Great. Good morning, everyone. My name's Jess Fye. I'm one of the senior biotech analysts at JPMorgan. We're continuing the 2021 Healthcare Conference this morning with Denali. I'm joined by the company's CEO, Ryan Watts. Before we get started, just wanted to let you know that you can use the blue Ask a Question button on the webcast to send questions into a portal. I can ask them to management once we move to Q&A after Ryan's done presenting. With that out of the way, let me turn it over to you, Ryan. Excellent. Thank you, Jess. Good morning. Great to be here with everyone. Very excited to share with you the progress we've made at Denali over the past year and what we see for the future of Denali. It's a very exciting time. Just a reminder that this is a user-advanced slide deck, so I will be highlighting the slide numbers occasionally in the bottom left-hand corner, especially for those that are watching the recording. You can download the PDF from our website and get access to each of these slides. Beginning on slide two, just a reminder of our forward-looking statements. Now let's move to slide three. Just a little bit of background. The purpose of Denali, the reason that Denali was built is to defeat degeneration. We're focused on both rare neurodegenerative diseases all the way to the more common neurodegenerative diseases. This is an area with a huge unmet need with very few disease-modifying therapies. Happy to say that over the last year, we've made significant progress towards developing medicines in these disease areas. On slide four, provide context of our discovery and development principles. We built the company around what we call genetic pathway potential or the Degenogene. These are akin to the oncogenes in neurodegeneration. This is how we identify our targets and the pathways we're working on. The second principle is engineering brain delivery. In this case, it's about inventing medicines that readily cross the blood-brain barrier. Third, and I think importantly, and a very exciting year last year, is biomarker-driven development using biomarkers to identify target engagement, pathway engagement, and patient phenotyping. These three principles, when applied, should increase the probability of a positive patient impact and increase our likelihood of success with our therapies. On to slide five, I want to highlight our portfolio. Here we're just focusing in on our development portfolio. We've made significant progress on moving our programs through early clinical development, and in the coming year, we'll be advancing two programs into late clinical development. Those are highlighted here in the beginning in the lysosomal function pathway. The portfolio is organized based on our degenogene pathways, so lysosomal function, glial biology, and cellular homeostasis. The two programs that I'll spend some time discussing today is our LRRK2 program for Parkinson's disease, which is now in a co-development and co-commercialization partnership with Biogen, as well as our iduronate 2-sulfatase or Hunter syndrome program, which is the first of a number of programs using our blood-brain barrier technology. Also give updates, important updates for our other clinical-stage programs, as well as the expansion of our portfolio. We have 15+ programs in discovery. Many of these are enabled by the Transport Vehicle technology for biotherapeutics. Moving on to slide six. 2020 was an incredible year for Denali on many levels. Starting first with our clinical-stage programs, we were able to achieve the first proof of concept for our blood-brain barrier technology, the Transport Vehicle technology in Hunter syndrome. We also presented data for the first time in Parkinson's patients with our LRRK2 program. We have five clinical-stage programs. We now have 15 Transport Vehicle-enabled programs. These are large molecule programs. Importantly, we entered into a partnership with Biogen around our LRRK2 program in Parkinson's disease, as well as an option for two Transport Vehicle-enabled technologies. This has laid the foundation for the coming year, and in particular, we have about $1.5 billion in cash or equivalents investments to basically advance our portfolio and build the company. Focusing on our future on slide seven, want to highlight some of the organizational growth ahead. First and most importantly, we'll always be deeply focused on the science. We have a commitment to discovery as well as now a comprehensive global clinical development strategy and capabilities, advancing medicine both within the U.S. and outside the U.S. in our clinical trials and beyond. Importantly, this year, we'll begin building or further building our internal manufacturing capabilities as well as commercial infrastructure. The vision that we have for the company is we begin with our lysosomal storage disorders as a place to basically validate the platform, but also realize significant value in our portfolio. Move to rare CNS diseases and then more broadly to large neurodegenerative diseases where we already have a number of important partnerships in Alzheimer's with Takeda and Sanofi, as well as in Parkinson's with Biogen. Let's now turn our attention to the Transport Vehicle platform for brain delivery of biotherapeutics. We're now on slide nine. I'd like to introduce the BBB challenge and our solution. The blood-brain barrier has been limiting for a number of medicines, but in particular, biotherapeutics or large molecules. That would be antibodies, enzymes, and even ASOs, where systemic delivery achieves very little exposure of drug and brain. Our solution is to take advantage of a natural transport mechanism known as the transferrin receptor pathway. The transferrin receptor is used to get iron across the blood-brain barrier and into the brain, and then also into other tissues. What we have done is I'll highlight now on slide 10, is basically engineer what's called the Transport Vehicle technology, in which we have taken the Fc portion of an IgG. This is shown in the middle image. And engineered binding of that Fc to the transferrin receptor, which is expressed on blood vessels in the brain. The idea here is that basically we can achieve 10-30x increased brain uptake of biotherapeutics, such as antibodies shown in the middle. In fact, here's an image of a cynomolgus monkey brain after systemic delivery, looking basically two days after delivery. You see in the image broad biodistribution throughout the cortex of its brain. To basically test this technology and expand its utility, we made Fc fusion proteins first to enzymes. On the right-hand side, the image is of our Enzyme Transport Vehicle, which is a fusion of iduronate-2-sulfatase to the Transport Vehicle Fc. What's shown in the bottom right-hand corner is basically data in a Hunter syndrome knockout mouse where you have accumulation of its substrate, the glycosaminoglycans, and that substrate is reduced by dosing of either 1 mg/kg or 3 mg/ kg of ETV:IDS, and in this case, the name of this drug is DNL310. The Transport Vehicle achieves high concentrations and broad biodistribution biotherapeutics, and we've shown this in mice as well as in monkeys, and then most recently, clinical proof of concept in humans showing a robust reduction of the substrate in Hunter syndrome. We also see a dose-dependent reduction of these substrates in many of our animal models and are now applying this technology to 15 portfolio programs. Moving on to slide 11, just a highlight of the modularity of the Transport Vehicle technology. I've highlighted antibodies in the upper left-hand corner as well as enzymes for Enzyme Transport Vehicle. In addition to this, we can transport other types of proteins, and one example of this is progranulin. On the bottom right, an example is the Oligonucleotide Transport Vehicle or ASOs. Here we are able to achieve gene knockdown. I'll show some data on this in which we're able to inject systemically the OTV, or the Oligonucleotide Transport Vehicle, and knock down gene expression in brain. The benefits of the Transport Vehicle platform, first and foremost, is to increase biodistribution in brain by about 10-30x. By achieving this, we're able to unlock certain targets. An example of this is brain delivery of biotherapeutics that are previously intractable. A good example are the enzymes in particular. Many enzyme replacement therapies effectively treat, to some extent, the peripheral manifestation of disease but do not treat the central manifestation or neurological deficits. In addition to unlocking targets, we also have the ability to enhance efficacy through the synergistic binding of the transferrin receptor with the target. Two examples in our portfolio of this is our TREM2 program for Alzheimer's disease as well as our HER2 program in oncology. Most importantly, we have achieved our first human biomarker proof of concept using DNL310 as the lead program for the Transport Vehicle technology. I'm going to turn to that program next, now on slide 12. Brain delivery is a critical unmet need for Hunter syndrome. Just a reminder that Hunter syndrome is an inherited MPS lysosomal storage disorder that's caused by the deficiency of iduronate-two-sulfatase. One of the hallmarks of this disease is the accumulation of the glycosaminoglycans, in particular heparan sulfate, which leads to both peripheral as well as central manifestations of the disease. Current approved therapy, enzyme replacement therapy, partially addresses the physical manifestations of disease, however, does not address the neurocognitive phenotypes in this disease. Our solution is basically ETV:IDS or DNL310, which is designed to treat both body and brain. The goal here is to replace enzyme replacement therapy, again, focusing on the entire both body and brain. Transitioning to slide 13, I'd like to highlight some data that we've just presented, very exciting data, four-week data, proof of concept of the platform. I think importantly, this data illustrates that transferrin receptor is a viable and robust path to the brain for biotherapeutics. This both exceeded our expectations in terms of timing as well as magnitude of effect. I'd like to walk you through the data here, which is critical. On the left-hand side, the way that this study was designed, these are five patients, Hunter syndrome patients, that are on idursulfase. They go off, and they switch immediately to DNL310. DNL310, again, is idursulfase fused to the Fc with the Transport Vehicle. What you can see on the left-hand side is that the levels of the substrate for this enzyme, in this case, heparan sulfate, are about 11x normal levels. In the bottom left-hand in black, you can see what are normal levels of heparan sulfate. After four weekly doses, this is basically one week after the fourth dose or at trough concentrations, we see that four out of the five subjects have achieved complete normalization of heparan sulfate. In addition to that, I'd like to highlight new information in which we see that total urine heparan sulfate as well as dermatan sulfate levels decrease further after switching from idursulfase to DNL310. This is important in that Elaprase is able to effectively treat the peripheral manifestation of the disease. In this case, we see even a further reduction even in the periphery with DNL310. Based on these data as well as the safety data to date, this supports the expansion of this phase I/II study to an additional cohort known as cohort C. We also plan on initiating the phase II/III study in the first half of 2020. I now turn to slide 14 to highlight the study design and what we expect in terms of data. Cohort A, as mentioned, are five patients ages five to 10 with neuronopathic disease. The starting dose was 3 mg/ kg. We're now enrolling cohort B, which is age range between two and 18, both neuronopathic as well as attenuated disease. Importantly, we've expanded the study for cohort C to include patients younger than four years of age. The goal here is to look at exploratory clinical effects with DNL310. On the bottom, I'd like to highlight some of the key data. We recently presented the four-week data, and in the late-breaker presentation at WORLD on February 12th, 2021 we'll present 12-week data looking at key primary and secondary endpoints, as well as our first look at exploratory biomarkers, specifically lysosomal biomarkers. We expect by midyear as well as the beginning of 2022, cohort A completing the 24-week study, looking at key primary and secondary endpoints, as well as additional exploratory biomarkers, including neurofilament midyear. This is a six-month study. We also expect cohort B to be completing by end of 2021, beginning of 2020. In addition, we'll look at now an expanded study, 12 additional patients. What does this mean for our portfolio? Now turning to slide 15, I want to highlight that we've expanded our Enzyme Transport Vehicle platform to drive near-term growth, and also there's a huge unmet need in terms of the CNS manifestations. There are over 50 lysosomal storage diseases in which many of them have CNS manifestations. We've selected five additional ERTs to add to our portfolio, in addition to already ETV:IDS as well as SGSH. We've highlighted recently that our SGSH program has achieved preclinical proof of concept, and now we're advancing that program towards IND-enabling studies and plan to advance additional enzymes over the coming years. With this in mind, I just want to highlight more broadly on slide 16 the wide range of indications and targets that we can go after with the Transport Vehicle technology. Our current focus is on neurodegeneration as well as lysosomal storage diseases. There is opportunity outside of this, including in neurology, oncology, and infectious disease. I'd like to highlight two of our most advanced TV programs here on the next slide, on slide 17. On the left-hand side is our ATV:TREM2 program. Importantly, this molecule, when dosed systemically, can increase the number of newborn healthy microglia. What was shown on the left-hand side actually is a comparison of a standard TREM2 antibody given at 100 mg per kg to match the amount of exposure of our ATV:TREM2 antibody shown in orange, again, on the graph in the bottom left. You can see a 2- 3x increase in microglia with delivery of ATV:TREM2. The next program, PTV:progranulin, we can normalize lysosomal dysfunction. Again, these are likely lysosomal dysfunction in FTD, specifically in microglial cells. Here we see a robust and sustained normalization of lysosomal function with a relatively small dose of PTV:PGRN. These two programs are on the path to IND filing by the end of this year and early next year. They're also part of our partnership with Takeda, and we plan to advance these programs into the clinic. The third program to highlight is our Oligonucleotide Transport Vehicle. Here we've taken the Transport Vehicle antibody, and we've fused an ASO. What is shown here is either single dose, some reduction in mRNA brain. However, with multi-dose, we see a very robust reduction of mRNA in brain. This potential is for us to deliver systemically, basiclly ASOs fused to this antibody to knock down gene expression. On the right-hand side, and finally, just illustrating the expansion of the Transport Vehicle portfolio is our ATV:HER2 program. Here what we show is basically a combination of pertuzumab and trastuzumab on the ATV. We have a robust enhancement of antitumor activity with ATV:HER2. Moving to slide 18, this is an overview of our entire Transport Vehicle portfolio, again, with the clinical proof of concept, the expansion of the portfolio, and several of these programs are currently in partnership. For example, we have an ATV:Abeta program designed to increase exposure of Abeta antibodies to decrease plaque, and that's in collaboration with Biogen. We'll now focus on our small molecule programs and turning now to slide 20 in particular. Let's focus on our LRRK2 inhibitor, which we are now advancing into late-stage development. Importantly, a new information I'd like to share here, we've achieved robust target engagement and pathway engagement for DNL151 in Parkinson's patients. That study is completed. This is now two LRRK2 inhibitors that we've taken into patients and shown a robust and sustained reduction of LRRK2 activity. Just a reminder that LRRK2, when mutated, is hyperactivated, leading to increased risk of Parkinson's disease. There's also substantial evidence that LRRK2 is activated more broadly in idiopathic Parkinson's disease. To date, we've treated over 300 individuals with either DNL201 or DNL151. DNL151 has been selected based on its favorable profile, including the potential for once-daily dosing. We are now planning two late-stage studies in both LRRK2 carriers as well as idiopathic Parkinson's disease. Just a reminder that this is a co-development and co-commercialization agreement with Biogen to advance this LRRK2 program. We're very excited about moving this program by end of year into these late-stage studies and late-stage development, and we look forward to seeing clinical data in the years to come. Moving to slide 21. I'd like to introduce our eIF2B activator program in a little bit more detail and share for the first time some clinical data from the phase I study. A reminder that in ALS, roughly 95% of ALS patients develop TDP-43 positive aggregates in motor neurons. It's roughly 50% of FTD patients and actually 30% of Alzheimer's disease patients also develop this pathology. What's been discovered is that TDP-43 and other RNA/DNA binding proteins co-localize with what are known as stress granules. When stress granules form, they initially form to protect cells from stress. If they remain intact and these aggregates form, the cell eventually starves and dies. What we can see on the upper right-hand corner is that these stress granules in red and TDP-43 in green, the co-localization in yellow, when these form and we add an activator of eIF2B, DNL343, we can actively dissolve these stress granules and put cells back into a normal homeostatic state, allowing them to translate proteins. On the next slide 22, is the design of our phase I study. This is a healthy volunteer study with a single-dose escalation as well as a multi-dose. Shown in color are all the doses that we have given, including two of the multi-dose. On the upper right-hand corner is a highlight of the translational pharmacodynamic assay. I'll take a moment here to describe this particular assay. In mutant mice and when the integrated stress response is activated, we see an upregulation of CHOP1, which is a gene downstream of the integrated stress response. As we show on the right-hand side, increasing concentrations of DNL343, we can basically reduce expression of CHOP1. On the bottom right, we've developed an assay in humans, basically an ex vivo PBMC assay in which we can activate this pathway. What's shown in color is correlating with the color on the left-hand side of the single dose-dose escalation. In fact, it's the level of reduction of CHOP1 expression 24 hours after this single dose. You can see that as we increase in dose, we're able to robustly inhibit this CHOP1 expression in this ex vivo assay. Based on this, the safety tolerability in PK and PD to date, this supports further development of DNL343, and we continue to dose escalate in the multi-dose study. We look forward to advancing this program into ALS studies the second half of 2021. Moving to slide 23, I'd like to highlight our RIP kinase inhibitor program, which is in partnership with Sanofi. Importantly, DNL788, which is the CNS penetrant RIPK inhibitor, has initiated phase I studies. A reminder around this pathway, RIP kinase one is downstream of TNF receptor one as shown on the left-hand side of this slide. Blocking this pathway is a way of inhibiting the TNF receptor cascade, specifically the RIP kinase portion of that cascade. In addition to DNL788, which is being developed for CNS indications, we have also invented and have moved DNL758 into clinical studies. These programs are currently being led by Sanofi and focused on peripheral inflammatory diseases. Looking ahead, let's move now to slide 25. I'll highlight some of our plans, specifically our 2021 key milestones. 2020 was a big year for Denali in terms of generating clinical data and laying the foundation for the platform, including entering into key partnerships. 2022, you can see a number of important data points, specifically around our Hunter syndrome program, the expansion of our other ETV-enabled programs. In orange is the biotherapeutics portfolio. In terms of blue, the advancement of our small molecule programs as well. Just want to highlight again that a month from today, we'll be presenting interim 12-week data from cohort A in our phase I/II study. We're looking forward to these data to further support the platform and advance other Transport Vehicle programs. Also in terms of DNL151, our LRRK2 program, we plan to advance this program into late-stage clinical trials with Biogen, and eIF2B has just highlighted entering ALS patient studies. We work closely with Sanofi to continue to advance our RIP kinase programs as well with important data in healthy volunteers for DNL788 coming this year. Finally, in terms of our other Transport Vehicle-enabled programs, TREM2 and progranulin, filing INDs and moving these towards the clinic is the goal for 2021. This has led to the expansion of our broader Transport Vehicle platform, specifically adding new enzymes to the Enzyme Transport Vehicle portfolio, and also the growth of both manufacturing as well as commercial capabilities. I want to end on slide 26 by thanking two important groups. The first is the employees at Denali. 2020 was extraordinarily difficult, and I've never seen a group of people come together and unify in difficult times to generate such important data, both for patients and beyond. The second group I'd like to thank are the patients that put trust in us to join our trials, especially again, during difficult times, and it's been incredible to see what we've been able to achieve together. With that, I would like to thank everyone, and we look forward to the Q&A, Jess. Great. Thanks Ryan. We'll just give it a moment here for your colleague's video to come online. While we're doing that, I just want to remind those watching the webcast that you can use the blue Ask a Question button to send me questions on the portal. Maybe just to kick off, you've announced this broad expansion of your ETV program. Sounds like kind of based on what you're seeing with DNL310. Can you elaborate? Was there some specific like, "This is the thing we wanted to see to make this decision to move so many programs forward"? Jess, thanks. Thank you for that question. Just a quick introduction. Alexander Schuth, our Chief Operating Officer, Steve Krognes, our CFO, as well as Carole Ho, our Chief Medical Officer, on the line now with us. The DNL310 program for Hunter syndrome, that initial biomarker proof of concept essentially validates that transferrin receptor is a viable path to the brain. That data was key in terms of understanding both the robustness and the timing of effect. As a result of that data, we believe we can get many other enzymes as well as other programs into the brain. It's a very exciting first data set. In addition, we are now building the internal manufacturing capabilities to go after these targets. It will allow us to move rapidly. We see a huge unmet need in the lysosomal storage diseases for these enzymes, specifically in the brain. Okay. Maybe we can spend a little bit of time on DNL310 and the ongoing trial there. We've now got, I guess, three cohorts. Sounds like A is fully enrolled, B is enrolling, and C, when will that start? Will that enroll concurrently with E, given the not totally overlapping ages? How do we think about that? I'll hand that question to Carole. Thanks, Jess, for the question. Those cohorts are staggered. After enrollment of cohort A, we initiated cohort B, cohort C will follow cohort B. I think the way to think about the cohorts is cohort A was a dose escalation that was really designed for dose exploration. Our data that we presented with our four-week data really helps us understand that even with our initial doses, that we were able to demonstrate quite substantial effects on GAG, as Ryan noted, normalization in four out of the five subjects. Cohort B is really for dose confirmation. We have parallel cohorts at the same dose for each cohort, where we can get additional data for longer term at those different dose levels. Cohort C allows us to explore clinical endpoints in the patient population less than four years old that are most likely to see changes in their neurocognitive development at that time. Okay. Got it. Given that they're staggered, when do you expect cohort B to complete enrollment? At this time, our plan is to have, as Ryan noted, cohort B 24-week data by end 2021, beginning of 2022. Based on that, the plan is to have that enroll in the first half of 2021. Great. You kind of highlighted this upcoming late breaker at WORLD, where we can look for not only kind of continuation of the CSF GAG reduction, but also should see some exploratory biomarkers of lysosomal function. Can you elaborate a little bit on the exploratory biomarkers that you're evaluating and what you're hoping to see? What would be a win? I realize these are kind of exploratory in nature, but kind of help orient us ahead of that update. Yeah, great. We actually have three podium presentations at WORLD this year, and one of these is the late breaker, as you've noted. The data that we're going to present is both the primary and secondary endpoint data that importantly includes more detailed data on the safety profile as well as additional data on the CSF GAGs and urine GAGs to demonstrate durability of response with longer-term dosing. In addition to that, we will present for the first time the exploratory data on lipid biomarkers. At this point in dosing, after a relatively short period of dosing, we would find it very positive if we were able to see directional changes in these lysosomal biomarkers. As noted, we will be looking at CSF neurofilament in mid- 2021. That will follow after cohort A has completed six months of dosing, which we think is the earliest time point that we would be able to see effects on neurofilament, and this will be in the five subjects in cohort A. Okay. Got it. If just directional change is kind of what you're hoping for on the lysosomal biomarkers, do you think the 24-week time point might be able to show you something more substantial? We think that based on the data that we've seen in our preclinical animal models, that we should be able to see changes in these lysosomal biomarkers. As you know, we have profiled these lysosomal biomarkers for the first time in a recent publication by Bala et al. that we presented at the R&D Day. I do want to emphasize that this is really pioneering work in the sense that this characterization of these biomarkers has not been previously published. What we're looking for is those biomarkers where we're seeing the greatest changes between patients and non-MPS controls that we see effects on these biomarkers with DNL310 dosing. Okay. You interpret the stock price as suggesting there's a lot of enthusiasm around what you've shown for DNL310 so far, among other things. Maybe to kind of turn this around, is there any scenario in which the proof of concept data for DNL310, kind of like you were saying, Ryan, kind of proving out the transferrin receptor, is there a possibility that that would not translate to the other TV programs? We've now looked at over 15 programs in many of our preclinical models. The models are basically a human transferrin receptor binding domain in these models, and we see consistently across the different modalities, the same 10-30x increase uptake. I think it's why it was so critical to ask in humans, what is the capacity of transferrin receptor to get biotherapeutics into the brain? Again, both the magnitude and the timing of the response was so robust compared to other platforms that attest transferrin receptor or other approaches that we see this as highly validating in humans. I think it now just becomes a project-by-project question. We know that transferrin receptor works. We know that it's essentially well-tolerated, the Transport Vehicle. The question now is, can we apply it to all these other enzymes and then antibodies and ASOs? I gave the example of TREM2 and progranulin. It's less around validating the platform and more about a program-by-program specific risk. Thinking about maybe in the context of kind of varying risk profiles depending on the program or potential indication, which might come with different amount of development and investment as well, how are you as a company thinking about what you want to keep wholly owned versus what you want to advance in partnerships? I would love to hand that to Alex. Yep. Thanks, Ryan and Jess. Our goal ultimately is to build a fully integrated company that discovers, develops, and ultimately markets programs as well. Partnering has been a key part of our strategy to build and execute our portfolio, and we have three partnerships with Biogen, Sanofi, and Takeda. The partnerships focus around those indications, the large neurodegenerative indications like Alzheimer's and Parkinson's disease, where the risk and the cost profile lends itself to work with a partner and leverage existing infrastructure. The way that those deals are set up is that essentially through the milestone payments and the cost share, the cost for those programs is essentially covered while we maintain 50% of the upside through the co-development agreements. With respect to lysosomal storage diseases specifically, and those that Ryan mentioned, like ETV, IDS, and others based on that portfolio, we made the decision to develop those programs internally and build internal first clinical manufacturing capabilities and also commercial capabilities. Those are programs based on the timelines, based on the cost, based on the expertise that we have in-house and that we feel that we can build, that we would want to maintain. Okay. Maybe switching to LRRK2. You provided a qualitative update on DNL151 in the 1B data in patients. Is there any more kind of color you can provide. I know you're going to present this in the future. You talked about the prior products data in the past as well. Should we think of this as, can you use that as a benchmark maybe to talk a little bit more about what you're seeing there? Yeah. I'll hand this to Carole. Just to comment, just to remind you the difference between 201 and 151. I think the biggest difference is the PK profile, where 201, you'll remember in the patient study, we were giving TID, and we'll formulate it to be able to give BID. In the case of 151, we're able to basically dose once daily. So we're looking at the totality of that data package, and we're actually very enthusiastic to present it at an upcoming medical conference, similar to what we're doing with ETV, IDS at the WORLDSymposium. We're looking for a medical conference in which we can present that data. Basically, the biggest difference is the dosing regimen once a day for 151, and that's sustained, and we hit our target goals, I think, very robustly in the patient study. Carole, I don't know if you want to add anything to that. Sure, Jess. The paradigm is very similar to what we previously presented with DNL201, where we're looking at target pathway engagement in what we call patient phenotyping. Looking at LRRK2 kinase activity and reduction in LRRK2 kinase activity effects on Rabs, which is a biomarker that directly reflects lysosomal function, and then also BMP, which is an example of a lysosomal protein that's elevated in patients that have the G2019S kinase-activating mutation and demonstrating that we can lower that in the range of magnitude that is abnormally elevated in disease. These are the panel of biomarkers that we've been looking for to demonstrate adequate target engagement, pathway engagement, and essentially provide the data package for dose selection for our phase II, III late-stage studies. Great. As we think about those phase II, III studies kind of nearing initiation, what's it ultimately going to take to get this product approved both in the sporadic patients and the LRRK2 mutants? Would you need two studies in sporadic patients to get approved? Would it just be one maybe in LRRK2 mutants? How should we think about this thinking all the way through to approval? Carole. Sure. Yeah. At this point, we're in the process of discussions with regulators regarding the number of studies that we need to support approval. As noted, we are initiating both one study in mutant Parkinson's disease as well as an idiopathic Parkinson's disease study to address both populations. The mutant study will take longer to enroll simply because of the number of patients, and so I think it's still an open question regarding just for the timing of completion of that study and the idiopathic study, whether we would do another idiopathic study in addition to those two studies to support the Rule 405 registration. Maybe switching to RIPK1. I think this was going back a little ways. You moved to DNL788 from DNL747. What gives you the confidence in the safety profile of DNL788 to move forward with that product? Yeah. Carole, do you want to answer this one as well? The chemical scaffolds are different, and in addition, we profiled both compounds in IND-enabling studies looking at immune toxicities, and we do not see any of those dose-limiting findings that we observed with DNL747. Just to remind everybody, the DNL747 was very well tolerated in the clinic. However, we did have preclinical safety that would limit or slow down our progress on dose escalation. Because we had a ready-to-go backup program on DNL788, we rapidly accelerated that into the clinic. Based on the preclinical profile, we believe that we have much broader range to dose escalate and reach those higher levels of inhibition that we demonstrated in our clinical study, phase I-B study, that these higher levels of inhibition may be required to translate to clinical efficacy. We get a couple of questions in from the portal. It says TDP-43 pathology in ALS is controversial as being causative to the manifestations of the disease. How do you assess the risk of targeting this marker as a positive outcome in your trials? Yeah. There's often a difference between a marker versus a pathological protein. Interestingly, TDP-43 itself, when mutated, causes neurodegeneration. It's not simply just a marker. Interestingly, what we're looking for is colocalization of markers with stress granules. The target of eIF2B is not directly TDP-43, but rather the dissolution of stress granules, which is, I'd say, not very controversial. What's really fascinating is if you look at the totality of the genetics in ALS, many of the genes are these RNA DNA binding proteins. The way that it's likely working is that when the cells are under a stressed environment, you form these RNA stress granules, and any protein that's predisposed to aggregate with these stress granules basically aggregate and keep the stress granule locked in place, and it starves the cell. I agree that actually TDP-43 is a marker of these stress granules that allows us basically to dissolve them, but there are other proteins that would aggregate as well. Okay, great. Well, I think we're out of time, we will leave it there. Thanks so much, everyone, for tuning in, thanks to the Denali team as well. Great to see you, Jess. Thank you. Take care. Bye go ahead.