Great. Good morning, everyone. My name is Jess Fye, Senior Biotech Analyst at J.P. Morgan, and we're continuing the conference this morning with Denali. I'm joined on stage by the company's CEO, Ryan Watts, and after the presentation, we're going to go right into Q&A. If you're in the room and you want to ask a question, just raise your hand, someone will bring you a microphone, or you can use the portal to send me questions up here. So with that, let me pass it over to Ryan.
Great. Thank you, Jess. Great to be back at J.P. Morgan. Great to see many of you, friends and colleagues over the years, and very excited to present our update for 2024 and talk a little bit about what's happened in the last year and set the stage for the company going forward. So let me begin by saying that as we founded Denali, our primary purpose that we set out to after was to defeat degeneration and to focus on some of the broader degenerative diseases like Alzheimer's and Parkinson's. But you'll recall, you know, 8 or 9 years ago, it was a very difficult time in this space, and yet so much has changed in the last 2-3 years, especially in the Alzheimer's space and ALS space.
So we're very excited about the progress being made in the field. We're also excited about leading the way in crossing the blood-brain barrier. But we started with focused on lysosomal storage diseases, our first area, in part because we believe it was biologically tractable, and what we needed to prove is that we could cross the blood-brain barrier with a new technology. And I'd have to say that the last year, the data has really shown that indeed we can cross the blood-brain barrier and rescue cellular deficits and ultimately halt neurodegeneration. And so we're looking forward to the progress of that part of the portfolio, but then getting back in a serious way into focusing on Alzheimer's and, and Parkinson's disease. So the company has evolved rapidly from discovering platforms and molecules to now a very robust development portfolio.
We have seven clinical stage programs, four of which they're in late stage development, having major readouts, you know, even beginning the first half of this year. So we've transitioned from discovery to development, and now we're preparing for our first commercial launches with really a commercial team focused on MPS, the lysosomal storage disease, but also ALS and other indications. We built the company around genetics, getting medicines across the blood-brain barrier and biomarkers. And what's evolved is a transition from what we've called genetic pathway potential to genetic pathway realization. Genetics is, in fact, leading to new medicines that are truly disease-modifying. And from a brain delivery perspective, we wanted to cross the blood-brain barrier, we want to engineer brain delivery, and now we're seeing validation of that technology, and I'll get into some extensive details on the platform.
Then ultimately, what we'd love to see is biomarker-driven, not just development, but now approval. Can we use biomarkers as a way to get approval for some of our medicines? And here again, we have to lay the foundation, especially in rare disease, using some of the biomarkers that we've looked at for the first time, such as neurofilament, which is well known in the neurodegeneration space, but not so much in rare diseases such as lysosomal storage disease. And so here we have to blaze the trail using biomarkers, hopefully to drive approval of our medicines with ultimately relating to clinical benefit. Here is our portfolio, and rather than go through details in our portfolio, this is, I'd like to actually focus on the portfolio as what we call Peak One and Peak Two.
The reason for that is that Peak One is the current clinical stage portfolio, and it consists of both small molecules and large molecules, as I mentioned before, four of which are in late-stage development. You can see them here. It also spans disease areas from rare disease to more common diseases such as Parkinson's disease. What I'd like to highlight today is that we've now initiated our second enzyme replacement therapy for Sanfilippo, DNL126, which we put in Peak One, and that's part of the enzyme franchise. I'll spend a little bit of time talking about the enzyme data today, but talk at the end about Peak Two, which is the next set of molecules that are going into the clinic. And as you can see here, they're now focused on Alzheimer's and Parkinson's more broadly, using our transport vehicle-enabled technology.
I think importantly, what you will note is a transition from some small molecules in the early days to now entirely the TV-enabled portfolio. This evolution of our TV-enabled programs has allowed us to focus on blood-brain barrier technologies. But there are multiple modalities in the transport vehicle, including ASOs, enzymes, as well as the sort of traditional antibodies. Let's start first with the transport vehicle technology, and if you've been to our presentations before, you know this technology, but I'd like to introduce some new ideas and actually a new target that we've recently published on using this technology to get large molecules across the blood-brain barrier.
Here's a bit of the history for us, and it started with several publications prior to founding Denali, laying the foundation of what of how to get molecules across the blood-brain barrier. But beginning in 2020, we published our first work on the invention of the transport vehicle technology, and drawn in these images, the little orange piece is a piece that binds to transferrin receptor. I'll talk a little bit more about transferrin receptor in a moment. So in a back-to-back publication, we showed that we could engineer transferrin receptor binding into the Fc region of an IgG, and that we could get enzymes across the blood-brain barrier. A year later, we presented data on a protein, progranulin, and then we, a year after that, showed basically differentiation with other technologies in the space in particular.
Then more recently, we've shown that we can get antisense oligos across the blood-brain barrier with what we call the oligo transport vehicle or OTV. You can see that it's not a single modality, but it's enabled by a technology crossing the blood-brain barrier. You can see on the right-hand side, you know, a number of patents and paper publications, but we're now at the point where we are basically showing clinical validation of this technology.... Let me highlight here an example of clinical validation. This is data from our Hunter program, and we'll talk a little bit more about the path forward for Hunter, but I'm using this to illustrate the power of the transport vehicle technology. These are three separate groups of data. The first is substrate correction.
This is the primary substrate for the enzyme, getting across the blood-brain barrier. What you'll note is that we get a very rapid normalization of this substrate as measured in CSF, which we know correlates one-to-one with brain concentrations. After we correct the substrate, we're then seeing correction of cellular deficits as measured by markers of lysosomal damage, such as GM2, GM3, and glucosylsphingosine. Out to now 104 weeks, we're seeing normalization of these biomarkers as well. I think importantly, in 2023, we showed for the first time that from proximal to distal, we're now seeing a reduction in NfL. I wanna remind you of one important note about this study. It's a broad study. It is enrolled patients ages 2 to 18, and even patients who are older are seeing a reduction in NfL.
In other words, they have neurodegeneration for many years, and when we correct substrate and cellular deficits, we also see now this reduction in a marker of neurodegeneration, neurofilament light chain. So we believe this is critical in validating the TV technology. Also, many of these patients have been on drug for a very long period of time, over two years, given weekly IV infusions. So in addition to using transferrin receptor, which is the original, blood-brain barrier receptor that we focused on to get molecules across the blood-brain barrier, we recently published on a new BBB target, CD98 heavy chain, and this was published in Nature Communications in the middle of last year. We haven't talked much about it, but I'm just gonna share a little bit of insight.
I think the most important point here is that we continue to invent on the BBB platforms. Our goal is to be the leader in blood-brain barrier crossing and transferrin receptor. Now, with clinical validation, what is the next wave of BBB approaches for crossing the blood-brain barrier and getting medicines into the brain? So let me just highlight here with one example of data. What you're looking at is a control antibody versus an ATV with transferrin receptor and an ATV with CD98 heavy chain. These are whole mount images of mouse brain with where we use tissue clearing and image throughout the entire brain. On the left-hand side, this control antibody, you can see a lot of perivascular staining, and then both with transferrin receptor and CD98, is this broad distribution.
I think importantly, when you actually see it in three dimensions, you get an appreciation that a lot of the antibody aggregates in vessels for standard antibody. I think this is a challenge for, for example, the anti-amyloid therapies, this vascular localization. When you look at cross-sections now through the entire brain, what you'll see with transferrin receptor and CD98 is this broad distribution. However, uniquely with transferrin receptor, you see a lot of cellular profiles. So one of the things that is differentiated between TfR and CD98 is that TfR drives cellular internalization. So you get this high concentration in brain, and then the molecule is taken into the cell, which is ideal for enzymes and ASOs and many targets that need to brought, be brought into the lysosome, and then, and, in the case of ASO, get through the cytoplasm and into the nucleus.
CD98, on the other hand, antibody accumulates, doesn't get internalized, and we believe will open up a new target space using this technology. So here is our clinical portfolio, as well as our preclinical portfolio using the TV technology. So, as mentioned before, we'll begin dosing very soon for ETV SGSH and Sanfilippo. ETV IDS is in phase III, PTV progranulin for FTD, FTD-GRN being tested in FTD. And then we announced yesterday that SNCA, which codes for synuclein or alpha-synuclein, and MAPT, which codes for tau, are now IND-enabling programs. And these are basically antisense oligos that can get across the blood-brain barrier, given systemically and knock down gene expression evenly throughout the brain, as well as anti-Abeta entering IND-enabling studies.
So I'll now talk about Peak 1, which are the clinical stage program, and Peak 2, which are the next stage of molecules that will be entering the clinic. So these are the four late-stage programs that I'll talk about today. In fact, I'll focus on the Denali-led programs, both COMPASS and HEALEY for today's presentation, starting first with the COMPASS study. Just a reminder, for each one of these, COMPASS is basically our DNL310 program, which is an enzyme engineered, again, to cross the blood-brain barrier. I showed some of that data already in Hunter syndrome. The HEALEY platform study is testing DNL343, which is an eIF2B activator, and then HIMALAYA is testing a blood-brain barrier-penetrant RIP kinase inhibitor, and the LUMA study being led by Biogen.
By the way, HIMALAYA being led by Sanofi, and the LUMA study being led by Biogen, is testing a LRRK2 inhibitor for Parkinson's disease. So let's start with the enzyme transport vehicle franchise, and in particular, the idea of correcting enzyme deficits in the brain and in the body. And I think it's important to know that these medicines are delivered IV and treat both body and brain. So not only are we looking for differentiation on CNS endpoints, but we wanna maintain or even improve the somatic manifestation of the disease. Lysosomal storage diseases represent about 30,000 patients. We believe this is a relatively large franchise. There are a number, about a dozen of approved enzyme replacement therapies. And actually, very interestingly, unlike other areas of drug development, the success rate is roughly 90% on developing enzyme replacement therapies.
Obviously, our goal is to replace the ERT space with blood-brain barrier crossing ERTs. The goal here is, again, basically IV delivery, replacing the standard of care with an enzyme that's engineered across the blood-brain barrier. You can see here a number of programs, and right now I'll focus on MPS II, Hunter syndrome, but we have our next molecule now entering the clinic, and we actually plan to have data this year in Sanfilippo with that particular molecule. Again, an enzyme engineered across the blood-brain barrier. So what I want to highlight here is not the data on the top, which I already shared with you, which was normalization of CSF heparan sulfate and robust reduction in serum NfL. But what I want to focus on is both improvement in hearing and improvement in adaptive behavior.
But also remind you that this patient population spans a very broad age range from 2 to 12 at beginning of dosing. That being said, across age ranges, we're seeing improvement, not just in biomarkers, we're all normalized for heparan sulfate, and we see a robust reduction in NfL, but we're also seeing improvement in hearing and adaptive behavior across this age range. That being said, if you look at the totality of this development program, it's large. It's probably one of the larger development programs in Hunter syndrome. We have over 40 participants in our global phase I/II study, the data of which continues to mature. And also just point out that we plan to present additional data at WORLDSymposium in February with that ongoing phase I/II.
We plan to complete enrollment of our COMPASS study this year, and that's basically a phase III study looking at an active comparator, so head-to-head. There are two cohorts, cohort A and B. A is focused on a neuronopathic Hunter syndrome. And then in terms of the regulatory path and target indication, it's all about, you know, treating both somatic and central nervous system disease in this population. And there's been a lot of discussion around an accelerated path in rare disease, and we continue to push and engage with regulators and collaborate with regulators to try to identify an accelerated path. However, our base case is to read out COMPASS and to file on the full data package. And so we basically are pursuing both in parallel and are prepared for either path, should they become available.
Now, shifting gears to our other wholly owned, late-stage clinical asset. This is an eIF2B activator. This is now a small molecule, not taking advantage of the TV technology. Basically, DNL343 is engineered to halt the integrated stress response by activating eIF2B and reinitiating translation. And we've shared data in the past looking at ALS patients, where we look at ATF4 and CHAC1, which are both biomarkers of the ISR pathway, and show that we can robustly inhibit the ISR pathway through activating eIF2B. This study, we also plan to complete enrollment this year. The HEALEY Platform Study includes 240 participants, and the primary endpoint here is ALSFRS at six months.
And so from a mechanism perspective, just want to highlight the idea is that we're dissolving RNA stress granules in TDP-43 aggregates, which are found in about 95% of ALS patients. So we're excited about this program as well. So now I want to end talking about Peak2 and the next set of molecules that will, will enter clinical studies using the transport vehicle technology. So I'll start with what I actually began with at the very beginning of the presentation, which is the evolution in Alzheimer's treatment and more common neurodegenerative diseases with the recent success of the anti-amyloid therapies. So we believe that these anti-amyloid therapies have set precedent that we can actually treat these common degenerative diseases by removing amyloid.
That being said, there's even some evidence that TfR-based technologies can more rapidly reduce amyloid, and the idea is what will be the best-in-class approach with that technology. So we see numerous opportunities, and on the bottom right-hand side, highlight some of our programs, the ATV: Abeta program, which is licensed to Biogen, and our own ATV MAPT and ATV TREM2 programs. So let's start with ATV: Abeta. We get a lot of questions around this particular program, especially with the recent advances in anti-amyloid therapies. And on the left-hand side, I just want to highlight that we've optimally engineered this antibody so that when it's bound to plaque, it can fully engage the immune system, microglial cells, and drive plaque elimination. However, when it's bound to transferrin receptor, we don't see this immune engagement.
This is actually a very important point, as we've learned over and over again, that immune activation with TfR can actually deplete reticulocytes, which ultimately leads to anemia. What you see in the center is, after a single dose, the difference of immunodecoration of plaque with a standard Aβ antibody versus an ATV-enabled antibody. You can see much more plaque immunodecoration with the ATV, and I'll show that in an image in the next slide. In addition to that, after just a single dose, you also see 2- to 3-fold better plaque reduction with ATV: Abeta compared to a standard Abeta antibody given at the same dose. And these are all, what we call mid-dose and, you know, very normal dose in a mouse model. So where does the antibody actually go?
This goes back to my 3D images that I showed before of standard antibody localizing around blood vessels versus ATV-enabled antibodies showing this broad distribution. On the left-hand side are actually arteries in this particular mouse brain. We're looking at dosing after 24 hours and saying, where does the standard Abeta antibody go versus one that's enabled with transferrin receptor? And what you can see is a lot of perivascular localization. In fact, it co-localizes often with alpha smooth muscle actin, which is where you have cerebral amyloid angiopathy. And we believe that this largely drives increased risk of ARIA that's driven by plaque removal from vessels. On the right-hand side is ATV: Abeta, and you can see very broad distribution.
And these are also 3D reconstructions, and if you fly through the brain, you can see that wherever the plaque is, you get very nice immunodecoration. However, with the standard antibody, it's around these larger vessels that you're seeing plaque immunodecoration. So in collaboration with Biogen, in fact, this is Biogen's study in Biogen's mouse model, which is a 5xFAD model that has a fair amount of cerebral amyloid angiopathy and also has ARIA-like imaging endpoints using MRI. We compared a standard antibody versus the ATV: Abeta antibody and asked, how many ARIA-like events do we observe across these animals? And what you can see is that with a standard Abeta antibody, given again at the mid dose, similar, the same dose that drove the plaque reduction in the previous slide, you can see that ten out of eleven animals developed these MRI hyperintensities.
However, only 1 out of 11 animals, given at the same dose with ATV: Abeta, remember, that has about twofold better plaque reduction, developed these hyperintensities via MRI. When we picked a dose that matched brain concentrations and plaque reduction in these animals, we see no animals with ARIA. So the thesis is that basically, if the antibody crosses capillaries and distributes directly to plaque, as opposed to localizing in vasculature, you have less risk of developing ARIA. This program is now in IND-enabling studies and is being led entirely by Biogen. So if you have questions around timing, you can ask Biogen. Now I'm gonna shift gears to the OTV platform of the oligo transport vehicle technology.
And here, it's interesting, when we first founded Denali, we thought that there would be a large number of attractive antibody targets, but actually, the most attractive target space are ways of modulating gene expression in brain. So basically, ASO or SI or RNAi is probably the most attractive target space in neuro. And we call this, you know, the wheel of opportunity. There are many various targets that we could go after, and there's been a lot of debate within Denali. We've selected five targets to begin with and essentially made very potent ASOs against all five of these targets, and then have recently announced the two lead programs. The difference between intrathecal delivery and using the TV-enabled platform is very significant, and I'll get into that in a moment.
But right now, approved therapies using ASOs are injected directly into brain. I think the key point is that they're suboptimal biodistribution using intrathecal versus a transport vehicle-enabled technology. So on the right-hand side is an IT delivery in a non-human primate, and what you can see is the spinal cord. These are all to scale, so spinal cord is very small. It's in the sort of bottom right-hand corner of that left-hand image. You can see that the spinal cord is very bright. That's ASO. We're using an antibody that recognizes ASO to look at its distribution. What you see in the brain, however, in these hemisections, is a halo effect, so basically staining the outside of the brain.
We've shown a version of this, but as we drill in, in more detail, you can see that there are very few cellular profiles that label just those that are adjacent to cerebrospinal fluid through this intrathecal delivery. Now, recall, this is a non-human primate. Human brain is about 18 times larger, and here you're relying on Brownian motion and diffusion for the ASO to get to its location, so it's even a bigger challenge as you go to larger animals. On the right-hand side is the OTV. This is now crossing capillaries. It's given IV, and you can see broad distribution throughout the CNS. And again, we've shared a version of this and the associated brain knockdown. What I'd like to comment on now is the lead programs. These are MAPT and SNCA.
So MAPT is the gene that codes for tau, and SNCA is the gene that codes for alpha-synuclein. And what we have here is an experiment in which we're taking lead sequences and injecting them directly into the brain to identify the in vivo ED50. How potent are these compounds? And, and you can see they're very potent, especially relative to what's known in the field, and then we can select a lead based on this effort. So we've now have leads for both MAPT and SNCA, and the next step is now adding it to the OTV platform. So on your left, you can see that the OTV, the very first experiment we did, taking these very potent leads, we saw a actually, in fact, a modest knockdown of MAPT. And the question is why?
We have potent leads, we have the OTV, and actually, I think that the real insight and invention is in further optimization through three principles: the TV protein itself, the linker, and then ultimately, the oligonucleotide. I won't say anything else about this because I think this is really where the, the invention happens to improve. And what you can see on the right-hand side are versions, basically, of the same sequence, where we've optimized those three principles, and now you can achieve upwards of, you know, 70%-75% reduction in gene expression. So I think this is a key, enabling insight that is now, now we're in IND-enabling stage, using these insights, and inventions to knock down gene expression in the brain with systemic delivery, so no longer needing, intrathecal delivery. So now I'm gonna look ahead, and then we're, we'll take questions.
So in summary, our goal is to lead the blood-brain barrier engineering space, and so we're now fully focused on our TV technologies, and I've spent most of my time talking about transferrin receptor-enabled technologies, and then the next generation, CD98, transport vehicle. In terms of Peak Two, it's about commercial readiness for MPS II, and ALS as these programs advance and as we continue to explore a path to approval with the FDA. It's also about clinical execution in Parkinson's, FTD Granulin, and, and, and MPS IIIA, so our Sanfilippo program. In terms of Peak Two, I think the big transition for us is that we've built the enzyme franchise. Now we'd like to focus on solving Alzheimer's and Parkinson's with these technologies. And with that, we're well capitalized actually into 2027, and part of that is driven by our prioritization on the TV, TV platform.
I'd also just like to highlight that these are some of the major readouts, and I'm just gonna emphasize a few of them. So we'll have new data at WORLDSymposium coming in February. We plan to have our first data with DNL126, Sanfilippo later this year. We'll complete enrollment of COMPASS. I should have mentioned that at the very top, as well as complete enrollment in our DNL343 HEALEY program. And then on the right-hand side, in our partner-led programs, the most I think probably the most interesting milestone in terms of early this year will be the RIPK1 readout, which is the first half of the year in ALS, in the HIMALAYA trial. So with that, I just want to end and thank a few people.
So, obviously, everyone at Denali, who has been very involved in inventing these medicines, and also everyone who's on this slide. This is the first time we've actually used names on this slide. For example, Dominique, and his sister, Jasmine, who are Hunter patients, who we've got to know very well, and Seth, who is one of our patient fellows that have ALS. They're a big part of what we do at Denali, and in fact, the reason I love doing what we do. And I think with that, I'd like to thank everyone, and we'll go to questions.
Great. Thanks for the presentation. You mentioned that MAPT and SNCA are now in IND-enabling studies, I think, or about to. How should we think about the timelines for when we could see those enter the clinic?
Yeah. So I think for large molecules, your average timeline is about 18 months. It's a little bit more complicated with the ASO fusions, and you saw we spent the last year heavily engineering and optimizing this for the best-in-class. So I think we're on that sort of 18-month, 24-month time frame for IND filing. My answer, of course, to the team is as fast as possible, right? So manufacturing the GLP tox studies and then into the clinic.
Great. And you mentioned potentially sort of different uses or applications for the CD98 heavy chain technology. Can you talk a little bit more about, like, what those would be?
Yeah. So I think what's actually most interesting when comparing transferrin receptor and CD98 is the kinetics and the cellular localization. So TfR-enabled ATVs, you see this rapid maximum exposure and then this clearance, but the clearance is actually cellular uptake. It's being driven into cells, which is ideal for enzymes, ideal for ASOs. CD98 is actually very different, and in our paper, we described this. It accumulates over time. You still have a, a decent Cmax, but then it stays around. And what we notice is it's not driving internalization, so it's actually not ideal for enzymes, or antibodies. But what is great is that we can maintain full effector function. CD98 is not expressed in any cells, really, in the hematological system. We have no evidence of impact, for example, on reticulocytes, where there we carefully engineer and make our cells immune silent.
So you can imagine targets in which you want full immune function, CD98 may be ideal. So maybe, you know, some of the immune targets in neurological diseases, for example.
Got it. I think you also alluded to data coming this year in Sanfilippo. What do you wanna see in that first clinical data set?
Yeah, I'm gonna hand it to Carole for that, so...
Yeah, so the Sanfilippo program is our second enzyme transport vehicle platform that is going into the clinic, and this is in MPS III Sanfilippo patients. I think the data that Ryan presented really lays out the roadmap for how we are executing on development and the data we want to see. So similar to MPS II, the substrate that accumulates in that disease is heparan sulfate, and so we can look at CSF heparan sulfate as an early readout that we're getting to the right dose and that we can reduce the CSF HS. As you've noted, we have a very rigorous biomarker-driven development plan for 310 that we can replicate from 12 6, looking very carefully at not only substrate reduction, but also downstream biomarkers of effects on lysosomal function as well as on neuronal function.
Are there any kind of bogeys for what you want to see or benchmarks that you want to achieve on those biomarkers?
We haven't provided a benchmark per se, but I think from our experience with our 310 program, we are looking for substantial reduction in the CSF HS levels.
Yeah, I think I can, we can go back in time a little bit when that question was asked about the Hunter data. And, you know, the animal data suggested that we might achieve, you know, let's say, 60%-70% reduction, and what we observed was 90% reduction, actually normalization very rapidly. And part of that we've now learned from our other programs, progranulin and TREM2, clinical stage programs, that the capacity for transport in the human brain seems to be greater than the mouse brain. It's probably the vascular surface area. So in addition, what we really like to see is that the reduction in heparan sulfate, we believe, correlates with cellular rescue and ultimately halting neurodegeneration. And that's why investing in the Hunter program really basically lays the path for all these additional programs. We'd love to see biomarker-driven approval.
That's the ultimate goal, you know, working with the regulatory agencies, that the belief is that if you reduce heparan sulfate, that actually leads to clinical benefit. So we think the HS readout, which is gonna be the primary readout for this year, is, you know, basically understanding, do we give the right dose? Do we have a robust effect on heparan sulfate? But in terms of that percent reduction, we don't know. The animals underpredict what we've been seeing in the clinic for all three of our TV-enabled programs.
What about neurofilament? Do you look at neurofilament here? And-
Yeah.
How do you think about the time point?
Yeah.
Where you would expect to see benefit?
Yeah, we're not going to give guidance on timing for neurofilament, but I think as we showed with the DNL310 data, it does take time, which would make sense relative to substrate reduction, lysosomal correction. In the DNL310 study, we see after 24 weeks, the neurofilament starting to decrease with statistical significance at 61 weeks. And so, you know, it may be different for MPS IIIA, but we aren't giving guidance, but certainly we'll be looking at that. I think it's just also notable that neurofilament has not been a biomarker that has been utilized much in lysosomal storage disease, and there's very limited natural history data available. We really pioneered the field by generating natural history data in MPS II very early on in our development plan to understand the context of neurofilament in these patients.
It is increasingly, I think, gaining interest. Regulators have asked us to see that data, and we do see that this is a potential powerful biomarker in addition to CSF HS, which is the substrate that is most proximal to the disease and supporting evidence of clinical efficacy before seeing changes on clinical endpoints.
You mentioned another update on DNL310 coming at World. What should we expect to learn there?
Yeah, Carole.
Yeah, so we are presenting longer-term data, both biomarker as well as clinical endpoint data for our phase I/II open label extension study. I think very importantly, we want to share data on the safety profile and durability of the biomarker responses that we've seen to date. So we'll have more patients now out to two years, about 15 patients out to two years, and at this point, we have more than 25 patients that have been dosed for more than a year.
I think you're also completing enrollment in the COMPASS study this year, and the press release had what I thought was sort of interesting wording. Maybe it wasn't intentional, but it said something along the lines of, "Upon completion of the phase I/II, and together with data from COMPASS, the combined data package is intended to support registration." So I guess first, when is the phase I/II completing? And, were you referencing in combination with full data from COMPASS, or is it intentionally a little open-ended?
Yeah. So there's been a lot of excitement and continued enrollment. We're enrolling now in 34 sites, 13 countries, and so we expect to complete enrollment of COMPASS this year. That is the 54 patients. That is the pivotal design of the global study that's randomized to standard of care to support approval. In rare disease, it's not just the pivotal program, but also the longer-term data that we're generating in our early open-label study that will be used to support approval. So, the phase I/II study, there's an 18-month portion, but then there's an open-label portion of the study. We are continuing to generate data in the open-label portion of the study that would also be used to support approval.
I think the key of that point is the totality of the data, not the needed completion of the phase I/II. I mean, we have already a substantial amount of data from the phase I/II, and obviously, that's what's driving the regulatory interactions right now.
Yeah, the endpoint for the neuronopathic cohort for the COMPASS phase III study is a 96-week, so 2-year endpoint. In the phase I/II, we actually have patients now that have dosed even longer than 2 years, so that safety data is really important in supporting the total package for approval.
Is there any update on the potential for accelerated approval of DNL310 based on biomarker data?
Yeah. So we have fast-track status, which enables us to have frequent interactions with the FDA, and we've had very collaborative discussions. I would say broader there. In a more broad sense, there's actually a cross-industry effort to really understand all of the data that's been generated across programs, and we've been working very closely with Amicus and Ultragenyx to bring this data together. There's a workshop planned in February that will involve the FDA, that we plan to share more of this data on, these biomarkers to potentially support approval. But at this point, as Ryan noted, our base case is for COMPASS to read out because we have not gotten specific direction for the acceptability of a surrogate endpoint for approval.
For DNL788, the phase II MS trial, I think you mentioned completed enrollment, but it wasn't called out as a 2024 readout. Safe to think that we could see data from that study in 2025?
Go ahead, Carole.
Yeah. So we, Sanofi runs both of those, both the ALS study as well as the MS study, and so timing, they will give guidance on that. We've only given guidance on the ALS study, reading out in the first half of 2024.
I guess when we get that ALS data, do you see that having any read-across to MS?
That's a good question.
Yeah, I think that's a great question. I mean, I think, you know, broadly, RIPK1 and that mechanism could be of interest therapeutically for a broad number of indications. I would say that the read-through is probably fairly limited across diseases, and so that's why we are running, or Sanofi is running multiple indications. Certainly, if it's positive, we would increase our enthusiasm for other therapeutic areas, but I think that the mechanism and the biology is quite different across the therapeutic areas.
Okay.
I think the rationale in ALS is driven around specific interaction with optineurin and TBK1, and this sort of genetic and necroptotic pathway for RIPK1. MS is more broad. I mean, obviously, there's no question that immunology plays a major role. In this case, it's downstream of TNF receptor 1. So the mechanisms may be distinct, and, you know, so we're not certain around the biological read-through between the two programs.
Okay.
For DNL593, I think you put on voluntary pause. Were you surprised by those infusion reactions? And is there anything else you can kind of share with us about kind of the profile?
Yeah. So infusion-related reactions are not uncommon in large molecule therapeutics. In early development, we choose not to actually pre-medicate at all to understand fully the safety profile as we do dose escalation. We had a healthy volunteer portion of this study, part A, where we dosed 26 individuals. We did not see any IRRs. We saw these 2 IRRs, grade 2 and grade 3, and because of that, we're voluntarily pausing the study to amend the study to include standard pre-medications and other procedures to limit infusion-related reactions. There is still a lot of enthusiasm for the study, but it is a very challenging study to enroll. We have pre-screened now more than 200 patients to enroll 9 patients. We're gonna continue that effort, and we expect the study should resume after instituting the amendment.
I'll maybe just take a make a comment about the strategic approach on progranulin. You know, right now, there's one major competitor that will read out. I think their study completes the end of next year. It, I think, was a little bit surprising for us. It's much more rarer than we expected. Again, as Carole highlighted, we basically screened 200 patients to find nine. So in part, we want to be in a position based on that competitive readout to go forward with the right dose and the right dosing regimen. So we're. It's basically a program that's not fast-tracked, right? It's basically, let's get to the right point, and then we can have that data in time to decide if we go forward at that point.
So also, I'd put in that sort of rare bucket in peak one, as you know, probably a smaller commercial opportunity than maybe others have assumed.
Okay, great. I think that's all we've got time for. Thank you.
Yeah, thank you.
Great. Thank you.