorders where there is a specific enzymatic deficiency that leads to substrate accumulation throughout the lysosomes of the cells really throughout the body. That, in turn, has not only physical impacts within the cell, but also many downstream effects, impairing lysosomal function, so impairing autophagy, triggering inflammation and leading into a complex pathophysiology that really defines these disorders and differs from one to the other based on a lot of factors where that substrate is normally distributed in the body. So we'll start with MPS II. And of course, this is one of the most common of the mucopolysaccharidosis, a subset of the lysosomal disorders. There are 8 distinct MPS disorders that share some features in common, but also our individually distinct and associated with different enzymatic deficiencies. We know about 1 in every 25,000 babies born has some type of MPS disorder and the estimates for Hunter syndrome or MPS II are about 1,000 and 100,000. We're actually learning through newborn screening that is probably a little bit more common than that, maybe close to 170,000 and but right in that same neighborhood. This is an X-linked disorder, genes on the X chromosome. So almost all patients are males. There are rare affected females, but -- they certainly constitute less than 1% of the population. It's very unlike Fabry disease, where the females with a single copy of the gene on the X. They're affected just like the males, although less severely not so with MPS to the women who have a single copy of the mutant gene typically are completely normal. So in the MPS disorders, the problem is with degradation of the glycosaminoglycans, which we used to call mucopolysaccharides. That's where the name came from. Now it's glycosaminoglycans or GAGs and in MPS II is iduronate to sulfatase DS. This leads to progressive accumulation of 2 major species of GAGs, heparan sulfate and dermatan sulfate. It's the heparan sulfate responsible for the CNS manifestations the dermatan sulfate that's primarily responsible for the somatic manifestations. And that's illustrated by MPS VI, where we just see dermatan sulfate accumulation, and they have no CNS involvement. They have severe somatic disease but no CNS. So GAGs are complicated molecules. We talk about them being complex sugars, there's basically a core protein and then a string of simple carbohydrates that are clipped off 1 by 1 with different enzymes responsible for each step. But they have multiple functions, and they're really ubiquitously distributed. So that's why we see such complicated multi-systemic manifestations in the MPS disorders. Now MDS I, like all lysosomal disorders occurs along a spectrum of severity related to the underlying mutation and whether there's no residual activity are just a little trickle a little bit of residual activity. So there's a spectrum of severity, but there's 2 major subtypes of the disorder that you see described the so-called neuronopathic or severe form and the milder although I hesitate to use that word, but the less severe or attenuated form. And the major differentiator is that in the severe neuronopathic form. We have progressive neuro degeneration and cognitive decline, whereas in the patients with the attenuated form there's normal or near normal cognitive development without progressive cognitive decline and progressive neuro degeneration. But the severity of the somatic manifestations can be comparable in the 2. There are certainly patients with the attenuated form of the disease who have quite severe somatic manifestations of the disorder. So it's not really fair to call it mild in those patients. There are some patients who kind of fall in between with some mild nonprogressive cognitive impairment, but the spectrum is heavily weighted at the 2 ends with about 70% of patients typically being classified as neuronopathic 30% attenuated. Of course, this is a progressive disorder. The GAG accumulation is progressive. The emergence of the clinical manifestations is progressive and the severity increases over time. But some of the earliest things that we see in babies with MPS II or hernias, umbilical and inguinal hernias. Recurrent upper airway and ear infections, recurrent otitis media, enlargement of the tonsils and adenoids with GAG deposition in those tissues. That leads to obstructive sleep apnea in many cases, coarsening of the facial features with soft tissue deposition of GAGs leading to the fuller lips, puffiness around the as broadening of the nodes and then developmental delay in some but not all patients. Obviously, if they have the attenuated form, development can progress perfectly normally. And in all kids, it usually does for the first year to 18 months before we start to see developmental slowing in the neuronopathic patients. And then progressive stiffness of the joint and of the fingers leading to joint restrictions. There's also a progressive skeletal disease, dysystosis, multiplex and patients may need orthopedic procedures over time. Later on, we see progressive airway involvement, airway narrowing, also cardiac valve thickening with that valve deposition and then that leads to dysfunction and sufficient and then later in some patients stenosis, cardiomyopathy, carpal tunnel syndrome, very, very common MPS disorders are the most common cause of carpal tunnel in the pediatric population. And a significant issue for [indiscernible] as they get older is retinal degeneration with progressive visual impairment. Now in the neuronopathic patients, like I said, we typically see developmental slowing followed by progressive loss of developmental skills and progressive neuro degeneration. Death typically occurs in the teens or at the latest early 20s for the typical neuronopathic patient, whereas those with attenuated disease may live into their or beyond depending on the severity of their manifestations. MPS II was added to the recommended uniform screening panel in the U.S. in 2017. So it's a disorder that's recommended for newborn screening to all of the states -- it is proliferating pretty rapidly. It has come on board a lot more rapidly than MPS I did. It took us 10 years to get to a universal screening for MPS I. This is moving along much more quickly. when I made this slide, we thought about 25% of newborns were being screened. Now I think it's even higher. The big states are doing it, New York, California, Texas even. So it's coming along very rapidly. And I think it won't be too long before we'll have a situation where virtually all babies in the U.S. are screened for MPS II. Now currently, we have one approved pharmaceutical product for MPS II, that's hydrosulface or Elaprase. Most affected individuals get this from the time of clinical diagnosis. But it's not a stand-alone therapy in the sense that we still have to monitor the patients carefully for complications of the disease and intervene symptomatically when we need to for all of the various things that I listed on the earlier slides. So these are kids who get a lot of surgery. They see a lot of different specialists hematopoietic stem cell transplantation is used in some cases. As you probably know, it is the standard of care for the severe form of MPS I. It does not work as well in MPS-I and there may be a variety of reasons why that's the case. But it is used to some extent, even in North America, a little bit more so in some other countries. And if it's done early enough in the first year of life, it probably does provide some CNS benefit, but not as much as in the MPS I situation. And certainly, it provides thematic benefit. It does work thematically -- so what are the limitations of our current therapy? Well, you already heard that the current enzymes don't cross the blood-brain barrier in significant amounts. So idursulfase does not arrest the progression of the neuronopathic disease in patients. We can keep the neuronopathic patients healthier. And as a result, they do live longer have a better quality of life, but we still see progressive neurologic decline and ultimately, early death. We also see continued progression of cardiac valve and airway disease, and these are the major causes of death in our attenuated patients. They also, of course, contribute to death in the neuronopathic patients as well. We have to figure out how much of this is due to the timing of starting therapy since we're just getting newborn screening versus we just don't penetrate all these tissues well enough, but I think it's a combination of those things. It does not prevent retinal disease and one of the most devastating things is to have a patient. And I have this who is doing really well thematically on long-term therapy, but now starts losing is vision, and it's devastating to our patients and really impacts their quality of life. And it also doesn't prevent hearing loss. So most of our MPS II patients do require hearing aids. So the unmet need in MPS II is obvious. We need a treatment to address that progressive neuro degeneration, stabilize the patient, allow them to live more functional and longer life. And we need better treatment for the peripheral tissues that currently are hard to reach and where we see disease progression despite our current ERT. Okay. Moving on to MPS III, also referred to a San Filippo syndrome. And here, we're talking about MPS IIIA. There are 4 different types of San Filippo syndrome, which clinically, we call San Filippo because they all look alike. The manifestations are the same. They all store heparan sulfate, but they are 4 different enzymatic defects. The most common of these is San Filippo Type A. That's about 70% of cases in North America and the deficiency here is in the enzyme and sulfur glucosamine sulfa hydrolase or SGSH for short. It's also referred to as sulfamidase or heparan sulfate, sulfur taste and again, primarily heparin sulfite accumulates. So this appears predominantly as a neurodegenerative disorder without the severity of the somatic manifestations that we see in MPS I and MPS II. The overall incidence of MPS IIIA is estimated at about 1 in 25,000 births. So it's little less common than MPS II, nonetheless, more common than most of the other MPS subtypes. Now with MPS IIIA, again, as is true with MPS II, infants are typically normal at birth. But in this case, we begin to see developmental slowing at about 2 years of age with speech delays. So in both of these disorders, they sit, they walk, they do that stuff normally, but then speech is delayed. Unfortunately, with MPS IIIA, a lot of times we diagnose it much later than MPS II because we don't have those somatic clues that I talked about, the coarsening of the facial features is less prominent there later and we may not have hepatosplenomegaly, some of the other things we see in MPS II. So what we have as a kid who shows up with developmental and then by about the age of 3, they're starting to get some behavioral disturbances, hyperactive aggressive behavior. So they get referred to a developmental pediatrician or a neurologist, a lot of times, they're misdiagnosed having autism or just nonspecific developmental delay or ADHD. They may get genetic testing, but usually it's the usual developmental delay stuff, micro array, Fragile X, they don't early on. Nobody thinks about GAGs because most of the time, there aren't a lot of clues there. But eventually, the developmental delay turns into developmental regression and then a light bulb goes off. So this is something worse. This is progressive and then they get whole exome sequencing or they refer to a geneticist, and they get diagnosed at that time. So the average age of diagnosis is not really until 4 to 5 years. The average age of death is 10 to 15 years by the time the patients are diagnosed. They're typically -- they have lost quite a bit cognitively because the decline in cognitive skills is much more rapid in MPS IIIA than it is in MPS but there are some attenuated patients with MPS IIIA also. Although it's weighted at the severe end of the spectrum, approximately 20% have a more attenuated course. Later onset of symptoms, later diagnosis, slower progression, longer survival. I have one where the girl was walking into her 20s. And she's in her late 20s now and in a wheelchair, but much slower progression. And there have been some adults with intellectual disability picked up on whole exome with this as well. Now they can have somatic findings. I said it's predominantly neurologic. That dominates the picture. But some of the patients will have hepatomegaly or hepatosplenomegaly. Some of them will have more coursing of the facial features. These are 2 siblings I took care of both of whom are now deceased, but you can appreciate, I think they had corse facial features, and he was thought initially by the referring physician to actually have MPS II because of the way you looked. And we can also see chronic or recurrent diarrhea. Sometimes we see that in MPS II. Also late in the course of the disease, there's very difficult prominent GI motility that makes it hard to feed them. They wind up needing G tubes because they can't. Sucks all of that, but then we even have trouble putting stuff down the G-tube because the GI motility is impaired. Cardiac valve disease does occur skeletal findings occur. So occasionally, we'll see 1 with hip pain, hip dysplasia. But it's sort of a back burner kind of issue. We do surveillance for it, but it's not nearly the same relevance currently as it is with MPS I and II. That may change if we get the patients living longer. I think it will. We're going to have to pay a lot more attention to the somatic manifestations. So currently, our treatment for MPS IIIA is very frustrating because we don't have any disease-modifying therapy available for them is primarily symptomatic. HSCT does not work at all in MPS IIIA. It's been done quite a few times. It does not alter the course of the disease in any way, even if you do it in a very young baby, most or many of the patients, certainly the most of the ones I take care of are receiving an anti-inflammatory drug, Anakinra, marketed as Kineret for a different disorder, off-label therapy. But there is one trial that showed some clinical symptomatic benefit in patients with MPS III, so many patients are on it. In the past, they were on Genistein and then some of them are minglestat and all of these kinds of things. But none of that really changes the course of the disease. You probably know there have been lots of therapeutic trials of different things in the past from intrathecal therapy to different gene therapy trials that have failed. Hopefully, the Ultragenyx gene therapy trial will come to fruition. But there have been a lot of failures, so the frustration in the patient community is extremely high and there's huge unmet need here and just waiting in the wings for something to happen. There is no newborn screening currently for this. it is feasible, however. So I think as soon as we get an approved therapy, there's going to be a big push to get newborn screening for this one because we really need to treat the patients early and we don't find them early enough clinically in most cases unless it's a younger sibling, of course. So really, tremendous unmet need here to slow down the relentless progression of the disease. It's a horrible thing for families to watch as their kids just slip away. And the focus is on the brain. But like I said, I really think if we treat the brain and we get these kids living longer, we're going to have to pay a lot more attention to the body and the somatic manifestation. So therapies that just treat the brain, some of the gene therapies that we tried in the past go directly into the brain. I mean that's not going to do it for us in the long term. So we're going to need a somatic treatment as well. Okay. And then finally, Pompe disease. Again, spectrum of severity from what we refer to as the infantile onset Pompe, where patients have no residual enzyme activity, no mutations to a later onset form of the disorder that looks a lot like limb-girdle muscular dystrophy and the major differentiator between infantile-onset and late-onset Pompe disease is the presence or absence of cardiomyopathy. The infants have cardio all have hypertrophic cardiomyopathy. They have it at birth, although it may not present clinically for weeks or months. But when we do newborn screening, we find them, it's there. That's the cause of death for those babies untreated, whereas, like I said, the late-onset patients don't have cardiomyopathy, they present with skeletal muscle and respiratory muscle weakness. And the term late onset is a little misleading. It's really later onset because they can present as late in the first year of life. All the way through childhood into mid adult life. So there's a wide range of age at which it's diagnosed. And survival is long generally for the late onset patients, but with a progression like limb-girdle muscular dystrophy. The deficient enzyme is GAA or alpha-glucosidase. This leads to progressive accumulation of glycogen and the lysosomes of cells. This is also referred to as asset multi deficiency or glycogen storage disease type 2. Some of you may follow the trials and other forms of glycogen storage disease like type 1. So you know that in addition to this lysosomal pathway for glycogen breakdown, the primary pathway for glycogen synthesis and breakdown is in the cytoplasm. And that's where the defect is in these other disorders in patients who have cytoplasmic defects have problems with hypoglycemia, lactic acidemia hyperlipidemia, all of that. We don't have any of that with Pompe disease. The cytoplasmic pathway is completely intact. But once the glycogen gets in the lysosome, it's trapped in there and can't be degraded and progressively accumulates. This is a pretty common lysosomal disorder between 10 and 15 and 1 in 20,000 more common much more common than the MPS disorders. I already told you about the infantile patients, hypotonia depth by 12 to 18 months without treatment. Now that we have treatment, they survive longer and there is a post-treatment phenotype that includes persistent progressive muscle weakness, hearing loss and white matter changes in the brain with progressive neurologic decline in a few. We don't really know what the natural history of these brain changes is going to be yet. There have been only a few patients. We don't have a lot surviving beyond the age of 20 yet. We had all these immunologic issues initially. But now that we have addressed those and we get longer survival, we're starting to see it. The MRI changes are very common. Most patients are still asymptomatic, but there have been a couple with progressive neuro degeneration. How common that's going to be, we don't know at this point, but there is that in IOP. We may very well need to get enzyme into the brain to be able to address that issue occurring later in the disease. Now in late onset Pompe, I mentioned a wide range of age of symptoms, that pragmatic weakness is very prominent, intercostal muscle weakness, so a lot of the patients need things like oxygen support, CPAP, BiPAP in addition to having to deal with their mobility issues and muscle weakness, but they don't have cardiac involvement. Every baby now is for Pompe disease. It was added to the RES in 2015. It's now on the panel in all 50 states. And we have 3 approved of enzyme replacement therapy. Our historical drug was Lumizyme, started as my Lumizyme approved for both IOPD and LPD. Now we have next biz and pambility. Both of these have enhanced glycosylation like the other enzymes, this gets into the cell through the mano-6-phosphate receptor. So these are -- have better glycosylation and then with the pomability we use the chaperone as well, miglustat. Patients with IOPD are treated urgently at the time of initial diagnosis. We really hit them hard fast when we get them through a newborn screening. And it makes a different weeks make a difference in outcome. Patients with LOPD now diagnosed through newborn screening, we do not treat. We monitor but treat them at the first onset of symptoms, which can be anywhere from a year to who knows when. So how well does the current treatment work? The answer is not very well at all. Pompe disease treatment is not very effective compared to Goshe, Fabre, any of the others, really. It helps some. mean, it's been of incremental benefit to the patients. We had the immunologic issues early on if we address those properly, which now I think we pretty much know how to do, it's very effective for the treatment of cardiomyopathy and infants. And so it's life saving. You can reverse that completely and get normal cardiac function. But it's much less effective for skeletal most disease, either in IPD or in LPD. Most patients show some modest improvement in muscle strength, mobility and respiratory function after the onset of treatment maybe up to a year, maybe 2 years in some cases, beyond 2 years, you never see any further improvement. You hope for a period of stability, but ultimately, most of the patients then begin to progress ultimately. We don't really have that long-term data for the 2 newer drugs that what I just said is true for sure for Lumizyme. But I can tell you that the improvement we see when we move a patient from Lumizyme to one of these others is, again, it's incremental, a little bit maybe, but we're not making the patient healthy. We're not making them well. We're not making them strong. They're not getting up outer wheel shares. Their life is not really changing dramatically. So there's still, I think, considerable unmet need in Pompe disease. So why is it not working very well for skeletal muscle? I think the biggest reason is very sparse [indiscernible] receptors. On skeletal muscle [indiscernible] and so forth. So no matter how much you glycosylate these things. There's only so much you can circulate get through those receptors during the time that the patient is seeing it. in the circulation. We know in the past, we used to go up on the dose, up, go up on the frequency with Lumizyme. We'd see a little bit better, little improvement. It's the same thing here, but there's a ceiling. So dosing was probably inadequate for most patients with Lumizyme. But now I think we're probably at the ceiling. Some patients, obviously, in the past have been diagnosed late. And if the muscles replaced with that, just like any of the other diseases, if things have died, you're not going to restore it. And the other thing is we get lysosomal rupture over time. So we get a lot of cytoplasmic glycogen and you don't target that when you're going in through the mano6-bospate receptor into the lysosome. So you can't fix that. So a lot of unmet need. We need treatment of the brain and IOPD, most likely, although we don't know how big a problem this is going to be at this point. But we definitely need better treatment for the skeletal must in both forms of the disease. And LOPD is 80% to 85% of cases. And prevalence wise, it's higher than that because of the fact that they live a long time. So that's it for me. Thank you for your attention. And Peter, I guess you're up next.

Great. Thank you, Dr. Burton. I want to thank Dr. Burton for painting the picture of all the clinical unmet need in lysosomal storage disorders. You've heard from Ryan, that this is a collection of disorders that causes enormous burden worldwide. And our ETV platform is designed to treat both brain and body. Now Hunter syndrome is our first target with tividenofusp alpha. And as you've heard earlier, traditional enzyme replacement therapy doesn't cross the blood-brain barrier. 2/3 of these individuals have CNS manifestations as a neuronopathic disease. And so our goal is to address that unmet need and address the unmet need in peripheral manifestations of disease as well. This is a study design of our Phase I/II study. You've probably seen it before. It's an open-label study, long-term extension in non-neuronopathic and neuronopathic patients. You can see the primary endpoint is safety. Secondary endpoints listed below. Early cohorts were dose-finding cohorts followed by 15 mg per kg on the target dose. And really, the takeaway is that this is a study that has generated substantial long-term safety and efficacy data that supports the accelerated approval that's under review and supports the positive benefit/risk profile in MPS II. These are the data that have been generated from the study. You can see on the left, normalization of CSF HS. There's a dramatic and rapid reduction in CSF HS. That's a primary substrate of iduronate 2-sulfatase, which is the deficient enzyme and MPS II. Greater than 90% reduction is achieved and sustained for up to 3 years. You can also see on the right-hand side, normalization of urine HS. And so again, primary substrate in the periphery, which shows the opportunity for us to address both brain and body to a great degree with normalization in both compartments. In the middle, we see that there is a dramatic reduction in NFL over time. And what we're showing is a normalization of NFL. This is a common neurodegenerative biomarker across neurological diseases. The takeaway here is that tividenofusp alfa is the first and only therapy in development for MPS II that has achieved normalization on all of these biomarkers. In addition, while tividenofusp alfa, the E2 study patients demonstrated clinical outcomes with skill gains and adaptive behavior on the left and cognition in the middle. So these are patients that are over time continuing to gain skills where we would expect from natural history that they would start to decline as Dr. Burton has alluded to earlier. In addition, you've heard that hearing is a major impact in MPS II and TV reduces the hearing threshold in auditory brainstem responses, significantly, and that is also sustained. And so these data support an impact on clinical outcomes with MPS II. The safety primarily infusion-related reactions are the main and most frequent adverse event. This is entirely expected with enzyme replacement therapies. Most of the events were mild to moderate in severity and they decreased substantially over time with continued treatment. So in totality, the Phase I/II safety and clinical outcomes data and biomarker data support a broad indication for the treatment of MPS II in terms of the full spectrum of the disease. This is a schematic of our Phase II/III global trial that is ongoing. It's called the COMPASS study. It's a rigorous design. It's a randomized, double-blind, active-controlled study with 2 cohorts. The first cohort is cohort A in neuronopathic disease, patients aged 2 to 6, and they are treated for 96 weeks and blinded comparison to [indiscernible] which is the current standard of care that doesn't cross the blood-brain barrier. The assessments in this cohort are going to be primarily neurological with CSF HS and Violin 3 as well as the Bailey scales for cognition. Cohort B is a 48-week double-blind comparison against hydro sulfate in non-neuronopathic patients age 6 to 2. And here, the comparison is multiple endpoints that affect the periphery, including 6-minute walk test as well as a number of biomarkers and imaging markers. Now you can see that -- there are a number of endpoints that are going to be assessed across the entire population for Cohort A and Cohort B. And again, this is to demonstrate the totality of efficacy both in the brain and the body. This is going to be the study that supports confirmation of the accelerated approval in the U.S. as well as global approvals. In totality, the development program, we consider very robust by the time both studies are completed. We'll have over 100. We'll have 100 patients treated with videos. Our target PDUFA action date for the U.S. accelerated approval is April 5. And as Ryan mentioned, the progress in the filing is going well. We've had our late cycle meeting and we're in label negotiations with the FDA. Now I want to share an investigator perspective on MPS II from Dr. Joe Monser, who is one of our lead investigators in the Phase I/II study.

Hello. I'm Dr. Joseph Muenzer, Pediatric Biochemical Genetics NersaNorth Caroline Chapel Hill and want to present 2 siblings enrolled in the Phase I/II DNL310 study from an investigator's perspective. Both boys have pathodetic-IDF variants, have absent enzyme activity and have elevated urine glycosemaoglycan to make the diagnosis. The older sibling was diagnosed at 3 years, 8 months based on clinical criteria. At that time, he had a younger brother at 5 months, unfortunately, also had Hunter Senior boast very quickly after diagnosis was treated with weekly ether sulfates at 0.5 milligram per kilo. Both enrolled in the Phase I/II study of DatAL310 and received weekly TV data alpha at 15 milligrams per kilo for greater than 4 years. The older brother started 6 years, 4 months and the younger ones started 2.5 years and I want to actually show you a slide of the 2 of them in a pool. The next slide shows you the older brother sort of just in a routine situation at home where he's very calm, interactive but is non-verbal. As you can see he enjoys a video and the last video I want to show you is the younger brother who is now roughly 7 years of age, in second grade. [Presentation] And this video just shows you how well he's doing and the power of prevention of neurologic decline, versus stabilization in the older brother. Thank you.

So we've summarized the data that we've accumulated going dramatic effects and normalization of primary substrate for IDS in both brain and body. And I think from that clinical perspective, you can see the power of what we are trying to achieve and what the potential opportunity is for us to transform Hunter syndrome with videos. So that is the cornerstone of our ETV franchise, but we're going to build on that with MPS IIIA with DNL-126 and DNL-952. A really, our goal with the ETB franchise is to deliver transformative treatments for the LSD community to address the unmet need that we've been discussing. As you've heard from Dr. Burton, MPS IIIA is debilitating and relentless disease with no current approved therapies. This is our structure of the DN 126, ETV SGSH. This is a program that has aligned with the FDA on a path to accelerated approval, again, leveraging CSF HS as a surrogate endpoint like reasonably likely to predict clinical efficacy. And the Phase I/II enrollment has closed. And so we're excited about the opportunity to address the unmet need here. Just a quick word on the study design. This is our Phase I/II DNL-126 study. You can see the study population includes both severe and attenuated patients with MPS IIIA. There are 2 dose finding cohorts, cohorts A1 and A2 and then 2 key efficacy cohorts A3 and B1. The endpoints are listed on the side. This is an open-label study. with an open-label extension following a 25-week core study. The initial data are going to be presented at the World Symposium in 2026. Just a note on the data that's going to support the accelerated approval for DNL126. We'll have at least 49 weeks of data for all study patients in cohorts A1 to A3 as well as Bone. And then SFH reduction from baseline in key efficacy cohorts, A3 and B1 are going to be the surrogate endpoint reasonably likely to predict clinical benefit. We'll also have supportive data from the entire patient population on both central and peripheral outcomes and long-term safety projected to be up to 2.5 years. And so we expect a BLA submission to support an approval in 2027. And with that, I'm going to hand it to Katie.

Thanks, Peter. Good morning, everyone. Thank you for being with us today. I thought I'd start this next section by sharing with you voices from the Hunter community. So on the left is a letter that we received from a family whose child is participating in our Phase I/II study. The family shared with us that their child is thriving and that as a family, they've been able to do things that they never imagined was possible when he was first diagnosed. In this letter, they wanted to remind us of a future. We're at the earliest possible moment a brain penetrant therapy is available and imagine what that could be for families in the future. In the middle is a survey that we did in partnership with an advocacy group called Project ALIVE. In this survey, 60% of respondents indicated that there is significant unmet need for a medicine that can treat the brain and that it is urgently needed to deal with the cognitive issues with MPS disease. And on the right, or common voices that we hear from the MPS community change is very hard, but they are watching carefully of the emerging therapies, but they do need confidence and reassurance from patients that's gone ahead. And for us, our goal is to ensure that every family feels confident to be able to consider a switch. And we need to make sure that the experience early on with TV is a very positive one. These voices established the story of lived experiences of hopeful anticipation, but certainly a community ready for change and we have been listening to these voices every step of the way as we're preparing for our launch. You heard Dr. Burton described very well the disease, and we've learned along the way that this disease is a spectrum and what's important here is that progression continues, not just in the CNS, but in the periphery as well, and you heard this from Dr. Burton. We've also learned for the attenuated patients, the onset may be later in life but the progression does continue over a lifetime. And we're also now hearing from adult patients that they're experiencing some CNS manifestations. And that could come in the form of attention. And also Dr. Burton mentioned ocular degeneration. Our hope is that TV will be able to address all of these manifestations for all patients with Hunter syndrome. Peter and Dr. Burton refer to the incident population of 70% severe and 30% attenuated. But what we're seeing in the prevalent population that there is definitely a skew towards the less severe population, which isn't surprising given their longer lifespan. With the introduction of TIV, our hope is that all patients will have a reduction in the severity of their disease and that over time, there will be more patients, people living with MPS II Peter shared the data of Tivi, and we believe that we will set a new standard for treatment in MPS II. TV is the only therapy that could treat all Hunter syndrome. The first to be able to treat both brain and the body and to be able to normalize GAGs. With the data package we submitted, we are hopeful for a broad indication, and we feel like our molecule is very differentiated from the emerging treatments and the current standard of care. With the ability to normalize GAGs, we also believe TIV has the best chance to demonstrate superior clinical outcomes. We've also received very positive feedback from key stakeholders. And it's not just Dr. Burton, who sees the unmet need across both brand and body. Many of the physicians we spoke to sees the unmet need in the brain, but certainly in the periphery as well. 90% of physicians believe that the TV data is very motivating prescribe and there has been no major concerns on our safety profile. We hear similar feedback from patients and caregivers on the unmet need, and there's high awareness, 80% are aware of new emerging therapies and many are excited to try TV. We have now started significant engagements with payers, and we've also received similar feedback that they believe in the benefit/risk profile of TV. But we also have heard that they believe in the therapeutic possibility and the benefit of a molecule that crosses the blood-brain barrier. So our launch strategy has 3 key imperatives: the first is that we continue and maintain the strong partnership we have with the community. We know that patients and families get most of their education and information from this community. So we have to work very closely with them to ensure that our messages can reach the most amount of patients. In addition, we have to build an engagement model that can support physicians, patients and caregivers throughout the entire journey, the treatment journey. And of course, the last is we have to make reimbursement and coverage of the molecule streamlined and efficient and easy for families. Given what we've put in place, we believe we'll be able to activate and maintain a switch and as well as drive broad coverage and fast policy establishment. I also wanted to highlight some of the prelaunch activities that we've been doing. We've always had strong engagement and presence at medical congresses. But I'm really excited to share for World 2026, we've been accepted for 2 oral presentations and 5 poster presentations. This is an important meeting for us given that it will be our launch year. We've also been busy on the Hill, supporting policies around newborn screening, as well as ensure that there are biomarker accelerated group pathways for rare disease. And of course, ensuring that there are not policies put in place that will hinder a patient from getting access to new treatments. And we've also, in launch preparation, formed a patient council. Council members have been helping us design our communication, and they have been instrumental in ensuring that we have the right patient services when we launch this asset. Now I wanted to touch a little bit on our pricing philosophy and what we think about before we price Tivi. So for us, we need to ensure that there could be broad access and sustained access for patients. We also consider affordability and. So we design our financial support programs based on how much we can support patients on the affordability front. In addition, our molecules have to incorporate in the price, our ability to fuel future research. And of course, the price has to represent the clinical value that the molecule brings. And given the package and the clinical data you've seen with TV, we expect to price at a premium, while importantly, balancing broad access and ensuring that it represents the clinical value that it delivers. In terms of the payer landscape, when we first engaged payers, there were very little awareness of MPS II which is not surprising, given that there's only 1 to 2 patients per million lives covered by their plans. But given the efforts that we've put forward, we feel very pleased that there is now strong recognition that the burden of disease is still significant even with the current standard of care. And given the low budget impact, for MPS II, we are hopeful that we will be able to get similar coverage and good coverage that the standard of care sees today. There's also some interesting dynamics with MPS II. It is not uncommon in rare disease to see high coverage by Medicaid plans. But in MPS II, it is quite unique. 50% of families or patients are covered by Medicaid and the other 50% by commercial payers, which is uncommon and also for Medicare, it's actually very few patients covered under Medicare. Given this payer dynamic, we do expect payer policy and coverage to take a little bit of time. In terms of the U.S. landscape, we believe there's about 400 to 500 patients in the U.S. and they're concentrated at major centers of excellence. And there's about 100 genetics managing the majority of these patients. Since we've implemented the -- or we've deployed MSLs more than 4 years before we've launched, we have very well-established relationships with all of these centers. In addition, now that we've hired our field footprint, we believe that we'll be able to cover all of the accounts that treat more than one patient. And here's just a quick profile of the team that we've put in place. You can see all of the team members have significant experience across commercial and medical affairs. In addition, we've launched many successful products, including in rare disease, and we're very familiar with buy and bill or IV infused products. We are also very pleased with the assembly of our field team who have launched many rare disease medicines and have significant experience, 12 years on average of experience, either in lysosomal storage disorders or in rare disease. Now how are we thinking about launch? And what does the trajectory look like? In terms of the adoption curve, we expect to see a very similar S-shape curve that you often see with rare disease launches. Even with all the excitement around TV and the high awareness, we expect that we will have to work through some mechanics of launch. For new therapies, new ERT therapies, patients have to come into the clinic to receive their infusion. And right now, an MPS disease, a majority of patients get their infusions at home. So we'll have to work through the mechanics of scheduling infusions but also in the beginning, in the initial phase, more than likely we will not have payer coverage right out of the gate. So we will have to get reimbursement through medical exceptions process, and that will take some time. So in 2026, we expect modest revenue, except what is really important is that we get as many patients as possible started on TV. And the reason for that is in rare disease, persistence is high. So once treatment is established, patients will stay on treatment. But as more experience grows and the coverage improves over time, we do expect to see an inflection point where we'll see significant adoption and revenue growth. Okay. So in terms of global expansion, what are we doing with our U.S. approval? Well, we feel very happy that we will be able to leverage the U.S. accelerated approval as well as the Phase I data to expand into the international space. There are many countries that accept a U.S. CPP or have a conditional pathway to move forward. We believe we can tap into about 60% of the addressable market even before the European Compass launch. And our -- my last slide here touches on what Ryan discussed with our first 2 near-term assets, we believe we have a revenue opportunity of more than $1 billion. In addition, as we unlock the U.S. and other markets with these 2 assets, you will see sustained growth over time. We will also have significant synergies with our first launch because the customer base is the same for TVN as well as DNL 126. We are building a commercial model that we think will be sustainable, repeatable. And with our leadership in LSDs, our future launches will be even more successful 1 after the next. And we're excited to be building a very sustained long-term high-growth rare disease business. Thank you. And I'd like to invite the panel up here for our next session.

Thank you. My pleasure to be able to introduce our panel. I think we're going to start with you. Dr. Stevens. Is that right? You're going to give us an introduction in your experience and why you're with us today. And then we're going to hear from Jason, and then we're going to open it up for questions for both all of you, but I also have a few questions as well.

Okay. Good. So I'm Kim Stevens. I'm the mother of a boy with MPS II, and I'm going to introduce you to Cole. [Presentation] He doesn't talk. At the age of 5, he stopped singing at the age of 7. He held on to 2 words, help and mommy by 9, it was Mommy, and that was the last word I ever heard him say. He's now 15. Some might heard him speak over 6 years. You've heard a lot about the sort of journey that an MPS II child goes through but what I don't think we've grasped yet in this room is how devastating this disease is. I had Cole 15 years ago, there was no sign of disease. I had no idea that he had Hunter syndrome. At 1 year, I started to notice he had a large spleen and our pediatrician started talking about obesity at 1 years old, which was just ridiculous. Six months, as Dr. Burton had said, he had double hernia repair, our tubes is constant running nose. And then at 2.5, he had ear tubes again. Tonsils removed and he started enzyme replacement therapy. So I also want to emphasize at this point that is standard of care. For standard of care right now for enzyme replacement therapy, you go into a center or a hospital much like Tiny will do for 6 months. If you're okay with the infusion at that point, then they will send you home. So this is something our community is used to. Everyone used to ask me at 2.5. How do you get coal to sit still for 3.5 hours for an infusion? He just does it. It's part of his life. We made it fun. He got a cupcake after every infusion. And he would finish his fusion cupcake, and I give him a cupcake, you get a toy. And we just knew our whole life just started around enzyme replacement therapy because I knew that was going to keep them alive. And as I said, he went into a clinical trial at about 4.5 million right before we did that, you stop potty training. We were starting to potty train like most kids do at 2.5, 3 years old. You could see the words just getting stuck in its head -- he was very frustrated. He was banging his head on the ground because he was just so frustrated. They would call me from school, I'd have to go pick them up preschool. Is tension spend was very, very low. He was starting to bite people as well as himself. He no longer could say any animal sounds his favorite thing to do was to do animal sounds. He would often say to Dr. Muenzer, who you saw earlier, Sir, and that's what he called them. Sir, what animal has a long neck. And then he would laugh and say, Giraffe. He didn't do that anymore. And then you really showed and the ability to really do anything academically just started to go away. We have what we call in our community, the Hunter syndrome star, where it's just nothing. It's like nothing is going on. So that was what's starting to happen here. So I really want to emphasize this. You're slowly watching your child disappear. And with TV, we're very excited in the community to have this opportunity to have something that's crossing the blood-brain barrier. Our community is waiting. I get calls every day or text or an e-mail. When is this going to be ready for me? When can my child get this? I have discussions with newly diagnosed families telling them they have to wait for this particular drug to get approved. And also to point out, Kohl's had over 500 IV infusions with enzyme replacement therapy. It's just our part of our line. And we're willing to really do what we need to do to keep our children alive, and that's what I've tried to do a whole is keep them alive until something better comes along, and it has.

Thank you. Hello, everyone. My name is Jason Madison. Thank you all for allowing us to also share our stories with you. So my Hunter syndrome story is a little different than a lot of other families because we can trace our back for generations. So I have a few pictures here of my family history. We have Glenn Silverthorne, Glenn and Jane Silverthorne. And these guys were around even before Hunter syndrome is even known. So it's just a mystery illness and the same thing with my great uncle John. And it wasn't until my unkeen was around that my grandmother was like. This is in our family. We got to figure out what was going on. So we went to the Shiner hospital in Erie, Pennsylvania and they're like Hunters. So then when I was born, my mother saw and we had such a long family history of something that we -- she actually got me genetically tested, and then we finally knew what was going on. So I also want to bring up real quickly, if you notice progressively, the agents have increase their lifespan, which is pretty amazing. And my ankle even has a wife and 2 children. So that's incredible. And that's a great sign of just how far for health care has come. And I did want to bring up real quickly that Glen and Jay, I thought they just passed way naturally, but I learned later that they actually unfortunately killed themselves. And I can understand why because you don't know what's going on or anything like that. And that really reflective of just the quality of life issues for people, especially who are attenuated -- it affects their mental health as well as our physical health. So my great uncle John, he ended up passing away from pneumonia. And I've just got over a real bad case of COVID pneumonia. So that really hit home if I didn't have the care that we learned, I would have just way. So that's just a little indication of just where we've gone. But once again, as you've heard before, there's a lot of unmet needs fast. So through this time and experience with the family, I've really been a part of a lot of nonprofits MPS society and just being a part of the -- just the community because I want to be a part of that. I've actually been one of Dr. Munter's first patients back when he was a fellowship. So my whole family has been pushing really hard just to get things better to improve not only our lives, but the lines around us. So and as you can see in this first picture, I meet with the hospital say , these are all hunters patients, and you can see just the difference and all the severity. And it was really funny because the little baby was we're getting a picture. And I talked to the family, who had just been newly diagnosed, they're from the where I live in Allentown. And I never met them before, but they recognized me. So as soon as they saw all of us getting together for a picture, this woman just kind of comes up to me, can't be may -- all right. Well, thank you very much. So I took a picture of it. we also mean the really well behaved kids. And I've just taken part of a lot of social media campaigns like bake the purple pie you wouldn't believe how much die went into that to make it that for both. It was really difficult, but for a good cause. And then there's also another picture of just the entire MPS community that just includes all the different varieties of MPS just to show that there's a lot of unmet needs, even though we do have treatments, there's still a lot of things that need to be done. So I'm working with everyone here going forward. So that's my story. Thank you.

What we'll do now is open up for questions. And maybe I will start and we pass the mic around. I know floor, if you have a mic, we're able to pass around. It's been brilliant to get to know all of you over the last 5 years as we've been developing medicines for Hunter syndrome. And I think maybe I'll start with Dr. Stevens or Kim. Kim, you and I have at least, I think, interacted for the last 5 years. Tell me what the communities mindset is right now around new therapies. I think it's been 19 years since Elaprase was approved. And I know there's been probably a lot of up and downs over the last 19 years, but would love to hear your perspective.

Yes. So Elaprase was approved in 2006. Nothing crossing the broad brain barrier has been developed, that's approved. So community is anxious, especially in the community with severe MPS II. We know what's coming. You saw on a slide earlier, and Dr. Burton had said that these kids die between 10 and 15 years old. I would say Kohl's cohorts, the folks that around his age. Most of them have passed away. And I'm very aware that coal turns 16 next July, and he's bucking the system just a little bit. It's very scary. So we live with that fear every day. I still go in every morning hoping that he's still live and checking on him and making sure he's still breathing. And all of our families in the community feel that. It's really just a devastating disease. And to have something so hopeful, and I tell parents, just hold on we've got something that really is going to help our community. It's really amazing now, and I'm so excited, and I've seen these kids on TV, and it's just amazing. And I also want that for Cole.

I know it actually minds me here we are. side you hear all the horns hunting that anxiety to get there right close to the finish line. I know you and I have had that conversation a lot. I don't know if there's any hands. Okay, good. Over here. A couple

Thank you. It's Sean Laaman from Morgan Stanley. I have a couple of questions on the newborn screening. So if I think read it right. I think newborn screening rates are about 25% in the U.S. and it started in 2017. So I'm wondering sort of what are the impediments for rolling that out to is the first part of the question. Second, I imagine that Hunters is a very well defined and diagnosed disease, but would newborn screening change your estimate of the incidents at all. And then just looking forward, I guess, the earlier you treat the disease, the greater the improvement in clinical biomarkers, it seems. So I'm just wondering in payer discussions, just those older patients, do you expect sort of potentially any pushback because there may be lesser benefit on clinical outcomes that led you lever it to treat the disease

So maybe we'll hand it to Dr. Burton for the RUSP and the newborn screening.

Yes. I'm not sure I caught all of that, but the major impalement implementing it right away is money. I mean every state has to do this independently. Newborn screening is a state health department prerogative. So they have to they have to get it set up. I mean, that takes some time to develop a new test in the laboratory, establish their own normative values and all of that. But the main thing is money. They have to get state appropriation or right their newborn screening fee and state governments are very -- they're dinosaurs, their slow, things don't happen very rapidly in many cases. So that's it. But I think it is going to -- I think probably by the end of this year, we'll be screening 50% of newborns, and I think we'll get to that 100% probably within the next 2 to 3 years faster than with too, but it's not instantaneous. There is significant time involved. What else was in there?

And I think what's interesting in your own slides, Dr. Burton is the difference between MPS I, MPS IIIA and Pompe, where Pompe, you have 100% screening across the U.S., and you have no screening yet for MPS IIIA, probably driven by the availability of medicines.

Absolutely, you can't get newborn screening. If you don't have a therapy. I mean in no state panel will agree to that. Even though families may argue there are other benefits beyond having a definitive therapy. There's got to be some. And there's got to be evidence that giving it early makes the difference as opposed to just doing it at the time of clinical diagnosis. That's why we don't have widespread newborn screening for Gaucher disease, for example, because that evidence hasn't come to come forth or fabric for -- we have it in scattered states, but it's not certainly moving anywhere toward uniform. But once we have that, I think we can move much more rapidly with MPS IIIA.

And I think that Part B to question 1 is, will there be an increase in the incident once you have newborn screening across the U.S. I think for Pompe, it was clearly that...

Very much. It was at least doubled over what the projection were before Pompe. Some MPS-I that has not been the case. Really, it's turned out that MPS I was just about as common as we thought it was. MPS II, I think we're going to see -- it's a little more common. We don't have enough published data yet, but our own experience in Illinois was that we see about an incidence of about $170,000. So somewhat more common and dominated by attenuated cases. So we have found families where there are baby is diagnosed -- we studied the family. We find adult family members who have MPS II but have not previously been clinically diagnosed. So a big part of our newborn screening follow-up is to study the family because that not only helps us find other affected individuals, but it helps us predict the phenotype in the baby that we're dealing with, too. So these are all attenuated cases. some really interesting various to any weighted cases, 1 family that I found where the dominant manifestation is just retinal degeneration. With a few other little minor things, but without a lot of the other disease manifestations. So we will learn as we do with every disease with the proliferation of newborn screening more about incidents and also about the spectrum of the disease, and it makes sense that the mildest cases are the ones that have escaped diagnosis.

Your other question on payer. So we and the patient advocacy community are engaged with payers. We want to make sure that it's covered. As I said before, enzyme replacement therapy or ELAPRASE is the standard of care right now. So we're hoping that it stays in the price range with that. And that's sort of the expectation when we're talking with payers and their understanding, and we're working with them to understand this disease. And talking with physicians, I think this will be a standard of care because certainly, you're going to prescribe something that crosses the blood-brain barrier as opposed to something that's just treats the somatic disease. And also, this is what I've seen from my own observation is much stronger than what we're currently able to get with the dose size that's for ELAPRASE. So like I said, we're all anxious to switch.

Next question.

Salveen Richter, Goldman Sachs. With regard to switching versus naive, maybe help us understand how rapidly you would switch over attenuated patients versus non-attenuated patients and within the overall prescribing community, what physicians will need to see core leader adopters versus kind of the early adopter physicians. And then if we could just overlay that with how you think about the landscape when and if gene therapy drugs were to emerge as well.

Maybe start with Dr. Burton. I'd love to hear Jason's perspective as well on switching, let's start with Dr. Burton.

Yes. I think we're going to -- I feel the most urgency to quickly switch an attenuated patient who is experiencing obvious disease progression or has a manifestation that I hope may be treated. I have one young adult man who just within the past several years, has lost most of his vision from retinal dystrophy, all those doing very well in every other way. He's hoping and praying that what he has left may be salvaged if we can get them on an enzyme that crosses the blood brain barrier. So I'm urgently wanting it for him and for some of these other patients who are clearly progressing. I will offer it to all of them. I think there may be some patients with attenuated disease who feel like they're very stable right now, who may not be anxious to come back to the clinic and get a new drug and maybe have IRRs that they're not having currently deal with that. But certainly, I'll talk with them about the fact that we think certainly on a theoretical basis and knowing the mechanism of how it's getting in the cells, the dosing, the decline in urine GAGs, this could be more effective in treating their peripheral manifestations. I'll encourage it, but I think there may be some who are less anxious than others. I think as far as physician doctors, obviously, those of us who had the opportunity to participate in the clinical trials. We'll be the earliest adopters. We know how to use it. We know the drug. But I think genetics as a whole in the U.S. are used to putting new drugs online, even kind of complicated ones. We had to go through this dose titration thing with the lipid alpha for ASMD. So that's not really unique. I think, of course, with the newly diagnosed naive patient, it will be offered right out of the gate without question. I think switching over the more established patients it's going to vary somewhat patient by patient. Some will be very anxious like Kim is talking about. I think there may be some of the more severe neuronopathic patients whose kids are very advanced in their disease and where they're getting home therapy and they're not having reactions and all of that where the family make question whether the benefit is worth the burden of coming back to clinic and maybe having more reactions. And certainly, that's going to be true if they're at the very end of their life, tube fit and bad, all of that. But some of the very severe ones, I think, might feel that way, but I'm going to encourage patients that I feel like it's going to prolong their lives and keep them more functional for longer. So I think most of the patients will be ready to switch. And I think most doctors are going to be anxious to have an alternative therapy. In terms of that versus the gene therapy, I mean, we'll look at the label and who we can use them for and who it gets paid for but I think if we have a patient where either could be an option, they're going to sort themselves out. I mean there are some families that like that gene therapy concept and they like the idea that maybe for a while, they wouldn't have to have the weekly infusions. I know it's just going to be for a while. I mean they're all going to wind up on Denali eventually because you transduce the liver in these young kids, and it's not going to last. I mean it's going to be a short-term fix. And when they understand that, I think a lot of them may just say, we're going to go with that from the beginning. But yes, we will offer to our patients all of the alternatives that are out there.

I want to hear Jason thought Tim probably has a thought.

Quite here switching. What do you think the barrier is to switching from Elaprase to [indiscernible] at this time, some patients might just be worried for something new. Elaprase works, especially with the attenuated the more geographic am I using the right return -- they might be more prone for. But sometimes there are people who do get scared to try something new. So one thing I try to do, I'm very early that, I'll do whatever. So I try to do it and then I try to use my position to communicate to those who might be hesitant the goods and the match or whatever, just so they have someone that lives it can experience it. So that's I mean I'm not hesitant. I want the stuff. So but that's what I think might be as far as the then goes.

So Jason, just along those lines, the last 2 years you and I have talked a little bit about like hearing and cognition changes? Maybe you can just describe.

Well, yes, certainly. I mean like hearing has gotten worse. And I'm beginning to think that there is a certain element of processing because I can hear the sounds, it just makes just in my brain, I can't quite get it like I used to. And I've also had some issues that are happening more frequently with the retinal and I'd love to have something to get in there. And I am experiencing more confusion, and I know we all get confused a little bit when we get older, a little brain fog, but this is something that I've noticed it that seems to be a bit more. So I'm looking forward to just -- hopefully, it helps. I'm confident with what I've heard from other parents and their kids and also from the data that I'm confident that I'm ready for it.

A nice siren in the back test our confusion. Do you want to say anything, Kim? Maybe let's do one more question. I know we're over, but this is, I think, very important.

Tom Shrader very related question, but what is the switch process? What is the downside? And Dr. Burton, how difficult is the discussion? What do you have to warn patients might happen? But how tricky can it get? And maybe for Dr. Stevens, how eager would you have been when your son was 5 and still singing and I'm sure you like every bar you were hopeful I apologize for the questions.

I think many of our patients in North America are on home therapy. We bring them into the clinic, the first few months of treatment. If they're stable, not having reactions or over their reactions, send them to home therapy, they are going to have to come back in for -- to switch to Tivi. Some of the Gaucher drugs will do switch at home because you don't once they get over reactions, they're not going to have a reaction with the next one. That's not true here. So there's a high incidence of infusion-related reactions. So we have to warn the patients that they may have reactions, what they look like, but we can handle it. I mean we know how to handle it, but we are going to have them in a medically supervised setting. For that switch process. So that's usually going to go from maybe 4 months if they do fine and not really having anything major, get over it quickly to a little bit longer. If they have more difficulty and we have to titrate up the dose and so forth. So that's the main disadvantage to a patient, I think, of the switch that they have to take that risk of having the reactions and the inconvenience of coming back into the clinic and weigh that against the benefits.

Kim?

Yes. And I think when we think -- unfortunately, when we think about the Hunter syndrome community, the turnover because the kids pass away, like I'm an old mom now because I'm one of the ones that they seek information from when I was the one when Cole was 5 or 2.5, and I was having those conversations. So certainly, at 5, I would have been anxious for something to least stabilize Cole. And we should emphasize syndrome stabilization is a win. It's huge because as we said, this disease is very progressive. So I think as we've talked about at a point, it's going to become standard of care so that we won't be having the switching conversations for that long.

All right. I think we will I mean so much more that we could discuss, but we'll move on. Maybe thank you to the panel maybe a round of applause for these great people. Thanks,. So we will finish our discussion around the ETV franchise. Peter?

Thank you, Ryan. And I also want to thank Jason, Dr. Stephen and Dr. Burton for being wonderful partners and guides as we embark on trying to address these unmet needs. So we'll continue with our discussion about building an ETV portfolio. And we'll start with DNL-593 or PTV progranulin, which is indicated or being developed for an indication in FTD granulin. Now this is a molecule that delivers a full length progranulin that retains binding to the sortilin receptor and is also tuned to deliver progranulin to the CNS with uptake to both lysosomes of neurons as well as glial cells. And so this is an approach that is highly differentiated from other progranul approaches. Now it's not only science that actually elucidated that FTD progranulin is a lysosomal storage disease. And what you can see on the left is the co-localization of progranulin with BNP in the lysosome. BNP is a critical molecule set of molecules that regulate lysosomal function. On the right-hand side, what you see is a granular knockout mouse with a TfR knock-in and the ability of PTV progranulin or DNL, to improve both glial activation and neuro degeneration biomarkers with GFAP and NFL. Now we've noted that this mechanism is distinct from other therapeutic approaches. And anti sortilin antibodies bind to the source selling receptor and increase extracellular concentrations of progranulin, but leave the intracellular lysosomal dysfunction unresolved. DNL-593 is a protein replacement therapy that is designed to restore extracellular concentrations and lysosome wall progranulin to normalize function. This is a schematic of our Phase I/II clinical study that's ongoing. There's a SAD cohort, single ascending dose cohort in healthy volunteers that has been completed. And this demonstrated a dose-dependent increase in CSF progranulin. What's ongoing is the MAD cohort in FTD granulin patients, aged 18 to 80. This is still enrolling, but enrollment is nearly complete and we anticipate Part B interim data with FTD granulin patients to read out in 2026. We are accumulating clinical experience across multiple ETV programs in our platform. And this is a summary here. Safety from a safety perspective, we've already talked about tividenofusp with IRRs commonly seen in enzyme replacement. We also observed anemia frequently at baseline prior to exposure to treatment. Early declines in hemoglobin on treatment were generally returning to baseline and these were clinically manageable. So importantly, no patients in up to 5 years of exposure with tividenofusp have discontinued treatment due to anemia. ETVsGSH or N26, the Phase I/II is ongoing. We have initial data. And so far, the IRRs appear to be clinically manageable and also decreased with time similarly. One patient has experienced a mild anemia -- but this is a patient that also had a predisposition or iron deficiency at baseline prior to exposure to treatment. And then finally, PTV progranulin is blinded. It's a randomized double-blind study. But so far, IRRs appear to be manageable with standard measures. And there have been no anemia TEAEs reported to date in the blinded study. The efficacy to date, we've already talked about, and I think the key takeaway that I want to emphasize is with this accumulated ETV clinical experience across multiple programs, we've demonstrated robust CNS activity and manageable safety that really supports the platform potential DNL 952 is AT-GAA. This is for Pompe disease. As Ryan noted, we've rapidly amended the protocol and responded to the FDA in response to their concerns about a clinical hold. This is a molecule we're very excited about. As Dr. Burton highlighted earlier, there's great unmet need, and there's a limitation in the ability of the existing approved therapies to actually deliver GAA to muscle cells. And so this is a molecule with the TFR TV contract that actually delivers GAA to the whole body including difficult-to-access tissues. It's tuned to maximize delivery both to muscle and to the CNS. And so our therapeutic aim is to demonstrate superiority over existing standard of care and deliver GA to the brain. We have preclinical data in a GAA knockout mouse model with a TFR knock in. And what we've demonstrated with multiple doses is that lysosomal volumes are decreased in a dose-dependent manner with administration of DNL 952 -- and this is in comparison to avalglucosidase, which is one of the second generation standards of care. We've demonstrated similar effects on neuro filament. And so again, DNL-952 approves muscle and CNS biomarkers that are relevant to FTD granular. Sorry, to GAA. This is a schematic of the Phase I study with DNL-952. The study plan includes late onset Pompe disease. There are 2 cohorts planned, A1 and A2 with optional additional cohorts, including a treatment-naive cohort. Importantly, the cohorts A1 and A2 are intended to be treatment experienced with second-generation therapy. And we anticipate having Phase I biomarker data in 2027. So this is a schematic of our view on the ETV franchise portfolio, and we have many opportunities to address unmet need the serious genetic disorders that involve both delivering cargo to brain and body. And we're very excited about the opportunity. There's a lot of unmet need and we feel confident that we have a transport vehicle that can deliver in multiple diseases. So with that, I'm going to hand it back to Ryan.

Thank you, Peter. I mean, as you can tell, ETP franchise has been a key starting point for Denali. In fact, we often get the question, why not just do TVs. Why not just focus on lysosomal storage disorders. And I think that, that's a fair question, and we believe we can create a really important business and franchise and a great relationship with the community, which is, at least for me, been very personally rewarding to work in the lysosomal storage disorders. However, a decade ago when we founded Denali, our ultimate goal was to develop medicines for Alzheimer's disease. And similar to the devastation that you see in lysosomal storage disorder, you see this end of life with Alzheimer's disease for many of us. I mean, I'm sure many of you in this room have people that you love who have had Alzheimer's disease. I know certainly I have -- there have been recent advances that bring new hope in Alzheimer's disease. This wasn't the case a decade ago. But with several approvals of anti-amyloid therapies we see at least some opportunity to delay disease. And I think we're all very eagerly awaiting the prevention study results where we remove plaque in individuals before they have cognitive decline. However, there is a real unmet need. And we've already seen some initial clinical data with other brain shuttle technologies that could lead to faster plaque removal, potentially lower doses and maybe even less frequent dosing. And so we see this opportunity to use the transport vehicle to transform these medicines in Alzheimer's disease with now, I think, a higher probability of success. And so what I'm going to do is introduce what I think is the future of Alzheimer's drug development. And then I'm going to hand it to Joe to go into some detail around our anti-A-beta program and our OTV MAPT program. Of course, that codes for tau. So these are the hallmark pathologies. We know that categorically, people were either believed to be believe in a beta or believe in tow and the reality is that both have very strong linkages to disease. One, very strong genetically the other histopathologically impact both from a histopathological perspective. These end up being the 2 prominent pathologies and also genetic linkages. And we still continue to see neuro inflammation as maybe a future for us. And we've worked in that space for a number of years, but now we're focusing in on amyloid and tau. I think what's really fascinating is now our ability to measure both in blood, but through imaging, these pathologies. And I think this is actually unlike many of the other neuro degenerate diseases. We don't have this ability quite yet in Parkinson's or Lewy-body dementia. But we do in Alzheimer's disease. And Part of this is the invention of these PET probes that will look at amyloid and tau. And what I'm showing you here on the left is basically a normal individual that's amyloid negative and then a normal individual that's amyloid positive and then becomes an Alzheimer's patient over time at each of these separate individuals. The same is true for Tau. And interestingly, both amyloid and tau pathology preceded cognitive decline and synaptic loss. And this is what the graph shows on the right-hand side. And so I think we've known this for now maybe 10, 15 years. And the question is, how do we develop safe medicines where we can intervene I think even more fascinating is how biomarkers transform the 3, I think, really important steps in drug development. First is identification of patients Second is stratification of patients and third is target engagement. And you can use these biomarkers, both blood-based and imaging-based to do this. I think that's why we're starting to see more clinical benefit because patients can be selected earlier in the pathology and hence, delay the disease. So how do we approach this? Well, today, the first-generation antibodies have shown that there is a potential to slow disease progression. The next generation will be TFR-enabled medicines, either the transport vehicle or other brain shuttle medicines. It's become very quickly a competitive space and an area that we focus a lot of time and effort on. And interestingly, for TAL, the way that TAL's being approached now and I think probably the most promising approach our genetic medicines or oligonucleotides that reduce the expression of tau. And there, we can also see the next generation being enhanced with transport vehicle. We can deliver now oligonucleotides across the blood-brain barrier and very excited that we've now filed our first medicine for testing in Alzheimer's patients. Okay. So this is the future. It's basically biomarkers to predict your risk of developing Alzheimer's and then safe medicines that allow you to then reduce that pathology before onset of disease. That's, I think, the where we'll go. But in order to get there, we have to have effective medicines that are easy to deliver, easy to monitor. And I think with that, I'm going to hand it to Joe to tell you about our approach to Alzheimer's.

Thanks, Brian. So what Ryan just talked about is really how advances in Alzheimer's disease have led to really improve tractability in drug development in this indication as well as opportunities for TFR-enabled molecules. And what I'm going to spend a little bit of time on today is to dive into more detail around our 2 molecules targeting beta and tau using our TV platform and why we're excited about the best-in-class potential of both molecules. So the first molecule that I'm going to talk about today is our ATDA beta molecule or DNA and here's a brief overview of the molecule on this slide. What you can see is it's an A beta a bivalent A-beta antibody preferentially targeting algomers. It has our transport vehicle with the TFR engagement tuned to maximize plaque engagement, and I'll show you a little bit about that data. And then lastly, it has a unique TV cis-LALA architecture. And this allows you to retain effector function, but do so safely while maintaining TFR binding. And the way that it does that is it does -- it allows the molecule to bind both Fc gamma receptor as well as TFR but not both at the same time. So we believe this molecule has potential to be a best-in-class compared to definitely first-generation anti-beta molecules, but also some of the second-generation molecules currently in clinical studies. And I'll dive into that data in a little bit more detail here. So what you're looking at in the middle of the slide is a mouse brain. And what's labeled in white there is co-localization of antibody with amyloid plaque. And so what you could see is that with the first generation antibody, the amyloid plaque that you're labeling is largely in superficial regions of the brain without very good penetration into deeper brain regions. And this is very consistent with what we normally see for an antibody in the CNS. In contrast, when you look at our DNL 921 molecule, you see much greater target engagement, so much greater plaque binding, and that plaque winding goes into much deeper regions of the CNS. And that's what's quantified on the right-hand side of the slide there with the orange graph, the x-axis is really depth in brain and then it's the amount of labeling on the Y-axis, comparing our DNL-921 to a first-generation anti-beta molecule. And I'll just note quickly, our scientific team did a really thorough investigation of this molecule as recently published in science. And so for those who are interested in more detail, I can look at that. I will show a few additional highlights here, and I'll start with -- the other staining that you see with that first generation anti-beta molecule, sort of those streaks and what those are perivascular regions. So regions around large blood vessels in the brain. And why is that important? So if we look at it in a bit more detail, looking at the right-hand side of the slide, now looking at that -- the yellow color, which is co-localization of vascular plaque with a beta antibody, that with the conventional anti-beta, because of the route of entry is through the CSF, you see a very high amount of labeling of this vascular plot, which is significantly reduced, even though there's really good overall plaque target engagement, the vascular plaque engagement is significantly reduced. And what this equates to on a functional level is if we look in a mouse model of Aria is that we see if we dose with a normal anti-beta molecule on the left-hand side of the slide in blue, that by the end of the study, 10 out of 10 animals in the study are showing signs consistent with an [indiscernible] related [indiscernible] vascular leakage event. But when you look at a dose or the same dose of an ATDA beta molecule, you see a significantly reduced level of ARIA. And then if you look at a brain exposure matched dosing there, you see really no Aria throughout the entire study. So what you can achieve with this molecule then is significantly improved target engagement. With significantly reduced occurrence of safety events, at least in preclinical models. So that's compared to our first -- the first generation anti-beta that aren't TFR enabled. What about a comparison to our TFR enabled A-beta competitor molecules so we went on to do a head-to-head study comparing our ATV Abeta molecule, to a molecule that is closely based on some of our clinical competitor molecules that has a C-terminal appended TFR binding region shown in orange on the schematic on the left-hand side of the slide. And what you can see is that both molecules have excellent plaque engagement, which is shown in the middle, that white staining. But with the C-terminal TFR beta on the bottom, you see plaque engagement but also a decent amount of vascular engagement of that molecule. And we believe we've been able to further optimize the molecule to eliminate much of that vascular staining and really maximize that target engagement. And that's what's quantified on the right-hand side of the slide there, where we look and we show at a 10 mg per kg dose level. We have significantly improved target engagement with our molecule compared to even TFR competitors. And in fact, our plaque engagement at 3 mg per kg is roughly equal to a competitor at 10 mg per kg. This is highly consistent within those plaque associated microglia. Why that's important? That's the effector function. The microglia or the cells that come and digest the plaque once the A-beta has found. And you can see that, again, there's consistent higher microglial engagement with our molecule compared to a TFR competitor. So just to summarize a quick summary of how we stand next to the most advanced competitors in terms of overall properties. And I'm not going to go through this entire slide, I showed some direct comparisons with what is a trante-like molecule. But if we think also about other molecules in clinical studies such as the Aliana, AbbVie molecule, where they've taken attack to improve safety -- they've eliminated effector function from the molecule. We agree that this will indeed improve safety, most likely, but it will also likely come at the expense of effective plaque clearance which has been observed in some of our clinical studies as well as the clinical studies that have been published or the preclinical studies that have been published in the literature. So we're very excited about this molecule. We're moving full steam ahead. As Ryan mentioned earlier on, we plan for a regulatory submission in the first half of 20 -- and we've designed the clinical study to achieve as rapid clinical proof of concept in terms of both plaque clearance and safety with data expected within 2027. I'll just also note that this is also a very streamlined design that could enable us to move directly from the Phase Ib study into a Phase III and really to try to make up as much time as possible in our clinical development. Okay. So now I'll move on to our second molecule, our OTV Map Ta molecule or DNL-628. So DNO-628 is essentially our TV-based molecule. Our TV biologic molecule, I should say, conjugated to an antisense oligonucleotide targeting MAPT or tau. And it's a site-specific conjugation, a drug antibody ratio of 1. But past that, the molecule has been highly optimized to maximize peripheral exposure, which enables brain delivery as well as safety. And so that included optimization of both the biologic portion as well as the [indiscernible] portion of the molecule. We believe that this molecule also has real strong potential for best-in-class, and I'm going to take you through some of the data of why we think that now. So first to go over biodistribution within the CNS, and you've seen many different versions of this type of data today. But with all the goes, of course, there's existing drugs that are delivered through an intrathecal route so they do have direct access to the CNS. However, when you look at the biodistribution within the CNS, it's quite uneven. And so what you're looking at here is nonhuman primate data comparing an antisense oligonucleotide delivered intrathecally or IT compared to our OTV. And I think that this is -- this study is done in nonhuman primates, which is particularly important because sometimes the impact of biodistribution is underestimated when using rodent models because rodents I mean, have much smaller brains. But when you go into a primary spaces or a human, that biodistribution, which is an exponential process, it really has much more of an impact. And so when you look at the intrathecal delivery, what you see is really only peripheral antisense oligo, which again is marked in white there, around the CSF regions of the brain, but not very good penetration into deeper brain regions. At the same time, you see very high drug levels in regions of the spinal cord, which is often the thing that limits dosing as you get such high levels in there that you can introduce toxicities before you're able to get sufficient drug concentrations to desired regions CNS. In contrast, when we look at our OTV platform, what you see is very broad and even biodistribution throughout the CNS. So in addition to enabling peripheral delivery of oligonucleotides. The Tivi platform offers significantly improved biodistribution, which we think has a chance to have an improved therapeutic effect as well. So just a little bit of data from our OTV MAPC molecule. This is now looking in mice that express the human tau that is the target of our clinical candidate and looking both at the RNA level as well as the protein level at tau levels. And the way this study was done in the first 2 weeks of the study, there were 4 doses administered and then measured NOPTRNA and tau protein over the course of the study. And what you could see this molecule is capable of potently knocking down to, and it does so in a sustained fashion. So in this study, it went out for 12 weeks after dosing, that's when we stopped it and it likely would prolong the knockdown for even longer time periods. So very exciting data to say that we have a very potent molecule and potential for long dosing intervals and sustained knockdown. So this molecule, as Ryan mentioned earlier, we submitted the CTA in October of this year. So also full speed ahead. We're hoping for a clinical biomarker data by the first half of 2027. And 1 thing I'll point out about this study is that we're going straight into MAD cohorts to enable us as rapidly as possible to assess levels of tau knockdown and to move on to further studies. SP-27 Okay. So those were the 2 -- 2 of our most advanced Alzheimer's programs. Now I'm going to take a step back and look at a broader view, which Ryan had also mentioned before around looking at our platform, the TFR has become increasingly validated but also increasingly competitive space. And so we want to spend some time talking about how we feel like the TV platform really remains differentiated from the wealth of TFR competitors out there. And I'm going to briefly touch on 4 aspects of our platform today. modularity, brain uptake, safety and architecture and just show you a few pieces of data on each of these to tell you about why we continue to be so excited about the TV platform and its potential to deliver a range of therapeutics. So first, let's talk about modalities. And I won't go over all this slide in detail. This is all data that you saw during the presentations today, but it really highlights our ability to deliver a range of different therapeutics. That includes antibodies with our ATV platform all of the nucleotides with our OTD platform and then, of course, a range of enzymes with our ETV platform. So really, really broad potential to deliver therapeutics to the CNS using the TV. Just to extend on that a little bit, I showed you data from our DN-0628, which is an ASO program. We also have gone on to show that we can deliver a range of different types of oligonucleotide therapeutics CNS using the TV. And here are just a couple of examples of that. So on the left-hand side, we're showing our ability to deliver siRNA. And both of these are just using MAPT tool molecules just because we have -- we had all of those reagents in-house. And it is something that we are readily able to assess using preclinical studies. So what you see on the left-hand side of the slide is we can show similar knockdown using siRNA to what we were able to achieve with our ASO. So this is a modality we're able to readily deliver with our TV platform. And on the right is doing -- delivering a PMO which is an oligonucleotide specifically designed to alter splicing of a gene, right? And what you could see is that we see in the bar graph on the bottom right, very nice alterations in splicing of tau with this molecule. Really highlighting that we can deliver any type of a nucleotide modality with the TV, and it further expands the range of potential targets that we can address. Lastly, in terms of modularity, I'll speak briefly about the receptor-mediated transcytosis targets themselves. So we focused a lot today on TR. But we've also published papers showing that we can -- we've been able to generate TV molecules with an integrated binding site to [indiscernible] that also effectively deliver CNS drugs to the CNS, pardon me. And the biology of C9 is very different. So it enables a whole different set of targets that you go after with CR. We've also very recently published that you can combine both the TFR and the C and NDA TVs. And what you get with this is really maximal brain delivery. So you can get to higher levels of brand delivery than you can with either TFR or CD98 individually. So we have a lot of potential in terms of the receptor media transcytosis targets that we can go after using the TV platform. But I will reemphasize, I think, something that was mentioned earlier, which is TFR remains the highest capacity and by far, the best validated platform for delivery to the CNS and there's growing interest in a range of different transporters, but there's a reason why we've continued to focus on TFR based on that validation and proven ability to deliver high levels of molecule to the CNS. Okay. Let's talk a minute about brain uptake. Here is just a comparison to 1 of the competitor platforms, which is used by 1 of the competitors we have in the enzyme space which is a high affinity bivalent binder to TFR, right? So one of the things about TfR-mediated drug delivery to the brain. It's a bit counterintuitive. Highest affinity is not the best. Medium affinity tends to be best within a range depending on the molecule. And that's what you're looking at here. We're all just focus in on those pictures in the middle where all of those squiggly lines, that's the brain vasculature and what you could see with the TFR high affinity molecule is it's associated with the brain vasculature but it doesn't come off. It doesn't come disconnected and enter the part of the brain parent. So it becomes permanently associated with the vasculature and is unable to dissociate and get to the target cells of interest, the neurons, the GLIA and all of that. In contrast, when you look at the ETV IDS molecule at 24 hours after a dose, you still see some molecules associated with the vascular vasculature, but a lot of it now is associated with neuron tea within the CNS. Those are the target cells that we're most interested in rescuing and consistent with that, when you look at brain GAG levels in these animals, you can see that our TV molecule has significantly improved reduction of brain GAG accumulation compared to this high affinity competitor. Okay. What about safety and this will touch on a little bit more of brain delivery as well? What we've taken the time to do it Denali is try to do head-to-head comparisons with as many of the competitors in the space as possible. That includes solving co-crystal structures of each of those molecules bound to TFR to identify where on the TFR protein sequence they bind A few examples are shown on that model, molecular model of TFR on the left-hand side of the slide. And then we looked at their performance in terms of brain uptake and impact on reticulocytes compared to our molecule. And what we found interestingly was in direct head-to-head study, and these are all roughly affinity matched molecules, I should say, that the TV outperformed a number of different competitive molecules that were both different architectures and different epitopes from our TV platform. And that's what's shown in the graph in the middle of the slide there. And what's more on the right-hand side of the slide, and this is something I highlighted before that we're able to deliver our molecules even when they have effector function without impacting reticulocytes, which is really the first sign of potential anemia risk, where some of these other architectures do impact reticulocytes. And they don't -- even if that's not something that they talk about a lot, then we do see this in our comparator data. And that's what's shown on the right-hand side of the graph. So really nice data to support that our platform seems to be the most effective at delivery to the CNS. So what might be the reasons that that's the case. I'll give you one of them here, which is architecture, right? So just a reminder that with our TV platform, the TFR binding is built into the molecule. So there's no appended sequences and this is designed to really minimize immunogenicity and maximize stability of the molecule. And in terms of stability of the molecule, that's exactly what we're seeing here. So in some of those same studies I showed you on the previous slide, look at the levels of intact molecule present after in vivo dosing, and we normalized it to one. So like, of course, everything with our molecule is going to be one because it's an IgG, right? And so through both detection mechanisms, we see the same amount. However, with many of these competitor architectures, we see a decent amount of instability and clipping of that TFR seat went off the end of the molecule and once that TFR sequence comes cliff off, it's no longer a CNS penetrant molecule, right? And that's what you see in the graph on the right is a significant amount of instability with some of these competitor architectures that have appended TFR binding domains. And this may limit the brain uptake of these molecules. So here's just a quick chart to summarize some of the landscape out there. I'm, of course, not going to go through this is very complex for your reference. But just to really say that overall, we feel like the TV platform continues to compare very favorably to our competitors in this space. And then just to close, to say we heard a lot about our ETV franchise today, a little bit about our advanced Alzheimer's disease molecules, which we're quite excited about. But there's a lot more to come in terms of the potential of the TV platform. We've fore shown our ability to deliver a range of modalities and there has potential in a range of different therapeutic areas. And so in addition to the molecules you heard about today, we have 3 additional molecules in the IND-enabling stage and greater than 10 additional preclinical molecules within our discovery portfolio. and a lot of exciting stuff that the team is really interested in moving forward. And of course, we're continuing to innovate across the TV platform and differentiate our platform from competitors in the space. So with that, I'll close and hand it over to Dana to talk about our integrated manufacturing.

Thanks, Joe. As Joe just mentioned, I'll be discussing some of the steps we're taking to manufacture these molecules. And one of the big benefits or another benefit of our TV platform is because the FC were able to purify these very efficiently and effectively and manufacture these. So we use that Fc to use protein affine chromatography, the same step used globally in antibody manufacturing. And so our processes are shown in the middle look very much like a typical antibody process. A choke fed bet cell culture front, followed by 3 purification steps to get your final product. And 1 of the benefits is now this is a very portable process. It fits very seamlessly in the global manufacturing capacity. We developed both by licensing and developing our own internal cell line of vector technology to give us sufficient production. So for all of our programs, we're currently projecting our COGS to be less than our target, which is about 20% of revenues and in some cases much less than that. Also, because this is a platform process and fits very much kind of a standard facility, is to reduce our cost and time to quickly move these forward to IND to develop an initial process. And high-productivity TV products, we believe also are very seamlessly fit and support large markets because of the productivity of the system. Now I'll be discussing the subsequent slides, the manufacturing we built internally to help support this. However, we also plan to continue using CDMOs contract manufacturers to support large-scale manufacturing to manage our capacity and efficiency as well as for items like drug product sterile filling and oligonucleotide synthesis where internalization is not yet beneficial. So once we had proof of concept and have this platform of products coming behind, we decided to build our own internal manufacturing capability. This was completed earlier this year. And we've started that up in Q1 and have since made 8 batches in our site in Salt Lake City, which I'll come to in a minute. One of the main drivers of this was to improve our speed and flexibility to move as many as programs as we can into the clinic quickly. Working through CDMOs, if you got challenging to quickly move things around. I mean, we're learning on the fly. We're getting data, and we have our own internal control of that. It gives you the ability that when data comes and rationale changes, you can quickly change directions or move a product forward quickly and reprioritize yourself. It's also giving us cost efficiency by integrating that internal development and manufacturing. In fact, our first couple of programs we're doing internally, we're tracking 20% to 40% cheaper than what we were spending externally CDMOs. And maybe less obvious factors, it also eliminates the reservation fee. Typically, when you kick off a project of a CMO, you make a commitment for the work this can be done in the manufacturing of several million dollars, and that can be significant bartaco moving a project forward. And so when we have the ability to do it eternal, we can move things more easily at risk, knowing that if we change our mind and we learn new data we can stop and change directions without that exposure to spend. And then finally, gives us more control over our supply chain and as we move towards commercial, helps mitigate tariff exposures as well because we're doing this domestically. In summary that I think where there's an integrated platform advantage of doing this together. And one is you can really leverage your learnings across the portfolio because we have similar projects with this across the same platform. And while certainly, you can learn things working with CDMOs and overseeing that work, in my experience, there's no substitute for that [indiscernible] you gain from having hands-on work doing it yourself in your labs developing the processes and analytics as well as the manufacturing to really be sure those learnings you really apply to the next project and continue to evolve your platform. So specifically, we started up a manufacturing facility, as I mentioned, at Salt Lake City, and it's 2,000 later pirmeters in a single purification train. It's designed for single-use technology, which will become increasingly common for these early-stage biologics manufacturing over the last decade. Now if you look at this figure, you're not familiar with this kind of manufacturing, you may look on the right and see you lost of stainless steel tanks and wonder how that is single-use disposables. But in fact, those are the shelves and for each batch, you drop in essentially pre-sterilized plastic bags and containers, you then run your process and when you're done at the batch, you pull those out, you dispose of them and then you're rate to drop in as a fresh set for the next batch. So quickly, enables you to more quickly move between different products is obviously really helpful in early stage manufacturing. And also by eliminating all of the stainless steel piping and complexity of having to sterilize tanks, clean them between runs. It actually significantly reduces the capital of these plants. One of the benefits of that reduced capital is because this is not as capital intensive anymore, now you don't need to run these super high utilization rates to be cost effective anymore. So in fact, our first year we're going to wait batches. And already, we're seeing cost benefits from doing that. But over time, we have a physical capacity to do up to 40 batches the year in this plant. So to do that, we'll just add staff at shifts and enable us to continue to manufacture in the same facility at different run rates all cost effectively. This was designed to support both early and should say, design and support early clinical manufacturing, but we've realized that with DNO-126, our nice project coming along, we can reshore this to manufacture this and actually commercially launch this facility as well. So that's what we're also intending to do. And then finally, I'll close with some more details on how we believe this integrated development and internal manufacturing really helps us drive speed, flexibility and value. And this cartoon on the first line is really how this works with traditional CMOs to move a molecule to IND. Initially, we develop internally what we think is the best molecule with working with our discovery group. At some point, select the final sequence and then kick off work at a contract manufacturer to make the cell line, do the process development, make GLP material, make material and then file the IND. What this internal capability enables us to do start more things at risk. So very commonly now is moving projects towards that gate. We'll actually start cell lines in parallel with often 4 or more molecules while Joe's team is figuring out which 1 is the best when we want to move forward. That way, we have a head start. We have some initial development work in a cell line most of the way made. So when we pull the trigger and know what the right molecule will move forward is we can immediately have a head start to move that quickly towards GMP manufacturing. A second benefit is, especially with more complicated molecules, when you set your initial schedule with contract manufacturers, One of the challenges is that their manufacturing slots are often very full. They need to do that to be efficient and cost effective. And so they'll set several conservative schedules to be sure they don't miss that manufacturing slot given the uncertainty in development the sell-in the process. In our case, we can set more aggressive schedules so that because we have the ability that if -- we get into the middle of talent and realized there was a surprise, something is harder than we think. We control that schedule. We can easily like swap things out, move things around. And I believe it will enable us to move faster. I can say because it's our first 2 projects we've developed internally, we're projecting to hit IND about a quarter faster than we did for any previous project, and over time, expect it to even better as we get more experience in doing this. Secondly, it has also enabled us to reshore DNL-126 I mentioned and launch from this facility. One of the big benefits of this is a challenge for companies when they are launching biologics is producing their launch material, which often is a significant expense, frequently before you even have your pivotal clinical data but then also reserving capacity at the contract manufacturer post launch to be sure you'll be able to make markets supply once you launch. These sums can be from tens of millions to in some cases, over $100 million in commitments and spend prior to launch. In this case, by having it internal, we can more measure spend what we need to make the initial material and then really see how the demand signals are and rapidly respond and make material so dramatically reduce that commitment to spending at risk. And in bringing this process in-house, we'd realize additional benefit of being able to optimize the scale specifically for this program within our facility. And for 126, we're able to modify the process to basically reduce our COGS by 50%. And this internal work, we're already seeing benefits of increasing our process understanding that makes it easier to later optimize the process to improve COGS and potentially also develop important IP around these programs. So in summary, developing this integrated development and GMP manufacturing capacity in-house, we believe and is already showing benefits in reducing our risk, accelerating our time lines and producing longer-term mechanic benefits as well. And with that, I would like to hand things off to Alex to bring his home.

All right. Thank you, Dana. So in my section, I will discuss about how to deliver value, how to realize the value. In the last 2.5 hours, we discussed that we have a clinically validated and highly differentiated technology, which opens up huge potential. We focus on lysosomal storage disease and neurodegenerative diseases. There are other opportunities, but that's the focus right now. However, to win in this space, an increasingly competitive and dynamic space to really win to win for patients and to win for all stakeholders involved, it needs more. It needs focused, efficient execution. So that's what's in my slide over the next few minutes here. Now where does this start? It starts with our broad portfolio. So this is the substrate that we work with. So every program in this portfolio has a very clear rationale how this program is either first-in-class or best-in-class and can provide real benefit for patients in these diseases. Each of these programs has a sizable market opportunity shown on the right-hand side. And collectively, there is a wealth of milestones, which will deliver or unlock value as we go along in the near term and in the long term. Now how to win starts first with the right team and the right setting. So illustrated here, 520 Denalians as we call them in our 3 sites, the vast majority of them in South San Francisco. And on the right-hand side, our now fully integrated capabilities. And this is more than an org chart. It really illustrates how now the seamless value chain of a molecule that is discovered on the third floor in South San Francisco, moves through the hands often alliance from discovery through development to Dana's manufacturing organization and then ultimately, to Katie's commercial organization as now with the team that is interacting directly with physicians. I do want to highlight 3 areas which we consider as true durable advantages, which will help us really differentiate ourselves from others in this field. So the first one on the top left is really unparalleled experience in blood-brain barrier science. So there are over 30 PhD scientists that are dedicated and understand this field better than anyone else. Some of the most prominent members in this field from academia have come and joined us and are part of this team. This team has an unparalleled publication record. We showed some of the published papers today and is working in the latest facilities with the in-house in vivo facilities. But then also imaging, the power of imaging, we saw some of the pictures today where we can trace the drug from -- really from the vein to the brain, all the way down into the deeper subcellular structures where we can demonstrate that the life that the enzyme actually gets into the lysosome, the site of action where it needs to work. On the bottom right, Dana just mentioned the manufacturing facility. This was a big investment that we made back in '20 -- or the decision for the investment that we made back in 2021. And when we have the first proof-of-concept data, and we have the confidence that we have a platform which can deliver many programs and with those many programs comes the scale. And as Dana described this advantage now allows us to be faster, to problem solve quicker and to also manufacture our molecules at about 30% to 40% less cost than it would take us at the CMO. And then lastly, our now fully integrated commercial organization that Katie spoke about. So the team is fully on board. It's onboarded I do want to say that after the FDA delayed our PDUFA date by 90 days, we did not delay our internal commercial readiness activities. We want to be ready if and when the FDA gives us the green light, and we want to be ready to commercialize on day -- now such an organization does require capital. It does require substantial capital, but it also requires really focused priorities and how we spend that capital. So first is really clarity on the strategy. So right now, there are 2 things, which is launch 2 drugs in 2 years. So that's Tivi in 2026 and then DNL-126 in 2027 but at the same time, invest in this rich and broad early-stage pipeline that can deliver so many more programs in lysosomal storage diseases, but then also in the common neurodegenerative diseases. The second is really to drive capital efficiency. So this is to learn from our experience to apply those learnings and to develop the NEXT programs subsequently at faster speed and at lower cost. And the last one is always to maintain capital optionality. So partnerships continue to be a core part of our strategy. We have 3 existing successful partnerships Biogen, Sanofi and Takeda. And we now look to diversifying sources of capital. And I'll get to the announcement from this morning about our partnership now with Royalty Pharma that we're very excited about in a second. So the commercial -- the financial foundation at this point. At the end of Q3, we had $873 million in cash with the expected additional EUR 275 million over time that will come in from our Royalty Pharma partnerships. In addition, over the next few years, we expect contributions from the 2 products, which we expect to launch. And then lastly, the 3 partnerships that we have, they contribute to our OpEx through cost share and milestone income. So a word about the deal that we announced this morning. We're very excited about the deal. We're very excited about the partner. So I can say that this was a highly competitive partnering process, where at the end, we're very pleased that we ended up with what we consider favorable terms for us, but also in a partnership with Royalty Pharma, who not only pioneered this type of structure, but is also known for their deep scientific diligence and being a reliable partner to their companies over time. So under this agreement, we are set to receive $275 million, of which $200 million would fund upon U.S approval of tivi and then another $75 million would fund a European approval of tivi, both within certain predefined time frames. In return, we agreed to pay 9.25% royalty payable on worldwide net sales of tividenofusp alpha. Up until the point when certain caps are reached, it's either in a 2.5% cap if reached by the first quarter of 2039 or 3x cap thereafter. So this investment, even though it's funded upon tivi approval, gives us significant planning certainty that we have the resources needed to successfully launch tivi and to expand the pipeline. Now before I wrap this section, I do want to show a case study here, a case study, which gets to the point of increasing efficiency and speed. And this, on the right-hand side, it puts side-by-side, the time and the cost it took us, or it takes us to bring tivi to the market with an expected launch in the first quarter of next year. And what it is expected to take us for DNL-126, so for the drug for San Filippo with an expected launch at the end of 2027. And on the left-hand side, there are all the elements that I spoke about sort of really using streamlined clinical development studies and validated biomarkers. When we started with tivi in 2020, we had to build everything from scratch, including the clinical development plan, and there were no validated biomarkers. Nobody had developed an enzyme that would cross through the blood-brain barrier. There was no way to assess the potential effect in the brain. Now as we discussed in the panel here today, this is we understand how to look at the effects in the brain. We understand the biomarkers. We had a successful interaction with regulators last year at the Reagan-Udall Foundation meeting to validate heparan sulfate as a surrogate marker that reasonably predicts clinical benefit in patients. We also now have established relationships with clinical sites with CROs. We have the in-house manufacturing. And of course, the commercial team that launched the first product is exactly the same commercial team that launched the second product because these patients are treated by the same physicians in the same centers and have shared many of the dynamics. So shown on the right-hand side what that translated to, well, for tivi, it will have taken us 5.5 -- a little over 5.5 years, which is not terrible in the greater scheme of drug development time lines, but it will have taken us $700 million because we build everything from scratch. Now with all the synergies and with all the learnings, we expect that 126, we can bring 126 to the market in 4 years. And in the end, it will cost us just under half of that amount. In addition to the great team that we have in-house, we also want to highlight our broad network of collaborators. Partnerships have always been a key part of our overall strategy. And this reaches from partnerships in academia that help us really strengthen our depth in the science to the partnerships with global pharma companies which help us on execution and on the global, and we have now a largely wholly owned portfolio, which opens up additional partnerships, which we always consider, but we do continue to set a very high bar with respect to the terms, the right partner at the right time. So that brings me almost to the end here. So we are very excited. We're in the 11th year of Denali. We started in 2015, and we're entering a new phase on what we call the path to the summit. So the first 5 years, 2015 to 2020, that was the discovery phase. That was the discovery and the invention of the transport vehicle and all the early validation work. In 2020, we had the first clinical proof-of-concept data. Many of you were with us at the time when we showed data when we saw, for the first time, the data after 5 patients treated with DNL310 and we saw normalization in heparan sulfate in 4 out of those 5 patients, which was a very strong result that, in fact, almost exceeded our expectations at the time. So that was when we entered into the development phase. That was when we had confidence that we have a platform that works that we can now expand to additional targets when we made the decision to build the manufacturing facility, and we built the broad clinical stage portfolio. Now 2025, we're just at the step to go into the next phase. That's the delivery phase to deliver medicines to patients with the launch of our first drug imminently. Now this is only, again, another step on the way to sum it for the next 3 years, Ryan, for the first time now introduced 3-year goals. So these goals will guide our path forward, they will also measure us on the path forward. So by the end of 2028, we want to have two growing brands, tividenofusp alpha for Hunter syndrome and DN126 for San Filippo. We also expect to have five meaningful clinical readouts with clinical proof of concept, two of those in Alzheimer's disease for Abeta and for tau, in frontotemporal dementia with progranulin program in GAA or in Pompe disease with our GAA molecule, but then also with our small molecule LRRK2 inhibitor program. In addition to that, Joe's discovery organization is enormously productive. There is no scarcity on ideas about where the transport vehicle could be really impactful, and we expect to bring four to six more programs into the clinic. Along the way, there will be a wealth of milestones. I will not go through this slide. It's in the handout version, but I look forward to having these discussions with many of you over the course of the next few month [indiscernible]. So that brings the presentation to the end. We couldn't be more excited about where we are today. We are entering this new phase about delivering medicines to patients to really unlocking the full potential of biotherapeutics for the whole body, including the brain and really doing this for the patients that are on these images, all of these are very close and very personal to us. and then hopefully to many more patients beyond that around the world. So thank you to all of you for joining us here today and for joining on the Denali journey over the last 10 years and for many years to come. Thank you.

So we'll have the management team, those who have presented come on up, Joe, Dana, Kate, Peter, and we'll take your questions. We have set aside about 20-plus minutes for Q&A. And then Laura, if you want to start passing it around, it'd be great.

This is [indiscernible]. I have one question for the Abeta program and two for the tau. The recent CTAD, the trontinemab, there are two Phase III trials. It was interesting to see that they kind of excluded the patients on anticoagulants. The question is, given the safety profile which you see, how do you look at -- I mean it's still more advanced, but do you think that it can be -- it can have more broader application where -- given the safety profile with ARIA. Do you think that you can probably get -- reduce that gap because that was one of the debated question which was asked during the tronti presentation.

Okay. Just so I can restate the question and probably Joe and I will will answer it. So with trontinemab, you're asking where is the gap -- what's the remaining gap for differentiation using DNL921. That's the question. And you mentioned the Phase III trial. And obviously, there were some data presented on long-term hemoglobin. So maybe I'll start, and Joe, you can add to that. So I think obviously, there's going to be many players in the Alzheimer's space. And a lot of this will come down to some of the nuances who will actually be the best in class. So obviously, for us, one area of differentiation is reduced risk of anemia. Now as we've seen in our own programs, where there's some baseline anemia, this is manageable, reversible, monitorable, right? But still, if you think about this long-term use, especially in the elderly population, I think there's an opportunity for differentiation there. I think ARIA, we're definitely -- and I think the mechanism we proposed and that we published in Science is probably a universal mechanism for transparent receptor approaches, meaning that type of biodistribution will reduce the risk of ARIA for any Abeta antibody because of this perivascular localization. Now we still believe that there could be room for differentiation there. But I think the last point is going to be probably subcu dosing, dose frequency and that dynamic. And Joe, I'll hand it to you if you have any other thoughts.

No, I think you said it well, Ryan. I mean, I think the potential for subcu is huge in terms of winning that market. I think in addition to differentiation, there's also speed. I think tronti for better, for worse, has blazed the trail in terms of how you can progress quickly in these studies and what type of data you need to make early decisions. And we are building that into our clinical development strategy to be able to move as quickly as possible and narrow that gap. In terms of differentiation, I think Ryan got it right. There are subtleties to the molecule, and I shared some of them today, but preclinically at least, we do feel like we have a superior profile. Of course, we'll have to see whether that translates clinically. But what's going to really win the day in this space, as you mentioned, is a really safe molecule. And if we can come as close as possible to eliminating ARIA as an effect, I think that's going to really change the landscape. So these are things that we're shooting for.

And I think at the risk of going too deep in our preclinical science, we -- the comparisons that we have are literal comparisons. We've made competitor molecules. We've solved crystal structures we've compared. And I think the most interesting data in that process that Joe shared and I just want to reemphasize it because I think it's so important is the stability of these basically tagged conventional fab approaches. So almost universally we're seeing that they don't have sustained exposure. And we knew that, that was an issue back in 2014 when it was first proposed, the brain shuttle like architecture. So we think that's a big area for differentiation. How that plays out clinically, we will see I think maybe the immunogenicity, I think, reported like 40% to 50%. That's probably an area where that plays out because now you have this sort of clipped molecule and potential immunogenicity.

Great. Can I ask -- so one question on the MAPT program. The recently Biogen published using our radio label tracer technique that their [ 080 ] cannot get into the deep brain regions. And so the question is how important it is for the tau program to reach the deep brain region in terms of differentiation. And the second very quick follow-up is, there has been a lot of discussions on endogenous tau 243 as a biomarker becoming more and more relevant in conjunction with the P tau 217. So as you were kind of designing your Phase Ib, are you thinking of integrating that kind of biomarker approaches to the trial?

Do you want to answer that, Joe?

Yes. So I mean I think the first question was around biodistribution, as I understand, right? And your -- I mean getting access to the deep brain regions, even when we talk about deep brain it's even deeper cortical regions, absolutely critical. And the best way to think about it is the brain is a super highly vascularized organ. TFR is delivered through capillary beds. And there's no neuron that's more than a few microns from a capillary. So when you're delivering through capital, you're really by nature delivering to all parts of the brain very effectively, right? So we do feel like -- and that's why I showed some of that nonhuman primate data today, really fundamentally different from a biodistribution perspective. When comparing to the Biogen molecule, I think the Biogen ASO does have very encouraging data, right? And so when you combine perhaps not the best biodistribution with already encouraging data, it makes us really excited about the potential that we can get with improved biodistribution and also a potent oligonucleotide. In terms of clinical development strategy, absolutely. I mean I think looking at total tau levels in CSF is a very easy first readout in terms of making sure you hit target in early-stage clinical studies. But there are a range of now tower biomarkers in development that have been developed and are increasing in validation that can be extremely useful. And that includes additional CSF tau biomarkers as well as to tau PET imaging you can really look at the impact on pathology. And the way that we've designed a Phase Ib study is we're able to get -- we're hoping to be able to get many of those readouts even from a Phase Ib before you decide to move forward to larger studies.

And then I think very specifically, the forms of Fospotau, it's a little different when you have an oligonucleotide medicine because you reduced total tau. I think when you look at an anti-amyloid, and you measure something like Fospotau217, you're trying to infer the additional protection based on that biomarker. But when you're actually targeting tau directly, our expectation is to produce probably all forms of Fospotau. So it's not going to be quite -- I just see it differently than, let's say, a non-direct mechanism like an anti-amyloid. Next question. There's a lot. We'll try to answer more quickly.

Madison Alsol with B. Riley Securities. I wanted to ask about the 628 time line. The CTA was submitted in October. You're saying data the first half biomarker data. We would have expected data a bit sooner. Is that related to any pool specifics, or are you just waiting to have a more comprehensive readout in first half '27?

Yes. So I'll give a couple of answers to that, right? Part of it is as we've matured as an organization, over the last decade, we realize that more mature data sets are more impactful. They're longer lasting. We learned this in the hunter program, that basically, over time, as we get -- and we're learning this obviously with 126 as well, we'll be presenting 126 at world. So part of that is allowing us to have a robust enough data package. The second, which is actually a very interesting dynamic about how Tao has a very long half-life. And I think it was referenced some of these silk labeling studies, which you look at the half-life of both tau and neurofilament. Neurofilament, for example, half life is 260 days. So you can run a short-term study and see a reduction of NFL if you're actually looking at that. tau also has a very long half-life. So part of that is the dynamics. We have to treat long enough to to see this reduction in tau. So we're building in this concept of robustness and understanding the actual dynamics of tau that targets that 2027 horizon.

Understood. And if I may also ask about manufacturing, so perhaps for Dana. I assume at the in-house facility, you're heavily utilizing solid face synthesis. Wondering if you are also looking to implement enzymatic ligation and then improving the COGS margin above the 20%. Is that just a result of scale? Or are there some other aspects at play?

So for the -- to be clear for the oligos, we're not doing that in-house, we're using contract manufacturers. We're only doing the biologic manufacturing and then do the conjugation in-house. We actually are looking at both approaches out for the oligo manufacturing, you mentioned both the [ endilgation ] as well as solid state synthesis. And then the total cost numbers will include combining both that contain antibody. So these are a bit more challenging and that you have more to make.

This is [indiscernible] on for Andrew at Jefferies. I just wanted to ask a quick question on Abeta. So you talked a little bit about potential subcu convenience I was curious like what dosing frequency you could potentially explore? And then if you're eligible for subcu, is this something that could potentially be dosed at home or you see lower rates of REF, for example?

Yes. I'll start. I'm sure Peter and Joe have something to add here. So the -- as I mentioned, in the future, of AD therapy, it's really going to be a diagnostic disease where you start to see biomarkers change and then we address plaque reduction and tau reduction very early before any cognitive decline. With that in mind, I think the two things you have to think about is safety, which is what we're really engineering on with keeping at least equal, if not better efficacy, but convenience. And so we think -- especially for ATV:Abeta, the subcu dosing, that would be the goal. And it's actually very interesting to see the dose frequency that our competitors that could be because of risk of reticulocyte depletion and anemia that you go from monthly dosing and then shift to once every three months, but also could be the fact that with the BBB technologies, you clear so rapidly that you almost are switching to a maintenance like dose, right? But I do think -- I mean I would be brilliant the future would be some type of subcu dosing that could be administered at home. But I think what you're going to be using is these biomarkers to determine, am I starting to develop amyloid plaque. Now I have this safe therapy that I can remove amyloid and then shift the entire disease. I don't know if Peter or Joe wants to add anything to that.

We were just mumbling about it. I mean I think subcu is a huge opportunity. We do believe our molecule is going to be compatible with subcu formulations, which is big. In terms of exact dosing regimens, that's not something we've nailed down yet. I think as Ryan mentioned, what we've learned from tronti is these TFR-enabled molecules have -- are extremely active, right? And so the paradigm that was the case for the first generation Abetas may not be exactly the same for some of these TFR-enabled molecules. And so we build in a clinical studies, the ability to do some dose finding and try to understand that early on.

Any thoughts, Peter, to add that there?i

So that's the only thing I was going to say is that there's optionality being built into the Phase I study to evaluate both IV and subcu doses.

Great. And then maybe one more, if I may. On the Hunter confirmatory Compass readout, do you expect presumably filing in 2028 or something. Would that include both the neuronopathic and non-neuronopathic patients?

Yes, Peter?

Yes. So that study is anticipated to recruit by the end of this year. And it's a 96-week time frame for Cohort A, which is the pivotal cohort. So we do expect having the entire data package knowing that Cohort B is a shorter time frame. So it's a 1-year comparison.

I'll just add another point. It's been really interesting to see the evolution of the FDA from Hunter to San Filippo. And our friends in the community here, Kim knows us very well, we were -- we did not want to run active comparator study [indiscernible]. There was no desire to have a comparison with [indiscernible], real demand from the agency at the time. Obviously, with San Filippo, it's an entirely different dynamic because now you have -- first, there is no active comparator. And both U.S. FDA and EU EMA are much more open to this idea of a natural history comparator, single study. And so that's -- it's been interesting to see that evolution. But anyway, we answered your question specifically on compass.

John Thome from TD Cowen. Just one on to the -- I guess, what's left with the FDA review? If you're already in labeling discussions, it feels like maybe you're more on track for the initial PDUFA date versus April, I guess, manufacturing site been inspected or anything left there? And then maybe on the payer side of things, if you do pursue a slightly premium pricing strategy, I guess, is there any concern that payers may require some sort of documentation of CMS symptom progression before reimbursement? And maybe just lastly, broadly, obviously, with some of these indications, you can take them through pivotal studies and market them yourselves, but some indications you're looking at are obviously larger. So I guess, how comfortable do you feel taking these to a certain level before looking for a partner.

Okay. I got the first and second...

Yes.

You got the second?

Yes. I got the second.

So let's start there. Let's start with the second.

Yes, in terms of payer coverage, at this point in time, based on our discussions with them and similar to the standard of care today, we don't expect additional testing required. And the payer reimbursement and coverage will likely be very much aligned to our indication statement from the label.

And then the first question is what else is left done. And I think as you all know, we had a in the PDUFA date related to this molecular weight discrepancy in the population PK calculation. At the time, we thought the FDA is pretty overwhelmed. They'll use this to take the extra time. Everything just continued. Late cycle meeting, draft label, we come back and forth on the label. So it's actually -- and then we continue to finish the diligence around CMC. And so we're at the point where we start discussing what would be the post-marketing commitments. That's kind of where we're moving towards. And so I can go into much more detail than that, but it's -- we'll just say that we're very enthusiastic that everything continued, and they actually said as much, and they said this is basically like a statutory thing because we have to change this population PK. We weren't sure we necessarily thought that would be the case, but they have continued. And it's been really productive, really engaging with the FDA.

And on the third part, with respect to partnering. So on the enzymes, I think we've shown and we plan to take those forward ourselves, that will be commercial foundation for the company. On neurodegeneration, it's a different thing, right? So we are very well equipped to take these programs to clinical proof of concept, biomarker proof of concept or maybe even clinical thereafter. Those are absolutely partnering open.

Charlie Moore with Baird here. I was just curious thinking about the OTV MAPT program. When you think about intrathecal versus intravenous, is there any risk that you're thinking about in terms of thrombocytopenia there that's been seen with ASO is the systemic versus potentially the intrathecal having somewhat of a better profile might be more restricted to the CNS.

Yes, it's a good question. I think what you're referencing is probably avidity and [indiscernible] maybe some of the others that are getting all the goes across well in the muscle tissue in particular, but with very high affinity and very high doses. I think the thing you have to look at is when others report just determine that MIG dose is that the oligo, or is it the entire construct, and you can actually calculate the entire dose that's being given based on that calculation. So I think dose is one. The second is we don't see that as a -- like we have seen it as a class effect for TFRs. What you're referring is maybe it's a classic with TFRs, combined with oligonucleotides. And I don't know if the one case or that avidity saw that, that would be the case. I can't comment on that. I mean there's a lot of debate what that means. So that's -- and then I think the other issue, and it's already pointed out, and I think Joe is exactly right, the initial data is very promising with intrathecal delivery, probably more so than we thought because we don't see great distribution, as Joe showed in the presentation in nonhuman primates throughout the central nervous system when you use intrathecal. However, when you use transfer receptor enabled, you get this even distribution. So I think our expectation is much better and much more uniform reduction in tau expression.

Yes. And maybe just one other thing to add to that is actually in one of our papers that Science Translational Medicine paper that we published looking at our OTV platform, actually did a direct comparison to a molecule much like ability, high TFR binding and looking at that head-to-head. And it's surprising how different those molecules behave, right? So that, in addition to a clean safety profile preclinically, we felt pretty confident about that, but that might be something to take a look at as well SP1 And just to highlight, we saw equal muscle distribution regardless of like the moderate affinity but essentially no brain uptake in the high affinity avidity construct.

Gina Wem from Barclays. So maybe one big picked questions like you mentioned a lot about subcu. And I do believe this is the future of the delivery to the brain. So maybe what are the technology challenge there and a different modality, what will be the hurdle if you can elaborate a little bit.

Yes. So if I can summarize the question, if subcu is the future, what's the limiting factor? And I think often it's dose. So you need to have a potent enough molecule that allows you to give a low enough dose to formulate subcu. So it's the concentration and Dana can add more to that. I think across each one of these therapeutic areas, we are going to optimize efficacy and then in the context of convenience. So subcu is often an issue of convenience. But I think the data that we see is that, at least with A beta and with oligonucleotides, they're extraordinarily potent. So it's very hard to deliver a dose like we just discussed in some of the egress with other TFR platforms that hot subcu. So it's really the amount of dose you need to drive efficacy that's the limiting factor. So it's the potency of the warhead. Now for enzyme replacement therapies, it's an entirely different dynamic because these patients have no natural enzyme. And as a result, it's -- you have to slow the infusion rate. So you can't -- subcu is not an option there. But that's categorically, I think, different. Do you want to add anything else, Dana?

I mean there's a lot of work going on with larger volume or subcu devices as well, which I think will also probably play a role in some of these modalities where we do think you may have fair amount of drug.

Julian Pino with Stifel working with [indiscernible]. I just have a couple of questions on Hunter. So I guess just for thinking about distribution between neuronopathic versus non-neuronopathic. I guess just how much consensus is there on the community with respect to the proportion of those patients with those diagnoses. And when thinking about accelerated approval, do you mind just putting some potential bookends on what proportion of sales you potentially be able to access ex U.S.? You talked about name patient sales before? And then just one more on the confirmatory Phase II, Phase III. Can you just go over the co-primary endpoints again on that study. We kind of went through that slide kind of quick. Does that apply to both cohorts in that confirmatory Phase III. And I guess just what gives you confidence in the ability to succeed, given there's some variability around these scales for these patients?

So 3 questions you're testing our memory. So Katy, you go the first 2, yes.

So in terms of what I showed from a prevalence perspective, we do have claims data. So we feel pretty confident in the distribution between attenuated and neuronopathic or severe patients. And that is because of the difference in the gift the teeth patients lifts well into adulthood. In terms of our global expansion yes, we've identified many markets outside the U.S. that will accept a U.S. CPP. And so many of these markets in the Middle East and Israel in Asia, they will accept marketing authorization using the U.S. approval. So definitely, we're going to pursue those markets and, of course, pursue reimbursement thereafter. So we do believe that 60% of the market can be unlocked. Now there will be discussions around reimbursement. So often you can get registration, you can get regulatory approval, but then the reimbursement piece will be critical. And that having the COMPASS data will help us consider what is the pricing on a pricing strategy for those markets.

And then the Phase III question around Compass, I'll hand it to Peter around may end points and our confidence in those.

Yes. So the co-primary endpoint for Cohort A is CS FHS and being in adaptive behavioral scale. The Bailey scales into development is an important secondary endpoint. And so we sort of view both of those as being really important for demonstrating the efficacy. The powering is based on the E2 data that we showed and the sample size was actually increased from the original based on that data. We feel confident because the way that we've designed the study is to recruit patients that are between two and six with a higher proportion that are younger, who are more likely to benefit. And so that's basically the the Cohort A. Your question about Cohort B, it's not powered for superiority, and it's not powered on the cognitive outcomes because this is a non-neuronopathic cohort. And so we'll be looking at comparability with other kinds of clinical outcomes that are more systemic.

And that was actually guidance from the FDA around Cohort B was comparability, so that actually can happen very early on. The FDA was very encouraging around sort of attenuated and showing comparability. That being said, we're -- we do see signs of improvement in peripheral manifestations beyond that. Let's take the question upfront here because like one more, and I know we're out of time, but let's just do because I just I feel bad.

This is Chang for [indiscernible], Oppenheimer. Maybe for tivi, I'm curious about we can talk about the commercial product, how it looks like in terms of the infusion time volume and also for the label, I know adipic has some box warning. So whether or expecting to have a similar label or maybe potentially cleaner label and happen, a quick question Abeta, if I may.

Okay. Let's start with the tivi, and maybe I'll answer it. We were going to get to this point on the panel, and Dr. Burton has since left. We had a great discussion last infusion time. So maybe you may that Elaprase, its infusion time is 3 hours. But as fast as 1 hour. And I don't know if I am I missing Dr. Burton back there, he not there. And basically, her take was that she never infuses faster than 3 hours. So we're looking at basically 4 hours for tivi within that same range. Obviously, our goal, and I think as we've discussed switching, the dynamic of coming in, establishing tolerance and enable to dose at home. And there you can use like a backpack. And so this is something -- and we had a long discussion in up to this, but we didn't get that question in the panel. So I think that's point number one. Do you want to address point number -- or so point number 2 is on the label and...

Yes, maybe the black spots or...

Oh yes, so our expectation is it will look like all enzyme replacement therapies, which have warnings around IRRs and anaphylaxics, like that's what ERTs, and that's just the reality of these medicines.

Got it. A quick question for Abeta. I think you mentioned you can move to Phase III from Phase I. So I'm just wondering if you're thinking about mild-to-moderate AD or maybe potentially preclinical AD because we may see some data from the 2 trials in the coming years. And also whether you are thinking about some other population like Alzheimer's patients with Down syndrome, which with our differentiated profile.

I'm going to hand it to Peter who's our invest neurologists and knows this field well, like what do you think of the Phase III -- without -- I mean, we're speculating now basically.

Yes, yes. So ways away. We've got to get through the Phase Ib first. I think to Ryan's point earlier, what we want to do drive treatment earlier. And so aiming for an earlier intervention, prodromal and mild may be the right place to go. That doesn't preclude studying moderate patients, but I think driving treatment earlier is where the field is heading.

Yes. And we'll see president will be set soon, as you point out. And I think it will change the sort of dynamic. And the question is, do you have a safe drug that hits the biomarker, and you see that correlation now with plaque reduction and cognitive benefit, that's really the dynamic that you want to go after. So I agree that we would probably go as early as possible. I think, Laura, we probably should call it. I mean, we'd love to answer all of your questions. Thank you so much for coming here in early December. It's been great to be with you all. It's great to see you in this context as well. So thank you.