Good day everyone, thank you for joining us at the virtual UBS Healthcare Conference on our fireside chat with the Denali management team. I'm Esther Rajavelu, covering smid- cap biotechs here at UBS, and joining me today are Ryan Watts, CEO, and Carole Ho, Chief Medical Officer of Denali. Thank you both for your time. We are excited to have you join us. Esther, thank you so much. Really great to be here. Looking forward to discussing Denali, and really appreciate your interest in our approach to PD degeneration. Great. Perhaps you could start us off with a brief overview of what you're most excited about as we look at the next, 6- 12- 18 months for Denali. Yeah. Would love to do that. It's an incredibly exciting time at Denali. Over the last year, we've completed a number of studies in Parkinson's disease, other neurodegenerative diseases, including getting our first data in Hunter syndrome, with one of our blood-brain barrier technologies. We're now advancing a broad portfolio of both small molecules and large molecules, all focused on genetic targets in neurodegeneration and rare neurological diseases, including lysosomal storage diseases. What we expect to see over the next six months is additional data with our blood-brain barrier platform in Hunter syndrome. The first clinical data with a novel target, eIF2B, which is a target that modulates RNA stress granules, a very exciting novel approach, and then entering late-stage clinical trials for our LRRK2 program, as well as our DNL310 or Hunter program, so Parkinson's disease and Hunter syndrome. I think in addition to this, the last year has really created momentum for us to hit a new phase at Denali, including starting these late-stage clinical trials. We've decided to expand our clinical manufacturing as well as commercial footprint. We're building commercial with an initial focus on an enzyme replacement therapy franchise in which these enzymes are engineered to cross the blood-brain barrier, and that's a great opportunity for us. It's an exciting time. I think last year also, we published a number of papers on our platform and on various biology and Alzheimer's disease targets. Again, it's an exciting time, and I think what we've seen is we've applied the principles that we built the company around. First is going after de novo genes, or genes when mutated that cause neurodegeneration. Second is engineering brain delivery, and applying those technologies to small molecules and then a platform for large molecules. Third, biomarker-driven development. I'm joined today actually by Carole Ho, who's the Chief Medical Officer, who's led our biomarker-driven development efforts, and Carole and I look forward to answering questions on a number of our programs today. Great. Thank you. That's a great overview. Lots of things to be excited about as we go on. Maybe we can start off with your wholly-owned pipeline. As some of your wholly-owned pipeline is maturing and you've also recently just said you're sort of building out a commercial infrastructure. Can you maybe talk about what specifically you're thinking about wholly-owned versus partnered programs and the commercial infrastructure, the thought process behind it focused on ERT, versus maybe some of the other neurodegenerative diseases. Just contextualize that for us a little bit. Yeah. Great, Esther, I love that question. When we founded Denali, we knew that partnering would be a central part of our business strategy, and that partnering came really in two flavors. The first was to bring in key technologies, key molecules. A good example is we have a partnership on Fc engineering that was a foundational agreement to allow us to engineer the Fc of an antibody to get it across the blood-brain barrier. We brought in our LRRK2 program from Genentech that we had worked on originally, RIP kinase from Harvard. That was an important part of the company, was to build some of these initial technologies as we hired people in the process. The second type of partnering were basically to share risk and share upside. You'll see that there is really a focus on big areas like Parkinson's disease and Alzheimer's disease. A partnership with Biogen on Parkinson's and Alzheimer's, LRRK2 inhibitors for Parkinson's, and A-beta antibodies that are actually engineered to cross the blood-brain barrier. We see those as significant cost and time, but significant upside. The partnerships were actually designed for us to share significantly, often 50%, in the commercial value of those programs. That has allowed us, through that partner strategy, to build a number of wholly-owned programs. I think one area that's really exciting along those lines are the enzyme replacement therapies, and our plan is to take those all the way to approval and to essentially market those medicines. They happen to be some of our most advanced programs in Hunter syndrome. The same for one of our small molecule programs, the eIF2B, which is entirely Denali originated. Our plan is to advance that into late-stage trials in ALS as well. We just are beginning now the ALS phase Ib study for biomarkers. You'll notice this balance between wholly owned and partnering, and that's always been the approach, I think, for Denali. I think where there's areas of significant cost and timelines, where there's also significant upside, we're willing to enter into some of these strategic partnering relationships, and I think Parkinson's and Alzheimer's is a great example of that. However, in areas where we can move very rapidly, like enzyme replacement therapies and even in ALS, we would like to go as far as we can alone, if not all the way, and we're definitely building an enzyme franchise now. Great. Let's talk about ALS and eIF2B first, if you will. You're first in class with this target, and it's a difficult to treat indication for sure, with a lot of unmet need. Maybe can you walk us through why eIF2B could be an attractive target here, and what are some of the implications of activating the eIF2B pathway specific to the cytoplasmic aggregation of TDP-43? Yeah, I'm happy to do that, and then I'll hand it to Carole as well. eIF2B is, in fact, a very fascinating target, genetically implicated, actually, in vanishing white matter disease or direct mutations. In ALS, you see the formation of these RNA stress granules and the accumulation of TDP-43. What we've shown in others is that when you activate eIF2B, you can very easily dissolve these stress granules. Let me provide a little bit more context, because I think it's one of the more compelling areas of biology and ALS research. A number of the genetic targets, greater than 40% of the genetic targets, are in our genes related to these RNA, DNA stress granules, or RNA, DNA binding proteins. I should say, in these RNA stress granules. What happens is when a cell is in a stressed environment, it will accumulate its RNA, stop translation to transiently protect the cell. What we've noticed is that in ALS in particular, that when these RNA stress granules form, they become locked in place. When they become locked in place, the cell actually dies. What's been discovered over the last decade is that when you activate the eIF2B, you can unlock these stress granules, and it's amazing, w ithin minutes, you can unlock the stress granules. We do this with cells that we can induce stress. TDP-43, which is an RNA, DNA binding protein, accumulates in these stress granules. You basically treat with DNL343, you can dissolve the stress granules, the cells live. This has been shown in acute injury as well as chronic injury. I think the data, both genetically and histologically, 95% of ALS patients have TDP-43 positive inclusions, strongly argues that basically, targeting the integrated stress response will be a successful approach in this disease area. That's the background, and that's the context. Maybe to provide another sort of high-level view of it, there's a correlation with extreme environments, like soldiers from Desert Storm or extreme athletes that have a higher rate of developing ALS. It's likely because when the human body is put in stress environments, but it's predisposed to lock these stress granules in place, basically that increases risk of ALS. A number of both environmental and genetic links to the integrated stress response, and specifically the eIF2B and ALS. That's where we began, and this is a small molecule program, so it's not using our novel Transport Vehicle technology, but it's a small molecule similar to our LRRK2 program, in which we've successfully invented molecules that can readily cross the blood-brain barrier. The phase I is focused on showing robust PK, robust exposure in brain, and then, as we've done with all of our programs, developing novel biomarkers to show target engagement and pathway engagement and patient phenotyping. Good. I don't know if Carole was going to add anything to that. I think Carole, as we start to discuss the clinical data. Yeah. Yeah. I mean, the pathway basically has multiple sort of targets, and choosing eIF2B versus maybe eIF2α or PERK, what was the thought process there? That's interesting. PERK is upstream, and PERK has other downstream targets other than eIF2α or B. As a result, there's risk associated with inhibiting PERK, and others have shown that. eIF2B, on the other hand, seems to be inhibited in a stress environment. When we activate it, we can dissolve these stress granules. We've seen none of the findings that you see with the PERK inhibitor, so it's much more selective. It's also directly genetically implicated, and I mentioned before, vanishing white matter disease, so that's why we selected eIF2B. Got it. In terms of, you've shown some in vitro data that shows disaggregation of TDP-43 clusters with your molecule. In terms of how important is that disaggregation versus preventing neuronal death in affecting functional improvement? Yeah, it's a great question. I think what it is, it's a marker, a biomarker of these inclusions. Now, what's really fascinating is when you inhibit eIF2B, let's say in an acute injury, you can rescue cells from dying as well. It's probably not related to TDP-43, but it is related to the integrated stress response, right? I look at TDP-43 as more of a marker of activity. We don't know, I think the question you're getting at is, can dissolving protein aggregates be basically a path to rescuing cells? At this point, we can dissolve them. We can also protect cells from dying, but we don't know how linear that relationship is. Understood. There are also other activator mechanisms that enable sort of correct protein folding in ALS. Can you share your thoughts on how eIF2B is perhaps differentiated versus the HSP approach to misfolding? I think it's a very different pathway. I think HSP is a general approach to protein folding. These are only stress granules, may not be an issue of misfolded proteins. They're actually a transiently protective mechanism, but when locked into place, essentially the cell starves. I see this as very different mechanistically. Also, the genetic implications around eIF2B is much more compelling and then map directly to TDP-43, as we've discussed before. It's not that you're refolding TDP-43. Its normal function is to form these stress granules. The problem is it just can't unlock, and when you activate eIF2B, you can. I see it as actually probably very disparate, t hey're completely different mechanisms. Understood. Okay. The interim analysis in the healthy volunteers, you showed up to 50% CHOP reduction. What amount of CHOP reduction could potentially impact the ISR pathway? Carole, do you want to take that? Let me first just give you an overview of that phase I study. This is a healthy volunteer study where we have 88 healthy volunteers that were studied in both a single-dose escalation study design, a food effect study, and then also a multiple ascending-dose study. In that study, we did look at biomarkers of ISR, Integrated Stress Response activity. As you noted, that the expectation is to see a reduction in ISR transcripts, specifically, for example, CHOP and ATF4. In terms of how do we think about the magnitude of reduction in those Integrated Stress Response pathways and what is required for clinical benefits, this is something that we've explored quite extensively in preclinical models to understand at what range of exposures do we need to see effects on different endpoints in diseased animal models. We've looked at a number of animal models, including an optic nerve crush, also looking at neurofilament in animal models as well. What we've shown in the interim data that led to our decision to move forward, we have shared single ascending-dose data where the PK profile of DNL343 is very favorable, and we're able to achieve exposures that enable us to demonstrate that we can reduce CHOP and ATF4. In addition, based on multi-dose data, which we have not shared yet, we have sufficient data to make a decision to move forward to a phase Ib ALS study later this year. Understood. Is that multi-dose study data something that you plan to share later this year, or what's the timeline for that? Yeah. We do plan to share that in a future medical conference. However, at this time, we have not shared the data, given that this is a fairly competitive field, and we certainly feel that some of the data and observations from that study are really important in helping us plan our clinical development plan, including our next phase Ib study. Got it. Okay. Should we expect then that the biomarkers that you could share with the multiple dose would be different from just the CHOP data that you've shared? Yes. So it's largely the same approach where we're looking at Integrated Stress Response pathway to demonstrate the link between the exposures and the degree of ISR response that we see. Given that these are healthy volunteers, not patients, there are only so many biomarkers that we can look at in the healthy volunteer population, so we would want to look in patients. This data does enable us to make parallels between what we've seen in our animal models to help define dose selection for our phase Ib patient study, which will be in ALS patients. Okay. When does that trial begin enrollment? We've given guidance that we'll start that study this year. This year. Okay. As you begin to enroll ALS patients, you're referring to the space as pretty competitive, i t is a competitive development space. What are your expectations for sort of site selection and really patient enrollment timelines? Yeah. We've had experience in this area, and recently, as you know, in our collaboration with Sanofi, have run an ALS study in phase Ib study for our RIPK1 program. We're quite familiar with this area, and we expect that we will be able to enroll this study in a reasonable timeframe, but have not given specific guidance on the timing of data release from that phase Ib study. Got it. Okay. Can you just remind us how many patients in the phase Ib arm? We have not shared the design of the phase Ib study to date. Got it. Okay. All right, m oving on to the Hunter program, perhaps. You plan to share the six-month data in July, I believe, and there'll be some new biomarker information from the cohort A patients. With regards specifically to the CSF HS levels, should we expect to see further reduction in those levels? I think we saw about 75%-85% in February. How much lower do you think that can go? Carole, maybe I'll start just very quickly as we switch programs here to give just a quick introduction on the ETV:IDS and then what our expectations are there. By the way, thank you for starting with the eIF2B. We almost never have time to get to that program, and we're very excited about it. Even though it's highly competitive, it's great to be able to focus on that program. The Hunter syndrome program, DNL310, is a enzyme Fc fusion or ETV:IDS Enzyme Transport Vehicle. It's designed to cross the blood-brain barrier using the transferrin receptor. The data that we've shown previously, first at essentially four doses, so at five weeks, at trough, and then again at three months, is that we in fact could normalize the HS levels, meaning that it's equivalent to what a normal, healthy individual would have. The goal is, with six-month data, is can we sustain that normalization? I think what was interesting about the data is that before this, all other programs had achieved anywhere between 15% reduction to a maximum of 60% reduction, and most of them in short-term dosing achieved about a 20% reduction. We're seeing a 90% reduction, but what's more important than the percent reduction is that it reaches normal levels. Both the timing and magnitude of effect exceeded our expectations. Actually, frankly, the first time we looked at CSF, which was four weeks after we began dosing, we saw that normalization. In terms of the six-month data, I'll hand it to Carole in terms of what we're going to read out and what we expect there. Yeah. Just to recap, from the three-month data, we saw an 85% reduction, and as Ryan noted, we had normalization in four of those subjects, and the fifth subject was in near normalization. We understood the reason for that slower response in that patient. They had very high preexisting ADA and anti-drug antibodies. Our expectations, what we would be looking for, is continued maintenance of that response, that there's not much reduction beyond normalization that one can see. We would be looking at safety profile maintenance of that response. In addition, we shared some of the biomarker data on lysosomal biomarkers demonstrating correction of secondary lysosomal dysfunction. Just in terms of what I mean by that is that the enzyme breaks down the primary substrate, which is glycosaminoglycans. When the enzyme is missing and you get this accumulation of this substrate, you end up getting dysfunction in the lysosome because of this accumulation of these glycosaminoglycans. Because of that, you get secondary accumulation of other things that are not broken down by IDS, for example, gangliosides, BMPs, sulfatide. We've been looking at those biomarkers which we characterized in patients which are elevated due to the lysosomal dysfunction, w hat we're looking at is to see if they'll decrease over time. That may take longer to see the same magnitude of change compared to glycosaminoglycans because they're further down the pathway, but they're very important in our mind for understanding lysosomal function and helping us select then the effective dose to take forward into our future registrational studies. We'll be sharing that data in addition to preliminary data on our exploratory neurofilament biomarker, and then as well, we plan to share exploratory clinical endpoint data for global function scales. Understood. Maybe just touching on the NfL data, why do you think NfL, which is typically seen as a biomarker for neurodegenerative diseases, is important to this young patient population? Yeah. That's a great question. I think as we look at this disease area, we're looking to essentially make an impact on the cognitive manifestations and behavioral manifestations of the disease. In Hunter, actually two-thirds of patients have significant cognitive and behavioral impairment, and this is really the highest unmet medical need that we hear when talking to patients and their families. In the one-third of individuals that don't have cognitive disease and are considered non-neuronopathic, they do still have elevated glycosaminoglycans in the CSF, and so it is possible that there is some milder impairment of CNS and cognitive function. It's very important in this area that we look at biomarkers that may tell us something about cognition. In our animal models, we have actually correlated very rigorously the reduction of glycosaminoglycans correlated with also reduction in these lysosomal biomarkers that I shared with you, also reduction in neurofilament, and then we correlated all of that with correction in motor and cognitive function in an animal model. We've shared that data before. We have an MPS II animal model where we can show that we can restore motor function in terms of running on a treadmill, ascending on a pole, and also a memory learning task, that we have correlated across these endpoints. How these all translate into the MPS patients, that's what we're trying to assess currently in our phase I/II study. Neurofilament we do view as a biomarker that may be important in looking at normal axonal dysfunction because in a way, lysosomal storage diseases that affect the brain are neurodegenerative brain diseases in pediatric patients. Okay. In terms of just taking a step back and looking at the ETV platform more broadly, you've shared your list of sort of next ETV targets, if you well, are indications that you would pursue. Can you maybe help us understand how you came up with that list and how you would prioritize them going forward, assuming success with Hunter? Right. After we saw the data in November of last year, we immediately initiated five additional enzymes. That's actually seven total enzymes in our portfolio. The way we looked at it is, clinical path unmet need. There are over 30,000 lysosomal storage diseases patients, two-thirds of which have neuronopathic disease, all of which could be effectively treated with an enzyme that could treat both body and brain. I think Carole highlighted that even in the non-neuronopathic, there may be some evidence of behavioral changes, our goal is essentially to replace enzyme replacement therapies with these Fc fuse enzymes that can cross the blood-brain barrier. This is the beginning of the building of essentially an enzyme franchise. The prioritization was essentially, is there an existing enzyme replacement therapy, yes or no? Is there a clinical path, yes or no? Basically, population, and we're interested in all of them, but those that we think there's a path that we can move quickly. Now it just comes down to plug and play, taking the Transport Vehicle and fusing it to the enzymes. The next one in line, ETV:SGSH, has shown very similar data as would be in Sanfilippo. What we saw in the Hunter mouse model, we're seeing the same in the Sanfilippo model, with rescue of basically production of substrate, we're again being very rigorous about developing the biomarkers for this. Got it. Just stepping back to Hunter really quickly here. How are you positioning the product? You're building out a commercial infrastructure, but it is a competitive space, and there are others that are kind of looking at this from potentially longer duration of action, less frequent dosing. Where in the treatment paradigm do you think DNL310 could fit in? Yeah. I think treating neuronopathic disease, two-thirds of the patients are not effectively treated. You see some variability in the gene therapy approaches there. That would be number one, would be the biggest differentiator, and then essentially replacing ELAPRASE. Now when it comes to dosing frequency, that's part of the reason why we continue to escalate into phase I is just to really understand the maximum tolerated dosage, and at some point, we can look at changing dose frequency. There are other ways of differentiating, but clearly going after the neurological component is the biggest differentiator here. Got it. To the extent that you're able to show the neurological improvements, let's just say worst case scenario, the peripheral improvements are not there. Is that scenario realistic, and how do you handle the program at that point? Actually, interestingly, thanks for asking that question. We've already looked at peripheral endpoints, specifically looking at urine GAGs, and at least compared to ELAPRASE. These patients are initially on ELAPRASE, then they switch to DNL310. We have further improved biomarkers in the periphery as well. We plan to share additional data on the six-month data. There's every reason to believe that systemically delivered, it should be equal to or better than existing enzymes in the periphery. This is really important, i t's designed to treat both periphery and brain. Whereas approaches that go directly to the brain with intrathecal delivery or even gene therapy to the brain still require peripheral treatment. This is actually a single medicine for both body and brain. Got it, p erfect. Let me see here. Sorry, Carole, were you going to say something? No, I'm okay. Maybe I'll switch gears here to Parkinson's a little bit, unless there's anything else you want to cover on these two wholly-owned programs. I think I would just make one other comment about the Transport Vehicle. obviously, the enzyme franchise is something we're moving forward, and we talked about wholly-owned. The two additional Transport Vehicle-enabled programs that are nearing the clinic are TREM2 for Alzheimer's disease, so ATV:TREM2, Antibody Transport Vehicle TREM2, and PTV:progranulin, which is basically a Protein Transport Vehicle progranulin for FTD. both of these programs are option programs by Takeda. again, for us, very favorable in terms of the value we retain 50%, w e lead them to clinical biomarker proof of concept. They would be the next two Transport Vehicle programs that will be moving towards the clinic, maybe my last point around the Transport Vehicle potential is the ability to get antisense oligos across the blood-brain barrier. We've shared data that we can take ASOs, fuse them to a full-length Transport Vehicle antibody, and get substantial knockout of expression when delivered systemically. I think importantly here with broad distribution throughout the brain because you're crossing every capillary. I think one of the challenges with intrathecal delivery of ASOs is broad distribution, and this is probably one of the reasons why the huntingtin program may have failed is through biodistribution. It could also be, not targeting the right form of Huntington, but this is actually I think highly differentiated. We see a lot of potential in the Transport Vehicle. We have some partnerships, but most of them, we retain ownership of the platform completely on our own. Got it. I know you've talked in the past about Hunter potentially being proof of concept for the entire ETV, for the entire TV platform, not just enzyme replacement. Each of these molecules is different, and getting enzyme to the brain has different challenges than getting an ASO into the brain. What are the other sort of metrics that we should be tracking to get comfortable with the Transport Vehicle platform across the different molecule types that you can transport in? I think the reason why the Hunter data is so important is both, as I mentioned before, the timing and magnitude, and now the duration of response. The six-month data will be very important to ask, can you continue to use transferrin receptor over a six-month period, dosing weekly, and have sustained pharmacodynamic response? That tells you that the transferrin receptor is robust and sustainable in terms of getting molecules into the brain. From an enzyme perspective, it is sort of a one-to-one relationship. We're seeing the same data when we bring additional enzymes forward. For progranulin, it acts very much like an enzyme. I think where it gets really interesting are the antibodies and the ASOs. Our antibody targets, we're going after targets that have an acute effect that then is sustained. In other words, you get a large dose of the antibody in the brain, then you have a sustained pharmacodynamic response. With ASOs, it's similar as you know,o nce you get an ASO in the brain, it can have a sustained knockdown of gene expression. I think the Hunter data is also very validating that transferrin receptor now is a viable path to the brain, and these other approaches have a high probability of success. I think it's a fair assumption that every molecule will have a little bit different dynamics in terms of its PK. What we see across the board with each one of these molecules, at least in our animal models that have a humanized blood-brain barrier, is the same robust maximal exposure and then sustained effects. All right. Okay. Going to Parkinson's then, maybe. Have you had further interactions with the FDA, and when would you be able to share the phase II trial design? Carole. Yeah. We've been engaging in global regulatory authority meetings, and we plan to start that study at the end of the year. We'll share the design of that study later on this year. We don't have exact guidance on the timing. This is a collaborative project, as you know, with Biogen, so we'll be making that decision at the time we share that data with Biogen. Understood. It sounds like you're targeting a global study. There is regional variations in the prevalence and penetrance of LRRK2 mutations. What is your thought process right now with regards to the all-comer trial versus the LRRK2 trial? Is one or the other going to be sort of focused in particular geographies or? Yeah. Parkinson's disease affects patients worldwide. From the perspective of idiopathic Parkinson's disease or Parkinson's disease where there is no known familial genetic mutation, we are looking certainly to enroll globally across the U.S. and Europe, as well as other regions. For LRRK2 mutation carriers, there are regional differences that we're aware. For instance, in the Ashkenazi Jewish population, there's a much higher rate of LRRK2 mutations, as well as in areas from Northern Africa and other areas where there are higher rates of LRRK2 familial Parkinson's disease. I think there, certainly by necessity, we are going to need to go global, but certainly we'll also focus on those areas where there may be higher enrollment rates of LRRK2 carriers. As you may know, we've had an ongoing collaboration with Centogene for more than two years now, where we have been recruiting individuals for genetic testing for LRRK2 mutations, and actually recently announced that we've completed screening of 10,000 patients to identify LRRK2 carriers. We have a fairly good idea of where many of these patients are, and some of the patients will be the ones that from the screening effort will be candidates for enrollment in the trial. As noted previously, we do plan to run two late-stage studies, one in all-comer Parkinson's disease or idiopathic Parkinson's disease, and the second study in LRRK2 carrier. Maybe just a brief discussion to take a step back on the rationale for that. From a genetic perspective and sort of the underlying concept of the interest in this target began with the knowledge of LRRK2 kinase-activating mutations are associated with familial Parkinson's disease that's transferred in an autosomal dominant form. Based on that, from a patient selection approach, we're very interested in the effects that we can see in these individuals that have this kinase mutation. However, there's been emerging data, both that we've generated as well as in the academic landscape, where clearly it appears that LRRK2 is important in Parkinson's disease beyond just those individuals that have a kinase-activating mutation. This comes really from both the genetics, where there are a number of other genetic mutations that affect the lysosome, and the way that LRRK2 works is by essentially inhibition revs up the lysosome and protein processing. We believe that this could be a general mechanism that applies to a broad array of mutations that are known and potentially environmental effects that impact the lysosome. We've generated data, for example, in the second most common mutation in Parkinson's disease for GBA. It's actually a gene that in its homozygous form is a lysosomal storage disease. We've demonstrated that we can correct the lysosomal dysfunction in a cell line that's homozygous for a GBA mutation with a LRRK2 inhibitor. Yeah. Thank you, t hat's very helpful. In just kind of looking at the phase I data that you shared recently, can you maybe just share some thoughts on the side effects and discontinuations you saw? Was there anything specific about the PD patients that experienced the hypotension? Yeah. We did experience hypotension in four individuals, in the phase Ib study. In all of those cases, these patients had longer duration of Parkinson's disease compared to the median in the study. I think it is also notable that the data that we recently shared encompasses both the phase Ib study as well as extensive work done in healthy volunteers, where we dose escalated in healthy volunteers up to a dose level of 400 mg BID. The highest dose that we studied in the phase Ib study was 300 mg. The reason that we dose escalated, in the healthy volunteer study, is it enabled us to rapidly experience, in the clinical safety in higher exposures, in healthy volunteers who do not have comorbid hypotension that can be seen in later stages of Parkinson's disease. Notably in that study, we did not see any dose-dependent or any effects on hypotension. Again, just in the phase Ib study, these are in Parkinson's disease patients, that in the case of all of the individuals that had hypotension, they had underlying orthostatic hypotension. In all of those cases, this occurred in the first one to two days of dosing, and in the two patients that did not discontinue, they were able to complete the study without further supplies. Got it. As you're thinking about inclusion criteria for the phase II, is this something that you are going to pay particular attention to, or sort of screen patients out for that? How are you using this piece of information, I guess, going forward? As we plan our late-stage study, I think that we are looking to include a safety cohort where we can do more intensive monitoring to further assess and understand whether there is any drug-related effects on hypotension. I think it is not entirely clear from the phase Ib study, which is a relatively small study. I think what we did feel is that based on the totality of the data from the phase I and the phase Ib study, this is very manageable and not unexpected at all from what you see in Parkinson's patients. Certainly moving forward, we will continue to do monitoring with long-term dosing in terms of looking at any effects on hypotension. This does not in any way affect our ability to move forward. In addition to that, we have animal data for chronic tox that enables us to move forward to our late-stage studies. Great. Okay. Just looking at the partnership terms, it looks like China, you obviously view China as a pretty important market for this, just given the economics that you're retaining there. I guess, what data points do you have or what sort of led to your view that China could be a pretty attractive market for this indication, much more so than Europe, for example? Interestingly, we view China as critical for all of our collaborations. You'll see in the Takeda collaboration and the Sanofi collaboration, we actually retain 50% of the value. We would like to have retained 50% of the value in China for LRRK2 as well, obviously it's a strategic imperative for Biogen, in that case, we retain 40% of the value. It's more around our view that China is an untapped market, that we see great potential, especially in neuro, as well as in the lysosomal storage diseases. It's more of a philosophy for all of our partnerships to retain U.S. and China value. Obviously, Europe is an area that we're investing in, and that's also critical for us, o ur wholly owned programs are going to be key as well. I think part of this is we see a future, really significant opportunity in neuro in China. Interesting. Okay. Then just in terms of looking at your partnerships outside of Biogen, I know there's been a lot of focus on that one for the last several months. Ryan you mentioned Takeda as one that could be exciting going forward. Maybe what can you share about that particular partnership in the program, what should we be looking for in that particular program? Takeda was one of the first and largest partnerships we entered into actually in the beginning of 2018. In that particular partnership, Takeda has the right to three targets using the Transport Vehicle technology. They were the first to see the value in the Transport Vehicle technology. Biogen, of course, saw that value again, w e had a deal on A-beta and a Parkinson's target we haven't disclosed yet using the Transport Vehicle. The partnership includes the ability to opt-in. We continue to lead the program to a clinical biomarker proof of concept. At this point, we've named the targets; t hey're TREM2, progranulin, and tau. You'll see that two of them are basically Alzheimer's targets, t he other is a genetic target in FTD. Excitingly, we just hit milestones on both the TREM2 and progranulin program, and now they're in the middle of IND-enabling studies, and we'll file INDs or CTAs by end of the year, early next year. Got it. Okay. In terms of your I guess what you had kind of given a cash runway guidance through 2024, and I know Steve is not here, but just kind of generally speaking, as you're building out the European infrastructure commercially and looking at ALS, your wholly owned ALS getting into the patients, does that guidance include those types of spend or how are you thinking about that now that your program is progressing? I'm very happy to answer this. I miss that Steve is not here, but I'm very happy, I'm looking forward to answering this. Yes, the short answer, it absolutely includes guidance related to our own spend on our wholly owned programs. Right now we have roughly $1.45 billion in the bank, o bviously significant runway. This year we probably plan to spend a little over $200 million, and that's advancing all of our own programs. That includes building out clinical manufacturing, i t includes developing a presence in Europe. Definitely an exciting time, but we also are not massively expanding, w e're very wise about how we deploy our resources and w e have ongoing revenue from our partnerships as our programs hit key milestones. Got it. Great. I have a question here on email, the listener wants to know, in terms of the regulatory pathway for ALS, would this require a full phase III trial, or given the orphan patient population, is there a faster path to get to filing here? Carole. Great question. I think that in the past we've seen that in ALS, a single phase II, III trial can be sufficient for regulatory approval. We do expect that this would be a faster path than developing other neurodegenerative indications, where typically two well-controlled pivotal studies is required. Got it. Okay, great. I know we're at the time limit right now, but is there anything that I should have asked that I haven't or anything else you want to leave us with as we wrap? Yeah. Many more things we could talk about. Yes. Great questions. Really great questions, g reat to be working closely with you. We're very excited for the next six months here at Denali, and as we continue to grow. We're actually thinking a lot about what this looks like in the next 5- 10 years in an area that needs medicines that are molecularly targeted against targets that have robust validation. It's an exciting time, w e're very excited about the BBB platform, and we appreciate you hosting us. Thank you for your time, and I'm looking forward to following the story closely. Okay. Take care. Have a good day. Bye bye. Bye bye.