Hey, good morning, everyone. My name is Jess Fye. I'm a senior biotech analyst at J.P. Morgan, and we're continuing the 40th J.P. Morgan Healthcare Conference with Denali today. I'm joined by the company's CEO, Ryan Watts, who's gonna give a presentation, and then there's gonna be some time for Q&A afterwards. If you do have questions during the presentation, you can use the blue Ask a Question button to send them to me, and I can ask them to management once the presentation is done. With that, let me pass it over to Ryan.
Jess, thank you. Thank you for the introduction. You know, very excited to be here today. It's always exciting for us. We get to summarize what's happened over the last year, share data from the last year to set context, but also to present new data, and then focus on what's gonna happen in 2022, which is an exciting time for us here at Denali. I'll start by just commenting that I will be making forward-looking statements in this presentation. Let's start with our focus and our principles. These have not changed over the life of Denali, so our focus is to defeat degeneration. We're focused on rare neurodegenerative diseases such as lysosomal storage diseases, as well as more common diseases such as Alzheimer's, Parkinson's.
We've made progress across the portfolio on each of these disease areas, and I'll focus on each of the programs in these areas. Our scientific principles start with genetics, the degenogenes or degenogene pathways, genes when mutated that cause neurodegeneration, brain delivery, and biomarker-driven development. We also have three business principles, a broad portfolio, global capabilities which we are building now as we go into global clinical trials, including clinical manufacturing, and then strategic partnering has always been a big part of Denali's approach. I'm very excited to share that we over the last number of years, but certainly in the last year, we've been able to generate some unique scientific insight, resulting in greater than 20 papers published, as well as 40-plus patents here at Denali.
These are Denali-generated data, and very importantly, highlight our BBB platforms as well as the degenogene pathways that we're working on. I'll use the portfolio here as an outline for what I'll be presenting today. In fact, we'll talk about each one of these programs, some of the data that was generated within the last year and what to expect going forward, but also including new data to be presented today. As you can see, we'll have a key number of data readouts in 2022. However, 2021 really laid the foundation for Denali, including preparation now for late-stage clinical trials across multiple molecules. In fact, I'll highlight those here.
We have seven molecules across developmental stages in 2022, and importantly, we'll have three clinical data readouts with high impact potential, including additional data on our transport vehicle platform with DNL310, new data in ALS for DNL343, which is an eIF2B activator, and then our first data on an antibody transport vehicle in humans, an antibody targeting TREM2 for Alzheimer's disease, and we expect that data by the H2 of 2022. It's an exciting time at Denali. Let's focus first on the transport vehicle platform programs. Just a reminder that the blood-brain barrier is a major obstacle for biotherapeutics as well as small molecules. We set out at the beginning of Denali to build platforms to cross the blood-brain barrier using biotherapeutics and small molecules.
Today, I'm gonna focus first on the biotherapeutic platform known as the transport vehicle technology. We've engineered the Fc portion of an IgG to bind to the transferrin receptor that's highly expressed on blood vessels in the brain. You can see in the middle here the binding site of that Fc to the transferrin receptor. The first example of utilizing the transferrin receptor is actually with an enzyme known as iduronate 2-sulfatase for Hunter syndrome. The goal here is basically to latch onto these natural transporters to get across blood vessels and get broad distribution throughout the brain. I'll be sharing data not only on enzymes, but antibodies and some of our first data on non-human primates using this technology to get antisense oligos across the blood-brain barrier.
This just highlights the various modalities in which we can use the Transport Vehicle by making Fc fusions with the focus initially on enzymes. Now as we transition our first antibody into the clinic, we'll be using this as our Antibody Transport Vehicle for other proteins and ultimately for ASOs to modulate gene expression. Let's start first with the enzymes and focus in on our DNL310 program, which is a program engineered to replace Elaprase, which is an enzyme given systemically for Hunter syndrome. We've shown data in the last year that we can see both a robust and rapid but also sustained reduction in heparan sulfate. I wanna draw your attention to the graph on the left-hand side, which is patients treated. These are Hunter patients treated with DNL310.
These patients were originally on Elaprase and switched to DNL310, and what we're looking at is the cerebrospinal fluid levels of heparan sulfate, which is the primary substrate for iduronate 2-sulfatase or IDS. What you can see is all patients reached normal levels of heparan sulfate. In fact, all patients except for two normalized the first time we looked at their heparan sulfate level. This is very important because highlighted are basically two bars which have been, we've drawn that highlight what would be considered the non-neuropathic levels. Others have shown that they can basically achieve reduction to about the non-neuropathic levels, and what we see is, in fact, at the bottom, a normalization of heparan sulfate. Importantly, we will be presenting additional data from our phase I/II study at WORLDSymposium coming in February.
In addition to that, we are initiating a Phase II/III study in the H1 of this year based on these data. What was surprising for us was both the magnitude effect as well as the duration. The question was, why was it? What is it about the transport vehicle that enables such a robust pharmacodynamic response? We decided to run a series of experiments looking at the architecture of the transport vehicle and what's unique based on other standard approaches. For example, using a standard IgG to get molecules across the blood-brain barrier. This paper in Journal of Experimental Medicine is in press and will soon be published, basically highlighting this comparison of the transport vehicle architecture with a standard IgG.
I wanna highlight in the middle, basically what we observe is broad distribution of our biotherapeutics when we use the monovalent moderate affinity binding of the transport vehicle. This is important because it's reading through our other programs for antibodies, and I'll show data on ASO that very similarly, we get this broad biodistribution. In contrast, an antibody, standard antibody with high affinity to transferrin receptor, you can note that the majority of the antibody is trapped within the blood vessels. This data actually correlates to a difference in the pharmacodynamic response when you're looking at DNL310 versus a standard IgG. In fact, the lowest dose of DNL310 is superior to the highest dose of a standard IgG fused to enzymes in terms of knocking down the substrate.
We've now taken this technology and are applying it to additional enzymes. I would like to announce that our next program for lysosomal storage disease is MPS IIIA or Sanfilippo. What I'm showing here is data basically with robust reduction of heparan sulfate in brain and CSF, similar to what we observed for IDS. This program is now in preparation for IND-enabling studies, and we plan to file an IND in 2023. If you look more broadly at our enzyme transport vehicle approach, our ETV portfolio, we'll now be moving our second enzyme into the clinic within the next year, and we have a number of other enzymes to follow, building an enzyme transport portfolio. Let's now turn our attention to the next clinical stage program for utilizing the transport vehicle, which is the antibody transport vehicle.
I'll show data on the lead program here, ATV:TREM2, but want to highlight that this particular program is in collaboration with Takeda. Takeda, we just announced that Takeda opted into this program, ATV:TREM2, which is being developed for Alzheimer's disease. As a reminder, TREM2 loss of function is a risk factor for Alzheimer's disease, and the goal of this program is to improve TREM2 activity. In fact, the data I'm showing you here in mouse models highlights the biomarkers that we believe will be translatable to the clinic. First, when we treat mice with ATV:TREM2, even at very low doses shown on the graph on the left-hand side, we can see a robust increase in microglia. This is basically birth of new microglia.
This correlates with the graph on the right-hand side, which is an increase in a microglial marker known as CSF1R. Importantly, when we treat with ATV: TREM2, we only see CSF1R elevating in the brain, not in the periphery. This allows us to have a brain-specific biomarker to read out crossing of the blood-brain barrier, activation of TREM2 in microglial cells, and formation of newly active microglia. Also importantly, we can compare to a standard anti-TREM2 antibody shown here in purple on the left-hand side as well as on the right-hand side. What we can see is that doses as low as 3 mg per kg can be 2x more potent than a 30 mg per kg dose of an anti-TREM2 antibody. Therefore, we expect that low doses will be required.
Only low doses will be required to basically have the desired effect on microglial cells. Importantly, we've filed an IND on this program. We'll begin the clinical studies the H1 of this year, and we expect to have biomarker data by the H2 of 2022, essentially validating the antibody transport vehicle, so the next molecule to enter the clinic using our transport vehicle technology. We've taken this now additional step and are applying this transport vehicle technology to HER2 to treat both peripheral tumors as well as CNS metastases. The reason we decided to take this approach is basically to show the modularity of the transport vehicle technology. In fact, we can create bispecific molecules that are highly potent.
Similarly to what I show with TREM2, where we have very, robust potency, what we notice is when we combine HER2 with TFR, we have a robust tumor-killing effect, which is more than the standard of care when you combine these two molecules. Importantly, we've now created a bispecific that brings both of these arms together, and what we see is just after a single dose, a robust sustained effect in inhibiting tumor growth as compared to not having the TFR binding site. In addition to this, we also see brain uptake, as shown on the graph on the right-hand side. Our goal here is basically to advance this program to treat both peripheral as well as central, tumors with ATV, technology.
We're at the stage now where we have GLP manufacturing ongoing, and then we have a planned IND for 2023 with this program. I'll now turn our attention to the transport vehicle and utilizing it for other proteins, and specifically for progranulin. This is an additional program that we've now filed as CTA and will be entering the clinic this year. We published a paper in September highlighting the role of progranulin in the lysosome and also the utilization of the protein transport vehicle to get progranulin across the blood-brain barrier. Our goal here is basically to restore progranulin levels, which are deficient in FTD granulin mutation carriers. The data I'm showing you here can be packaged into two groups. The top graphs basically highlight the rescue of lysosomal function, looking at various lysosomal biomarkers.
The bottom graphs highlight neuronal and glial biomarkers that are rescued with dosing with PTV progranulin. We're gonna begin clinical studies this year. As mentioned, we have now filed the CTA at the end of 2021 and look forward to generating data and validating this approach to treat FTD-GRN. I'll now focus on the last of the modalities, the OTV or oligonucleotide transport vehicle. I highlight that the majority of ASOs that are being developed for CNS diseases or are currently being marketed for CNS diseases are delivered directly to the brain through intrathecal delivery. Highlighted on the left-hand side is a diagram of injection in the lumbar region with an ASO, and what would be expected is the biodistribution throughout the central nervous system.
Our approach is to take an ASO using the transport vehicle technology to cross blood vessels directly and look for essentially broad biodistribution and uptake, including in deep brain regions. I'd like to highlight now for the first time data generated in non-human primates comparing intrathecal delivery of ASO to the OTV, the oligo transport vehicle ASO. What you see in the center of this slide is basically a hemibrain coronal section, so half of a monkey brain, dosed either with intrathecal delivery or intravenous ATV ASO. What you notice basically is with ASO delivered intrathecally, you get basically staining on the outside region of the brain, which is adjacent to the cerebrospinal fluid where the ASO would be distributed. However, you do not see deeper brain staining throughout any region of the brain, including the cortex.
On the right-hand side, when using OTV to deliver ASO, what we're seeing is broad biodistribution throughout the central nervous system and uptake across the various cells. In other words, OTV given systemically in non-human primates shows this broad distribution in cellular uptake. Importantly, this distribution correlates with robust knockdown. After actually just a single dose of OTV ASO, we're seeing greater than 50% knockdown in the frontal cortex. This is illustrated on the left-hand graph, the graph on the left-hand side. We took this one step further and asked, "What about the various cell types in which we can knock down gene expression using the OTV?" Here we went back to the mouse model, injected mice, harvested brains, and looked across the various cell types. What you can see is knockdown across neurons in all the various glial cell types between 50% and 80%.
This now validates the OTV as a potential platform to bring ASOs across the blood-brain barrier. Importantly, the OTV is designed to have superior biodistribution, superior knockdown, and importantly, IV dosing. What's shown on the right-hand side are the number of targets one could imagine going after. We have selected two targets to rapidly advance to the clinic with a number of targets, following thereafter. These targets include broad CNS diseases as well as diseases where we can have faster clinical proof of concept. Taken in totality, when we look at the TV platform and the value creation of this platform, what we can highlight is that we've now generated clinical data with the transport vehicle delivering an enzyme across the blood-brain barrier. Our next clinical data will be with an antibody transport vehicle and thereafter with a protein transport vehicle for progranulin.
We see a number of opportunities with the ETV and utilize this initial data with ETV:IDS to essentially validate the transport vehicle and the robustness of transport across the blood-brain barrier. Importantly, these opportunities extend beyond neurodegeneration, and I've shared data with you in oncology using ATV for an ATV:HER2 bispecific molecule. I'll now turn my attention to the small molecule programs that we have. Similarly to our biotherapeutics, the blood-brain barrier represents a challenge to get small molecules into the brain. We've taken a rigorous approach to design each of our small molecules to have the appropriate properties, to have robust blood-brain barrier crossing, as well as establishing a one-to-one ratio in brain versus blood. On the right-hand side is just an example of polar surface area versus molecular size, and these are three of our clinical stage programs that I'll highlight today.
DNL151 for LRRK2, DNL343 for eIF2B, and DNL788 for RIPK1. Let's start first with our LRRK2 program. As a reminder, LRRK2 mutations result in hyperactivation of the kinase. Our approach has been to develop kinase inhibitors that readily cross the blood-brain barrier, inhibiting LRRK2. LRRK2 activation is established as well, not only in familial PD, but also in sporadic Parkinson's disease. We have now designed two studies with our collaborators at Biogen, the LUMA study, which is a phase IIb study in idiopathic Parkinson's disease, treating over 640 patients, and is outlined on the left-hand side. We'll be using UPDRS for the primary endpoint for both the LUMA study as well as the LIGHTHOUSE study. On the right-hand side is the LIGHTHOUSE study, which focuses on the LRRK2 positive carriers.
I want to highlight that in 2021, we generated the data for DNL151, which is on the left-hand side, showing a robust inhibition of LRRK2 when given systemically. We're at the point now where we've began startup activities and finalized the protocols and are initiating these clinical trials here in 2022. I'll now turn our attention to DNL343. We've recently presented on this data. We had a webcast focused specifically on the integrated stress response on ALS as well as FTD, but focusing in on DNL343. The molecular mechanism of this molecule is basically activating eIF2B, which basically inhibits the integrated stress response. Highlighted here is a simple assay in which we put cells in a stressed environment.
We see that they form what are known as RNA stress granules, and these RNA stress granules colocalize with markers of neurodegeneration, such as TDP-43. In ALS, there are a number of mutations that are in this ISR pathway, specifically related to TAR DNA-binding proteins or these RNA stress granules. What you can see is if we add DNL343 to preformed stress granules, we can dissolve these stress granules. The marker that we're using here, of course, is TDP-43, which is relevant in ALS and other neurodegenerative diseases. Importantly, DNL343 has the ability to reverse these preformed stress granules, and we are now developing this molecule in ALS, as well as potential for other neurodegenerative diseases. On the left-hand side is data that we recently generated in humans showing that we can robustly inhibit the integrated stress response with DNL343.
First, let me focus in on the single dose. What you can see is a dose-dependent reduction in the ISR. The way that this assay is run is we dose healthy volunteers, we take blood, and we initiate the ISR pathway, and we can basically see what levels of inhibition that we achieve. On the right-hand side or the middle graph is basically multi-dose data with DNL343, and what you can see is a sustained reduction of the integrated stress response. We have now initiated a phase I-B study, and we expect to generate data in mid-2022 from the study in ALS patients. We'll be evaluating PK/PD at both high and low doses of DNL343. Importantly, we'll be focusing in on biomarkers of the integrated stress response.
We expect to be able to make a decision to go to late-stage clinical development based on this 28-day data, and the study will continue in an open label safety extension. On ALS, I will now talk about our RIP kinase program, which is in collaboration with Sanofi. This program is designed to target the TNF receptor one pathway, actually specifically TNF receptor one. RIPK inhibition allows this selective inhibition of TNF receptor one, and as a result, has broad potential in inflammatory diseases. Importantly, focused on the right-hand side, Sanofi has taken the lead on developing a peripherally restricted RIPK inhibitor in peripheral inflammatory diseases. There's an ongoing phase II study in cutaneous lupus, as well as plans to initiate a phase II study in ulcerative colitis. In the center is our DNL788 program or 820, the Sanofi number.
This is the brain penetrant RIPK inhibitor. We've shown robust target engagement with this compound and will be initiating a phase II study in ALS, which will have approximately 260 patients. There are also plans to advance this molecule in MS, and we're exploring the potential of RIP kinase in Alzheimer's disease as well. Let me summarize the outlook for 2022, which we believe will be a high impact year. First, we will see a number of high impact data readouts. The first will be a number of clinical data coming from the transport vehicle programs. First, DNL310 and Hunter syndrome will present data at WORLDSymposium in February. In addition, ATV-TREM2, in which we'll have the first data with the antibody transport vehicle validating this approach for antibodies. We also will have our first data in ALS for eIF2B.
Importantly, I've just shared data on the OTV in non-human primates, and we expect to rapidly advance the OTV towards the clinic. In addition to this, we are building towards commercialization. We have startup activities underway for a number of late-stage studies in which we've finalized those protocols and we're advancing those studies. We're also building commercial capabilities as well as clinical manufacturing capabilities. Our clinical trial protocols are designed to allow for potential for early filing, obviously. In addition to that transition from the clinic to ultimately marketing our medicines will be key. We also are grateful for the partnerships that we have, and I just wanna highlight that Takeda, of course, has now opted in to two TV-enabled programs.
Sanofi continues to explore RIPK across multiple indications, and we're working closely with Biogen on the execution of our LRRK2 late-stage programs where they lead operationalization. We have a potential for over $100 million in cash income or milestones from these existing partnerships in 2022. I think importantly for Denali, we are now building a global organization because many of our trials, both in the U.S. and also in Europe. We have a stage build-out of a comprehensive global clinical development team, as well as commercial and clinical manufacturing. You can see basically that each of the therapeutic areas we're going after have multiple drug candidates, which are now in clinical testing in the Denali portfolio.
With this, I wanna thank especially everyone at Denali who have worked on these molecules, but especially the patients who are on our clinical trials, their families. It's been an extraordinary year, 2021, and we very much look forward to 2022. With that, you know, Jess, we look forward to answering all your questions.
Great. Thanks, Ryan, for the presentation, and we'll let your colleagues join in here for a second. It looks like we're getting a bunch of questions in on the portal, so thanks, guys, for asking questions. We'll start with some coming in here. The Phase II/III study for DNL310, will this be in both, neuronopathic and non-neuronopathic patients?
Great. Carole, I'll hand that to you. Maybe just a quick introduction. I have Carole Ho, our Chief Medical Officer, Steve Krognes, our CFO, and Alex Schuth, our Chief Operating Officer. Go ahead, Carole.
Thanks for the question, Jess. Just to remind everyone, our goal for our DNL310 therapy is for it to replace standard of care therapy and address both the peripheral and central manifestations of disease. This study will include both neuronopathic and non-neuronopathic patients. We will provide more details on the study design at the upcoming WORLDSymposium.
Great. Let's see, there's a bunch here. For the first trial of DNL919, the TREM2 product starting this year, will you enroll healthy volunteers, or will that be in patients with Alzheimer's disease?
Yeah. Carole, I'll hand it to you.
Yeah. That will be a healthy volunteer study where we're able to demonstrate a biomarker proof of concept in that study.
Yeah. I think I'll just comment that we've rapidly transitioned to Alzheimer's patients as well, right? The great thing about the TREM2 pathway is that we have biomarkers that are relevant in healthy volunteers. What we've noticed is that these changes in microglia and the associated biomarkers, it doesn't matter disease state. We actually see it both in healthy animals as well as diseased animals or Alzheimer's models as well as non-human primates.
Okay. I guess thinking ahead to that biomarker data, what magnitude of effect on CSF1R is associated with a beneficial impact on the TREM2 pathway?
Yeah. I'll maybe take that initially, and then Carole, you can answer that as well. In the data that we shared showed a clear dose relationship between microglia number and CSF1R, which is, I guess, somewhat been debated in the field. For us, basically that you know, anything, you know, just a modest increase actually is a relationship to a pretty robust effect on microglia and new microglia formation. We haven't set the bar, but you can see the data, you can sort of draw the curve, and you can see the impact that you have both on microglia and associated changes in CSF1R. What's really important is that we see this at very low doses.
For example, a 30 mg per kg of an anti-TREM2 antibody has, you know, maybe 20% effect or 10% effect on increase in this. We see that at 1 mg per kg. At 3 mg per kg we have double that effect. Then we kinda hit this ceiling where you've essentially maximized the effect on microglia. For us, we hit that ceiling pretty rapidly.
Okay. Maybe sticking with the FTD products, but shifting to progranulin, when can we see data for that product, and what endpoints will you be evaluating in the first study?
Yeah. I'll hand that to Carole.
For the progranulin program, that's a little bit more challenging in the FTD population and specifically the granulin population. Just regarding timing, we haven't given specifics around that. We will be looking at biomarkers, including looking at obviously progranulin levels, but then also biomarkers looking at lysosomal function.
Number of questions on LRRK2 and the upcoming trials here. How long do you expect it'll take to enroll 400 LRRK2 mutant Parkinson's patients in the LIGHTHOUSE study?
Yeah. As you know, we've had an ongoing collaboration with Centogene for more than a couple of years, and we've already screened more than 10,000 patients as of May 2021. We are continuing to extend that collaboration. We're well on our way to identifying those patients. But as noted, this is a rare population in the sense that it's about 3% of all Parkinson's disease patients. It's certainly challenging. In terms of the design of the study, we are enrolling patients that are both on standard of care therapy as well as treatment-naive, which expands the number of patients that we can enroll into that study. That differs from the patient population in the phase IIb idiopathic patient population, where we're primarily enrolling treatment-naive patients.
Why are the treatment periods different between those two studies?
That's exactly because of the patient population that I just described. In the LRRK2 mutation population, we are expanding the inclusion criteria to include people that have later stages of disease. I think there are two reasons for that. One is, you know, it certainly helps with enrollment, but the second is that we think those patients are the most likely to respond, and the magnitude of response may be better. It allows us to study this in a slightly broader population of LRRK2 carriers. As you know, the disease course in LRRK2 mutation carrier is very much phenocopies the disease course in idiopathic Parkinson's disease. Here, given that we think that the magnitude of response may be better, we are studying more patients on standard of care.
When you say that the LUMA trial is a phase IIb that could support registration, is there a requirement in sporadic Parkinson's for two large controlled trials? If so, when would a second study in that patient population start?
Yeah. In the past, there has been a requirement for two studies to support registration. I think this is a unique program in that we have two different populations that are all Parkinson's disease and have very similar clinical characteristics. I think that is a topic that we'll continue to discuss with regulators over the course of our global development plan across both indications.
Is there any projection for the timing for data from either of those studies?
Given that this is partnered with Biogen and they're responsible for the operational execution, we don't have any specific timeline guidance at this time.
I think the key here, Jess, is it all comes down to enrollment. I think historically, you know, Biogen's done a fantastic job enrolling their Parkinson's studies. It was part of the reason we selected them as a partner. And also our investment with Centogene, as Carole already highlighted, to identify LRRK2 carriers. The key here is just the momentum around enrollment, which will really drive timelines.
Question on the primate ASO data you showed. What ASO was used in that study?
Yeah. This is a MALAT1 ASO, which is basically an ASO as a gene reporter. It's often used across all ASO studies as sort of validation of mechanism, in part because MALAT1 is expressed in every cell. You can sort of do the relationship between ASO and knockdown of gene expression looking across cell types. It's a reporter gene. We have data, of course, on some of our targets, but we're not at a point now where we will disclose what those targets are. Through our partnership with Secarna, we have now generated ASOs against the various drug targets.
For the ETV product for Sanfilippo A, what work needs to happen between now and the H1 of 2023 to file that IND?
I think it's very standard. It's all about basically IND-enabling studies and writing the reports and then filing the IND. It's the typical timeline of once the cell line is generated, basically now producing the material and running the IND-enabling studies.
Let's see. Other questions coming in here. ALS appears to be a very hard to treat disease. What is special about eIF2B that gives you confidence that it could tackle ALS from this new angle?
Yeah. I'll hand it to Carole, and then maybe I'll supplement.
I think that we start again with our principles and going back to genetic rationale and the eIF2B pathway and the integrated stress response pathway has been linked to stress granule formation, which is really a pathologic feature of ALS. Based on that, you know, we think that the rationale is very strong. Now, of course, you know, there are always challenges in drug development across neurodegenerative indications. I think in ALS we have seen, you know, really, I think a lot of involvement with regulators in understanding the unmet medical need and demonstrating some flexibility across other programs, including Edaravone and now Amylyx. I think we feel like the environment is certainly very supportive of development of therapeutics for this very high unmet medical need.
I think I'll just add to Carole's point that what's unique about eIF2B is the pathway that it's targeting is highly implicated in ALS. I think the other point is there's a direct genetic link to a disease known as vanishing white matter disease. Which has, of course, CNS effects. Our conclusion is basically eIF2B will rescue the ISR pathway in ALS, where greater than 50% of the genes sort of implicate basically these RNA stress granules. Allows us for a very high probability of basically reversing these stress granules and having relevance. I think 95% of ALS patients have TDP-43 inclusions. In fact, the only patients that don't that we're aware of are the SOD1 mutation carriers.
Okay. On business development, as your platform really shows promise, from enzymes to antibodies and proteins and ASOs, in addition to small molecules, would you consider spinning out one or even a couple of those franchises as individual companies?
I'm gonna hand this to Alex.
Yeah. Thanks, Jess. So we are indeed very excited about the potential of the TV platform. The promise here is, of course, that it can open up the brain for large molecule therapy. As we're seeing it further validated, first with ETV:IDS and now with another two additional programs going into the clinic, we do want to capture the full potential. We are looking at the full range of options here. Sort of what is more in focus immediately are areas that are not directly related to our core activities. Ryan highlighted one slide on the oncology programs, where very interestingly, we see not only do we get more drug into the brain, but TFR actually leads to an added antitumor activity through higher avidity on tumors. So that is one area where we're actively looking at potential options.
Another area is the OTV. Very excited here. In some way, OTV is a very rich target space. We have a collaboration with Secarna, where we're going after a number of programs ourselves. It may also be an opportunity to work together with partners on early-stage discovery programs. Yes, lots of ideas and lots of possibilities going forward.
Great. Maybe coming back around to DNL310, can you give us a bit of a framework for what we can expect to see in the update coming up at the WORLDSymposium?
Carole.
Yeah, sure. You know, I think just to go back to what we think are the very important biomarker data and safety data that supports further progression of this molecule into phase II/III in the H1 of this year, it really comes down to sustained reduction in heparan sulfate. Our goal is normalization, so going beyond lowering it to non-neuropathic levels, but actually lowering it to normal levels. We'll be sharing longer-term data on cohort A with more than a year of safety data and also more than six months of safety data in cohort B, as well as data on the reduction in CSF heparan sulfate and dermatan sulfate and lysosomal biomarkers.
In addition to that, we'll be adding to the clinical data that we presented previously, in the fall, which was six months of cohort A data to now include six months of cohort A and B data, which is about 17 patients.
I think the press release mentioned that we would get six-month data on clinical endpoints like CGI. Have we not hit 12 months of follow-up for the cohort A patients to be able to see slightly longer clinical measures for them?
Yeah. We have gone past 12 months of data now, as mentioned, with regard to safety data, but given it's very limited numbers, it's five patients, we think it's much more informative to provide that data when we have a critical mass of data. We'll be releasing that data when we reach the one-year time point across cohorts A and B.
You talked about normalizing heparan sulfate. I guess, as we think about longer follow-up with these patients, do they kind of reach a bottom and then stabilize, or is there any potential for continued declines?
Well, what we're seeing is very quickly. In fact, in most of the patients, except for two, the first time we looked at the data, you know, at four to seven weeks, we already see normalization. What we've seen so far that we've presented is sustained normalization. I think just in terms of what does it mean if you lower GAG levels below normal levels, I mean, I don't know really what physiologically that may mean. I would say overall, at least what we've shared so far, is that there is a stabilization in that normal range. I think that's a really important point because we do believe that to maximize efficacy in patients and really address this disease in the CNS, we want the goal of normalizing, not just lowering, levels to non-neuropathic or attenuated levels.
You'll note that if you look at the data, there's actually quite a bit of overlap in the levels of heparan sulfate and dermatan sulfate across neuropathic and non-neuropathic patients. In other words, there are some non-neuropathic patients that have higher levels that are in the neuropathic range and vice versa. To our view, you really need to normalize to maximize the benefit. I think the data that you'll see at WORLDSymposium also provides that continued data that demonstrates that also the safety profile supports the dose levels that we're using that enable us to have this sustained reduction to normal levels of GAGs.
I think I'll just add that normal seems to be the floor. If you actually look at the way this study's designed, we've looked at 3, 7.5, 15, and 30 mg per kg. All the patients in the 3 mg per kg normalized at the first time we viewed, except for one, which had, you know, high levels of anti-drug antibodies. As we increase dose, you know, up to 15 or 30, you don't go any further than normal levels. It seems that there's a physiological limitation to the amount you can reduce. I think that's probably 'cause there's other enzymes that are regulating heparan sulfate levels, as we know.
Okay, great. We are out of time. Thank you for the presentation and the thoughtful Q&A, and thanks everyone for listening in.
Yeah. Thanks, Jess.
Thanks, Jess.