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

Good morning. I'm Salveen Richter. Thanks for joining us. I'm the biotechnology analyst at Goldman Sachs. And with us, we're really pleased to have Denali and Ryan Watts, the CEO. Brian, thanks so much for being here. And to start, could you just remind us of the clinical data that is expected across your portfolio for the remainder of this year? And as we look to next year, in what you are most focused on?

Salveen, grateful -- really grateful to be here and thank you for the invitation. It's exciting to be with you at such an exciting time in neurodegeneration drug discovery and research, I think we're on the cusp of, I think, really important medicines for patients. And so you asked about what to expect from Denali in the next 6 to 12 months. And let me just start by saying we have 5 clinical stage programs across different therapeutic areas and modalities. And as a result, we had a lot of data coming in. I would say that, in fact, in just next month, we'll have an update on our DNL310 program, which is a ETV:IDS, or enzyme transport vehicle iduronate-2-sulfatase, for Hunter syndrome in which our plan is to replace Elaprase with an enzyme that is engineered across the blood-brain barrier using our transport vehicle technology. And so that data, we plan to present in a medical conference in the second half of July. It's the 6-month data on the first 5 patients and our focus here is can we have a sustained pharmacodynamic response, and we'll get into more detail, but you may recall that 4 out of 5 patients actually just after 4 doses had normalized heparan sulfate, which was pretty much unprecedented. And the second -- sorry, the fifth patient is now nearing normalization after the 3-month data, which we presented in February. And so we're very excited about that data. We're also looking for the safety in line with Elaprase and sustained pharmacodynamic response that will be driving our decision around the DNL310 program. I think importantly, that program is our first transport vehicle-enabled program. So it's a large molecule engineered across the [ blood-brain barrier ] and we have a number of additional large molecules engineered across the blood-brain barrier using this transport vehicle technology. And so the early data was critically important for validating that transferrin receptor as a viable path to the brain. And now we're asking the question from how to sustain the response. So I think that's probably the most eminent data that we have in the portfolio. The second program, these are wholly owned assets, ETV:IDS. And our plan, obviously, has been -- and we've discussed this before, is to build an enzyme replacement franchise using this transport vehicle technology. The second program that we should expect data on is our EIF2B small molecule activator program. And that program is in a healthy volunteer study. We continue to dose escalate. However, the data that we have in hand was sufficient to make the decision already to move to a Phase Ib in ALS patients. We plan to share data from that clinical study in the second half of this year and an update on our small molecule programs, but in particular the EIF2B program. The 5 other small molecule programs that we have in -- sorry, the 3 other molecules we have in development are one for LRRK2, DNL151, and that's in partnership with Biogen. And there, we're basically designing the clinical trial, the late-stage clinical trial for that molecule, working very closely with regulators, very closely with Biogen and plan to launch that study and share more details in, let's say, again, second half of this year. And in the last program, the RIP kinase program, this is in partnership with Sanofi. We have actually 2 molecules. One is a peripherally-restricted compound that's entering Phase II studies in peripheral inflammatory diseases, the DNL758. And again, Sanofi is leading that study. And then the second is a CNS-penetrant, DNL788, and that molecule is in healthy volunteer study, and we plan to make a decision to move it into Phase I studies and hopefully share data, but again, Sanofi is leading that program. So in summary, 5 clinical-stage assets, 2 programs moving to late-stage clinical development, the DNL310 program for Hunter syndrome and then DNL151 program LRRK2 for Parkinson's moving to late stage development. So it's a very exciting time with a lot of data expected even within the next month.

And Ryan, you started off by saying this is an exciting time for this space. Could you comment on with the approval of aducanumab in Alzheimer's disease, what this means for the field or the read-throughs through the field of neurodegeneration? And specifically your portfolio with the acceptance of biomarker as an endpoint here, how that might read through your programs?

So in the very early days of Denali, we built the company on 3 principles. First is genetic pathway potential, which we call the degenogenes. So genes were mutated that caused neurodegeneration. And APP is, I think, one of these hallmark degenogenes, mutations in APP lead to early onset Alzheimer's disease. Mutations in APOE lead to early plaque formation and much increased risk of developing Alzheimer's disease. And then there are protective mutation in APP that protect people from developing Alzheimer's disease. And actually, directionally they're opposite, meaning that mutations that increase Abeta cause disease, those that decrease Abeta [ protectively ] challenge has been translating that to clinical benefit. And it's still a challenge. We all admit that. But very striking genetic data supporting this as a part of it. The second principle we've built the company on is engineering brain delivery. So getting molecules into the brain. I think standard antibodies get limited exposure, they will definitely get into the brain but it's limited. And then, I think, the third area and principle that we've built the company on is biomarker-driven development. So obviously, the FDA recognizing the importance of these disease-relevant biomarkers is critical for the field, especially in diseases that take a very long time to develop and also are very difficult to assess ultimately clinical benefit when you're intervening very late in disease. So I do think it's an important step. I think anchoring these biomarkers on genetics that are definitive, knowing that these genetic targets are positive in these diseases is going to be critical. So obviously, we've talked a lot about biomarkers. We spent a lot of time presenting data on LRRK2 biomarkers and obviously, our Hunter program on disease-relevant biomarkers such as heparan sulfate. So I think it's great to see the FDA being forward thinking about how these biomarkers can translate to clinical benefit.

Great. And then the partnerships that you mentioned, you have one clearly with Biogen, but also with Sanofi. Could you just talk about your current strategic approach here? And as -- and how you think about what to advance and what to keep to yourselves.

Yes, great question. I love this question because partnerships have been such an important part of the growth of Denali. And we think it's really important to solve these problems in partnership. That includes big partnerships as with the Biogen partnership on LRRK2 and Abeta antibody enabled by our transport vehicle technology; or the Takeda partnership, which is 3 targets using the transport vehicle technology; or the Sanofi partnership. But what you'll see dramatically in these partnerships, they're often around large indications such as Alzheimer's and Parkinson's. And the way that we've built Denali is that some of the smaller indications that having extremely high probability of success such as Hunter syndrome or some monogenic disease and we're getting an enzyme across the blood-brain barrier, our plan is to keep those assets as wholly owned to build an enzyme franchise that basically manufacture and market those molecules ourselves. And so that's been very exciting to see that evolve. And those -- maybe there are 30,000 patients worldwide that are on enzyme replacement therapies that could benefit from the technology getting enzymes across the blood-brain barrier, across the multiple lysosomal storage diseases. The second area are these rare -- we'll call them more rares. Let's take, ALS, 200,000 patients. There, we have a wholly owned EIF2B program, and we plan to continue to advance ourselves to pivotal studies. And then you take, again, as I described, the larger indications where we're sharing both risk and upside. Those larger indications often have longer development time lines as well. So you see that balance within the Denali portfolio where we're essentially partnering on Alzheimer's and Parkinson's, and many of these, I would say, smaller indications, faster time lines, high probability of success, especially the lysosomal storage disease [ we'll advance ourselves ]. Now that's just the beginning because the transport vehicle platform can actually be applied to other modalities such as antisense oligo. So we've recently shown that we can knock down gene expression using ASOs, which is another sort of sub-platform like the enzyme transport vehicle, we now have the oligo transport vehicle. Again, we'll be strategic how we think about partnering. And maybe the last point is that there are indications outside of our core areas. So our core is really neurodegeneration and even neurodegeneration associated with rare diseases like lysosomal storage diseases. But there is potential for the transport vehicle in broader neurology, including pain, oncology, infectious disease. And in those cases, you may see us basically pursuing select partnerships to enable the platform to use it in these other areas where we haven't built our own clinical expertise.

Great. So moving to your lead program in the blood-brain barrier technology platform. So 310, could you just comment how meaningful the GAG reduction that you've observed in the urine and CSF are and frame the implications for -- of lysosomal biomarker reductions?

I think what's important to recognize with the lysosomal storage diseases is that monogenic is an enzyme loss of function. And there's a clear track record of clinical success in replacing the enzyme. So you replace the enzyme, you reduce the substrate, and then you have this downstream sort of [ distal ] effect of benefit. And so heparan sulfate is an incredibly relevant biomarker. It's a disease-causing biomarker. In fact, if you look across the various lysosomal storage diseases, you see that heparan sulfate itself is both necessary and sufficient to cause CNS-related dysfunction. So CNS involvement always is associated with heparan sulfate in lysosomal storage diseases. That's one point. The second is that it's a critical biomarker that again generally correlates with clinical benefit. And so our decision-making is really focused on the ability to reduce heparan sulfate. We had originally set the bar at about a 50% reduction in CSF heparan sulfate, in part because our animal models,kind of predicted that, that 50% reduction may translate to complete rescue of cognition and behavior and motor function, including bone defects. But then we were actually really surprised to see both in the timing and magnitude of response, basically normalization in Hunter patients with DNL310. So that it is the hallmark biomarker. It's the driving force for decision-making, and our goal is to essentially normalize that biomarker. Now we see also further reduction in urine. And I think this is in part because we have a higher dose in Elaprase, number one. And number two is on a TfR backbone [ design on ] the transport vehicle, which may improve biodistribution also throughout peripheral tissues where transferrin receptor is expressed. So if we actually go back and we look at the data, compare the animal data to the human data, we actually have never normalized heparan sulfate in the animal model. So probably like a ceiling effect. And yet in humans, we're seeing this normalization. We think this will be the strongest correlate with clinical benefit is, in fact, heparan sulfate.

And we're going to see first time neurofilament light data this year. But you've mentioned that in terms of the reductions there, it may take longer to demonstrate a difference. And that could be also dependent on patient age and severity. What gives you the confidence that patients in either your cohort A or cohort B could be capable of demonstrating a robust response?

So when we set out to basically develop a medicine for Hunter syndrome, we also decided to explore new biomarkers that have never been assessed before. So actually, neurofilament has only been reported once and it was by us. Looking at elevated neurofilament. We also looked at lysosomal biomarkers, such as GM3 or BMP, and the way we look at it is basically, once you lower heparan sulfate, you should essentially normalize at some point, these other biomarkers or at least reduce them. And what was really fascinating is in our animal studies, we really did 2 experiments. We did one, which is called prevention study where we treated animals before they had elevated neurofilament. And then we did a study where we treated them after they had elevated neurofilament. And what we saw is that among the biomarkers, neurofilament was the least responsive. We had a mild reduction in serum, about 15% and maybe 20% to 30% in CSF. And by the way, that could also be that we're halting further addition because in animal models, you see that it steadily increased over time. However, that reduction led to a complete rescue of cognition and motor function in the mouse model as well as improvement in [indiscernible]. So it may not be as responsive as maybe the lysosomal biomarkers and certainly not as heparan sulfate. But our expectation is that if we can intervene at the right time for the right duration, we should reduce neurofilament levels as well. And we're looking forward to seeing that data. We did a sort of a power analysis, and we've realized that 5 patients is not sufficient to see a significant effect. And we have the complexity that it's not in animal model, it's a human disease. And these patients, for example, in cohort A are 5 to 10 years of age. They have had neuropathic disease anywhere between 3 and 7 years with pretty severe neuropathic phenotype. So obviously, it's exploratory. It's heterogeneous. It's not elevated to the same level as you see in other diseases like CLN2 or SMA, but we're very interested in looking at this as a potential biomarker.

And then, I guess, what is clinically meaningful here?

Yes. I mean the reality is what's clinically meaningful is the clinical endpoint. So the exploratory, we're looking at exploratory global assessment in cognition and behavior and that's ultimately what is going to drive our -- the ultimate success of the program. We don't know what the correlation will be between, let's say, neurofilament and these endpoints or heparan sulfate in these end points. So when you're blazing the trail and you're the first one to show a biomarker, in some ways, it's your accountability just to sort of ask yourself how do these things relate over time.

You've also discussed that based on your powering assumptions and small size of cohort A, it may be difficult to demonstrate statistical significance. What would be -- what should we be looking for in this mid-2021 update?

Yes, that's correct. And I think part of that was an assessment of looking at variability of neurofilament overtime in different diseases, and we only had a handful of Hunter patients where we have longitudinal data. And again, so not a significant magnitude of elevation, some heterogeneity in neurofilament. And so we haven't -- we don't -- we haven't set expectations. We just want to see more data, longer duration, intervene earlier. And we look forward to seeing that data soon.

Great. And could you talk through your expectations for cohort B and cohort C? What are we looking -- or what are you looking to understand, particularly from the latter cohort to help you design the registrational trial or just give you the overall increased confidence on the program?

Yes. So when we started this program, cohort A really focused on somewhat older neuropathic patients. And the goal there was to assess, does the drug work, do you get target engagement, do you get pathway engagement and then looking initially at patient phenotype. Cohort B is really around dose. And so we have 3 arms, separate arms in cohort B: 3 mg per kg, 7.5 mg per kg and 15 mg per kg. And the question here is what basically dose is required for normalizing heparan sulfate. And we already know that 3 mg per kg and 7.5 mg per kg is very potent. That's where what we saw after 4 weeks, basically normalization. So we're going to -- these patients will be on those doses for a longer period of time before we select the final dose. Now cohort C is really interesting because this is in patients younger than 4 years of age, neuropathic, probably have the highest probability of basically cognitive benefit, behavioral benefit, other biomarkers related to neurodegeneration would be in this younger cohort. Certainly, if our animal models were predictive, that would be the case. And so that's where we'll have some of our first signs, although we'll look at exploratory data across all the populations. And we'll share that. In fact, our update in July will be pretty comprehensive for cohort A. So at this point, cohort B is on track, and we're looking forward to beginning enrolling cohort C around -- we're really thinking about selecting the dose for that population. So there's a lot of interest in the program and it's advancing rapidly.

And do you have any clarity from the FDA on the endpoints needed in the pivotal trial? Do you have to demonstrate functional benefit?

Yes. So very much right now involved with the FDA. We look forward to sharing the plans. There are others in development who have kicked off base to precisely get an idea of what the FDA is requiring, head-to-head comparison with Elaprase, looking at either behavioral and cognitive endpoints is generally where we're going. But let's not forget that there's a very powerful biomarker, which is heparan sulfate. And we're obviously engaging regulators in what does this mean. And I think here, it's just a question of that correlation with reduction of heparan sulfate, let say, in CSF for clinical benefit. And when you're pioneering a field, it's more difficult to -- you have to essentially establish that relationship. So at this point, we haven't disclosed the design of that [ Phase II/III ] trial, but it will certainly include functional endpoints, cognitive, behavioral as well as biomarkers. And what we're focused on now with the FDA is what does it look like to be registrational.

And given this data that you've seen for this program, it basically derisks to a degree your ETV platform. Help us understand how you see the read-through in derisking there. And also, what about PTV and ATV and OTV?

Yes. That's a great question, and we get this question a lot. And we've looked at a number of sub-modalities that you've highlighted. So the [ enzyme ] [indiscernible] I think there's essentially one-to-one relationship, meaning that we can plug other enzymes now onto the TV in which we'd get a very robust pharmacodynamic response. So I mentioned the animal model has actually in some ways underpredicted the [ probably ] capacity for transfer of the blood-brain barrier in humans, and that's again where we saw this normalization that happened [indiscernible]. So we're really enthusiastic about bringing additional enzymes forward. We had 6 more enzymes in the portfolio. We've made the decision to build our own clinical manufacturing to help accelerate this portfolio. And then it relates to the other molecules. So progranulin behaves very similarly to an enzyme. And in fact, has a really sustained pharmacodynamic response, meaning that we can give a dose and you have rescue lysosomal function in microglia and granular [ knockdowns ] for over a month after a single dose. And so it has this very similar dynamic. And we know that it's localized to the lysosome. So I think that's probably [ the end ] of one-to-one relationship. Where I think it is really fascinating is when you start to look at the antibodies. So in the case of the ATVs, we have ATV:TREM2, we have ATV:HER2 and we have ATV:Abeta, all of these moving very rapidly. It's obviously relevant to today's discussion -- or at least this week is what is it -- what happens when you put ATV on Abeta antibody? We see anywhere between 10 -- about a tenfold increase of brain exposure, so a much lower dose to achieve equivalent fat reduction. So we're obviously rapidly advancing that program and Biogen has the ability to opt into that program. And so if the antibodies, again, it's we -- the animal models data is really striking for TREM2, another example. And so I think what the [ ATV ] does and what the DNL310 data does is sort of derisks transferrin receptor as a viable path to the brain. It asks a real fundamental question which is, does this even work? Can we use the TV to get molecules into the brain? And now it's going to be all about the properties of each of these unique molecules, like TREM2 increasing the number of microglia, like how do we -- what does that look -- how is that going to translate to clinical benefit? What is the dose needed? And what I can say for the antibodies is that when you put it on a TV, they're highly potent. So a pretty low dose and you get very good brain uptake. I'm guessing that when we scale with humans, that will certainly be the case as we see a big capacity for transferrin receptor in the brain. Maybe my last one is that the ASOs, it's a lot like enzymes in the sense that once you get an ASO into the brain, it has this sustained pharmacodynamic response. So again, I think the data is really promising with DNL310 that essentially validating that OTVs may be a viable path as well -- or viable platform as well.

And on the TREM2 and progranulin programs that are IND-enabling, when could those enter the clinic?

Yes. So both of those are -- basically, we received milestones for initiating IND-enabling studies with Takeda, they have the ability to opt-in with share in cost and financials 50-50 in the U.S. and China. And both of those are on track basically for IND and/or CTA filings by end of the year or early next year. So a lot of work on those are in the middle of these studies right now and writing of basically the clinical protocols. So we're excited to bring 2 more transport vehicle-enabled molecules into the clinic within the next 6 to 9 months.

And then you've spoken about the need to expand your manufacturing capabilities as you brought in this portfolio. Could you speak more to this point? And what scale do you anticipate being necessary as you look to commercial use?

Right. So this -- so our manufacturing will be focused on 2 things: clinical, material. We still will use commercial partners to manufacture as we go transition to commercial and the biotherapeutics platform. So we focus on the transport vehicle. We have excellent partners now, and we'll continue to work with these excellent partners on manufacturing. So capacity, we have the ability to use others as CDMOs to basically advance the portfolio now and into the future. So because the transport vehicle portfolio has rapidly expanded, we, both in [ speed ], really, I think, maybe in speed, but also in cost, it will be more efficient for us to manufacture ourselves. So this will be a clinical manufacturing facility.and it will basically enable the future TV portfolio.

And how are you thinking of prioritizing your resources here as you look to -- as you expand beyond these first [ T3 ] TV programs, how are you going to decide how to -- which ones to move into next? And I guess, not even just in TV, but also in your other 2 verticals.

Yes. Right. So obviously, we have small molecules and other modalities. So for the transport vehicle, we've made the decision to build an enzyme franchise. So that's a priority for us. In terms of our TREM2 program, our progranulin program in partnership with Takeda. So that really enables us to advance the programs forward. Those -- the costs are covered there. And prioritization really comes down to there are the smaller indications with clear biological rationale and clear genetic associations. And then as you go to larger indications, there, as we discussed earlier, that risk-benefit is different, and there are often partnerships that have allowed us to advance forward in Alzheimer's and in Parkinson's disease. And so our portfolio has been prioritized by probability of success, potential for the platform and you'll see that we've essentially taken at, least, 1 molecule for each of the 7 modalities forward first. So we can validate that sub-platform and then we're expanding each of those sub-platforms. And in terms of small molecules, we'll continue as we have to find the highest probability of success targets and bring molecules forward on a regular -- into the clinic against these neurodegeneration targets.

Perfect. And then on the LRRK2 program, you presented some Phase I target and pathway engagement data last month. Can you remind us what you found with 151's profile? And what gives you optimism that the inhibitor will be meaningful in Parkinson's disease? And how then you're thinking about translation to clinical outcomes?

It's really exciting to see where we've come with LRRK2. I started working on LRRK2 in 2006. It was discovered in 2004. Mutations in LRRK2 lead to increased kinase activity, it represents about 3% of the Parkinson's population, this increase in kinase activity. So we began before -- even before Denali, working on small molecules that could cross the blood-brain barrier and effectively inhibit LRRK2. And we learned a lot about LRRK2. And one of the things we've learned is that LRRK2 modulates the lysosome. And linking lysosomal dysfunction to Parkinson's disease, and there's obviously a link with [ TVAs ]. And so it's really exciting. We got our first data with 201 and then our data with 151. And what we see with 151 is that we can maintain very robust inhibition with QD dosing, which is superior to what we had with 201, which was likely going to be BID dosing. And really, we think about the bookend, the one -- on the one end, we want to bring LRRK2 kinase activity back to normal levels. So the mutations increase kinase activity by about twofold. That would be sort of the minimal dose, is basically that normalization. And then on the other end, when you inhibit LRRK2 between 70% and 80%, you see changes in lysosomal biomarkers. These lysosomal biomarkers are actually elevated in LRRK2 patients, and we can normalize those lysosomal biomarkers at the higher end of the dose. So really excited that we've been able to basically identify a molecule that is generally well tolerated, and we can get QD and basically explore these 2 hypotheses, the kinase hypothesis well as the lysosomal biomarker hypothesis in terms of the dose moving forward. So now it's all about clinical trial design, looking at clinical endpoints and translating these biomarkers to clinical data.

And then remind us on the rationale for your RIPK1 program and why you're targeting that pathway for ALS and Alzheimer's disease. And then how we should think -- what we should be looking for from this healthy volunteer data in the second half.

Yes. So RIP kinase is actually one of the first targets we started working on, that and LRRK2 in the very early days of Denali. And what's really fascinating about RIP kinase is it regulates what's called the necroptosis pathway, [ downstream ] TNF receptor 1. And there's a lot of data across different degenerative diseases that there's an inflammatory component to these diseases that essentially TNF is elevated among other cytokines and what -- some of the hypotheses is when you actually activate RIPK in certain cells, such as microglial cells, they become inflamed and in other cells, they go through this necroptotic cell death. So the strongest rationale for RIP kinase inhibitor is actually in peripheral inflammatory diseases. And hence, the reason we've developed a peripheral-restricted compound, DNL758, that Sanofi's advancing. In neurological diseases, there are both genetic and pathway links to RIP kinase. So there's, for example, in Alzheimer's disease substantial evidence around microglial dysfunction and hyper-inflammation. And so that's one of the strong connections there. In ALS, there's actually more of a genetic link to Optineurin and TBK1 leads to RIP kinase signaling. And so that's one of the reasons we're pretty enthusiastic about inhibiting RIPK in ALS and in Alzheimer's disease.

And then on 343, which is your brain penetrant activator of EIF2B, remind us why this is an intriguing target also in ALS, but then in FTD. And you've guided to starting a trial in the second half. So what -- of all your portfolio, why this next?

Yes. So we -- in fact, we already announced that we're now initiating that ALS study. So a little bit ahead of time based on the data that we have in the healthy volunteer study. So let me tell you a little bit about EIF2B. It regulates what's called the integrated stress response pathway. And I think the simplest way to think about this is that when cells are undergoing cellular stress, they lock down their mRNA and they stop translating, it's a transient protective mechanism. And interestingly, mutations in this pathway lead to diseases like vanishing white matter disease. And in fact, in ALS, about 40% of the genetic associations are related to this particularly distressed response pathway. And specifically, RNA and DNA-binding proteins, such as TDP-43 [ or plus ]. And what happens in -- we believe what happens in ALS is that the body goes through some cellular stress and certain individuals are predisposed to lock these RNA stress granules into place, as a result the cells then starve and they die. Now when you activate the EIF2B, you can unlock these stress granules. And in fact, we've shown that in cells that form these stress graduals, TDP-43 associates with these stress granules, and we can add DNL343 and essentially dissolve the stress granules within minutes, which is really fascinating. So we want to go into a patient population that has pretty much definitive evidence of these RNA stress granules. ALS, 95% of patients have these TDP-43 positive inclusions. So I think the exception would be the SOD1 mutation population, which we wouldn't likely go in that population. And essentially, what we've seen across multiple models, including vanishing white matter, retinal ganglion cell damage, ALS is that when we inhibit EIF2B, we essentially protect cells from dying. And what it really does is it sends them back into a homeostatic state, allowing them to translate proteins. So in terms of the data -- sorry, in terms of the data there, we have begun that healthy volunteer study, now with dose escalated. We're in the multi-dose, and we have, obviously, the data in hand to make that decision of reporting to the Phase Ib. [indiscernible] it's a competitive target. There's at least 1 other clinical stage program. And so now, for us, it's really about validating the target going forward in ALS and exploring other indications as well.

And maybe as a last question here, what else should we be focused on with Denali as you continue to evolve as a company in this neuro space?

Yes. It's been an incredible transition in the last year for Denali. I think we went from getting our first patient data in Alzheimer's as well as in Hunter syndrome to then expanding our portfolio, expanding our partnerships, and now we're making that transition to basically manufacturing our medicines and beginning, really, the commercial stage, thinking about commercialization, building an enzyme replacement therapy, commercial franchise. And so I think that's sums up where we're going now is becoming a wholly integrated global biotech company. And I think it's exciting to see that the initial data validates the platform, puts us in a position to now build more broadly. And so that's it. I mean for us, it's about now getting our medicines to patients. I'm very excited that we're in a number of patient studies now.

Perfect. With that, Ryan, thank you so much for your time today.

Thank you, Salveen. Take care.