Great. Good morning, everyone. Welcome. My name's Jess Fye. I'm a biotech analyst at J.P. Morgan, and we are continuing the 43rd Annual Healthcare Conference today with Denali. First, you're going to hear a presentation from the company, then we're going to go into some Q&A. If you want to ask a question in the room, raise your hand. Mike will come to you, or you can submit them to me, and I'll read them up here from the iPad. So with that, let me turn it over to the company's CEO, Ryan Watts.
It's great to be here again. Looking forward to sharing our progress over the last year and then focusing on what we plan to accomplish in 2025. Apologies for those who I can't see over there. It's sort of an odd room, but a great opportunity to give an update and talk about what's important to us. So Denali is focused on crossing barriers and defeating degeneration.
And I think I would say the last year or so has really been the beginning of the era of blood-brain barrier crossing technologies and really tissue-targeting technologies that allow us to get medicines into specific sites within the body and, in our case, also the brain. So I'll talk a little bit about the blood-brain barrier here just as an introduction. So the blood-brain barrier evolved in such a way to exclude most molecules.
In fact, molecules, in order to enter the central nervous system, need to be actively transported, such as iron or glucose or neutral amino acids. There's a lot of directed transport across this blood-brain barrier. As a result, most medicines don't readily access the brain. And therefore, we wanted to invent a technology that allowed us to get medicines broadly into the brain. What you're going to see today is, in almost a fortuitous way, these technologies also allow for better penetration throughout the body, often like muscle and bone, specifically when we're going after the transferrin receptor, which is our primary target for crossing the blood-brain barrier.
We see similar effects for CD98 and other blood-brain barrier targeting approaches, but this was ultimately the goal of Denali, was to invent a platform to get medicines, specifically biologics, into the brain. Now we are seeing that transition from rare diseases to more common diseases using this technology, and you'll see how that evolves throughout today's presentation, so what we've invented is called the Transport Vehicle technology, and this is basically a new class of therapeutics. It's an Fc fusion protein, and using this technology, we can get enzymes, oligonucleotides, and antibodies into the brain. In 2025, this will be a unique year for us. We're preparing for our first launch, our first filing, our first launch.
This will be the beginning of our enzyme franchise that we plan to build, and actually, today, I'm going to describe the expansion of that enzyme franchise, which we believe will be an important foundation for Denali, and then in addition to that, we're advancing more broadly the TV technologies, and I think very interested in solving diseases like Alzheimer's and Parkinson's.
There are many diseases in between those massive diseases and these monogenic diseases, such as lysosomal storage disease. We'll talk about a few of those today. What is the Transport Vehicle technology, and how do we invent it? We had the luxury, when we began working on the Transport Vehicle, that there had been some progress made on blood-brain barrier crossing technologies, but no actual clinical validation at that point in time.
We set out to invent a platform that was unique from what was in the field, and I'd call them the conventional Fab approaches or the conventional antibody approaches. This idea of using transferrin receptor or other blood-brain barrier receptors to get across the blood-brain barrier was not new. It was actually first proposed in the late 1980s.
And we had, again, this advantage of what had happened in the past, and we could invent a platform that was highly modular. So what we did is we engineered transferrin receptor binding into the Fc portion of an IgG. This is what we call the Transport Vehicle technology. This is now supported with a large number of patents, some, I think, very important publications around how the Transport Vehicle works, and now a number of clinical programs, including a lead program in which we'll be filing a BLA this year. I think importantly, it's around optimizing affinity, valency, effector function, and high fidelity to the natural protein itself. Integrating this binding site into the Fc allows us to use a really well-validated approach of Fc fusions as well as antibodies and other modalities. So it's highly modular. This is some of the data.
In fact, what I'm showing you is a piece of data from each of the franchises: antibody, oligo, and enzyme across multiple species, ultimately including human. So on the left-hand side, it's showing broad antibody distribution throughout a non-human primate brain compared to a control IgG. We also see this for our enzymes and oligonucleotides. In the center, I'll spend a little bit of time later on talking about our MAPT approach, which is the gene that codes for tau and how we have sustained knockdown of MAPT and a prolonged reduction in tau protein.
This is in a humanized version of the mouse model that expresses both human MAPT and the human transferrin receptor. And then ultimately, and I think very excitingly, we see correction of neurodegeneration in humans, and in this case, it's in Hunter syndrome. Again, I'll show a little bit more detailed data on this particular program. This is basically evidence around antibodies, oligonucleotides, and enzymes using the Transport Vehicle technology. I think very exciting the progress that we've made with tividenofusp alfa, or as we call it Tivi, on the path to approval here.
We see this as really a market-leading profile in terms of the ability to normalize heparan sulfate and NfL, which has not been observed with other approaches. We're on the path for accelerated approval, again, filing early this year, and we have an ongoing Phase III trial, the COMPASS trial. Last week, we received U.S. FDA breakthrough therapy designation for this particular program.
I think it's important, not only is this program very important as a flagship program, but it sets the foundation for the rest of our programs, including one of the quick followers here, DNL126 for Sanfilippo. We can apply the learnings. In this case, it's actually the same set of biomarkers, heparan sulfate, for example. At the end of last year, we had announced top-line data that we're able to achieve normalization in Sanfilippo as well.
Similar mechanisms, similar approaches is what we've observed in Hunter syndrome. I'd like to show you a bit of data from the Tivi program that I think is foundational to the Transport Vehicle technology. Let's start by introducing lysosomal storage diseases. These are basically single enzyme deficiencies, monogenic diseases. Roughly 30,000 people worldwide. There are many of them, probably about 70-plus lysosomal storage diseases.
And a significant number of patients have CNS manifestations, meaning that as heparan sulfate is elevated in the brain, there's dysfunction in the brain, but also in peripheral organs. So traditional enzyme replacement therapies treat, and I'd say somewhat partially treat the body, but do not cross the blood-brain barrier. What we've discovered in the last four years is that not only do we see improvement in brain exposure of our medicines, but we're seeing better results in the periphery as well.
So the goal is to treat both the brain as well as the body using the Transport Vehicle technology. And I'll give you examples of that. In fact, this will be the pattern for the programs I discuss going forward, not just the Tivi program for Hunter syndrome, but also in Pompe and in Gaucher. First, what we see here is the ability to achieve normalization for both heparan sulfate and neurofilament, a marker of neurodegeneration. And notably, when we look at the periphery, we also see the ability to achieve normalization in these patients. And what that tells you is that likely most patients are undertreated with the enzyme replacement therapies.
We see this in other endpoints as well in terms of potential benefit in the periphery. In addition, we see improvement in behavior and cognition in this Phase I, II trial and improvement in hearing as measured by auditory brainstem response. So this is foundational data for the Transport Vehicle technology, and we'd love to see our other programs mature with this type of data set. And I think importantly, a lot has changed in the last year.
In fact, I remember giving this presentation a year ago, and really our plan there is enroll COMPASS, read out the Phase III, and file for approval. But because of the efforts of many on our team and specifically our Chief Medical Officer, Carole Ho, we were able to engage with the FDA and importantly, with collaborators in the field, key opinion leaders, and patient families and patient advocates, and worked with the FDA and the Reagan-Udall Foundation.
This happened a month or two after last year's J.P. Morgan Healthcare Conference. And what we saw basically is a shift in the mindset that indeed heparan sulfate is likely predicting clinical benefit, as you can see in the data that we've presented here. This has now allowed us to pursue an accelerated approval for the Hunter program, and we expect the same for our Sanfilippo program.
Now we're preparing for launch. This is an exciting time. I'll just talk a little bit about the MPS II landscape. Specifically in the U.S., about 400- 500 patients, roughly 2,000 patients worldwide. There are 80- 100 centers of excellence. We have engagement with all of these centers through our MSLs. There are some key centers that are very involved in our clinical trials that will be important as we imagine delivering this medicine to patients. I think importantly, we're building the right-sized team for the commercial launch.
The way we think about this is this launch will also enable the launch in Sanfilippo and the other two programs that I'm going to talk about next for our Enzyme Transport Vehicle. Our initial focus is in the U.S. and in certain countries in Europe and Canada. And we likely use a distributor model throughout the rest of the world, but this is, again, an exciting time as we think about approval in the U.S. and how that will catalyze approval in other countries. So let's talk about expanding the ETV portfolio. So I've focused primarily on Hunter and on the Sanfilippo program. We continue. We're now enrolling cohort B2 in our progranulin program.
We've actually put the ETV progranulin program into our ETV franchise, mainly because the biology tells us that we're correcting lysosomal dysfunction with this particular approach. And today, I'm going to talk about two new programs, one in Pompe. Both of these are in IND-enabling stage now, and the other with Gaucher, targeting Gaucher and Parkinson's disease, specifically GBA Parkinson's disease. So I'm very excited to present this data for the first time.
This is data using the engineered human transferrin receptor mouse and a GAA knockout, comparing against standard of care Lumizyme and Nexviazyme, and what you can see that, as expected, we get reduction of glycogen load in the brain, very robust. This is shown in the graph up in the left-hand corner, and that's what you'd expect with the Transport Vehicle technology but what we're observing, and I think we know this about transferrin receptor, we also get better biodistribution to other tissues, specifically the muscle, and here you can see a reduction in glycogen load in muscle, and we look more closely in these mice that have defects, specifically lysosomal defects in muscle.
We can essentially completely correct this with ETV GAA, and the reason for this is that the Transport Vehicle enables broad distribution throughout the body, including the brain. So this program is now advancing rapidly to clinical studies. The second program, ETV:GCase, basically the mutation or genes that encode GCase as GBA. GBA mutations lead to either Gaucher, homozygous, or heterozygous increased risk in Parkinson's disease. And I want to make two points here. One, we use the TV technology to improve GCase uptake in brain, as shown in the first graph. But also, interestingly, with this particular enzyme, it's intrinsically unstable.
So we did further engineering of the enzyme to improve its stability. And what we see now is a robustly active molecule that has sustained exposure throughout the body. And you can see the difference between an engineered enzyme that can get across the blood-brain barrier that's wild type, that's in green, and an enzyme that's engineered to have better stability using the Transport Vehicle in orange, and a very robust reduction in glucosylsphingosine.
We see this not only in brain, but also in liver and serum. So again, the concept of treating both brain and the body using the Transport Vehicle technology. So what's next? I mean, we definitely want to build an enzyme franchise. And I think what I really like about the ETV:GCase program is it's not only treating Gaucher, this, I'd say, traditional lysosomal storage disease, but also has the potential to treat Parkinson's disease. So this will be the first of a number of programs that we're developing in these broader, more common neurodegenerative diseases.
And what I'd like to talk about next is our tau program and our Aβ program using this technology. I think importantly, there are many indications that sort of are in between this lysosomal storage disease as well as these broader degenerative diseases in which this technology would be useful. And maybe I'll comment on those towards the end. So let's talk first about the Oligonucleotide Transport Vehicle. This is a very competitive space. I'm sure some of our competitors are probably here today and would love to talk about this particular technology, the ability to get oligonucleotides across the blood-brain barrier. We first showed this several years ago.
And this past year, we published our work in Science Translational Medicine. I think probably the most robust example of injecting an oligonucleotide systemically, but modulating gene expression in brain, I think something that we thought would be very unlikely to achieve. This data on the left-hand side is part of that publication. On the right-hand side, we're showing for the first time the ability to have a sustained reduction in gene expression and the subsequent impact on protein expression for the tau protein.
We dose for two weeks, and then we basically wait and see how long we can keep tau suppressed in the brain of these humanized mouse models that express human MAPT. What you can see is a very robust prolonged reduction. Now I'll turn my attention to our other Alzheimer's program. This one's actually received a lot of attention and I think a very interesting field. It's very clear that the Alzheimer's field has evolved over the last three or four years, but there's a lot of room for improvement, better plaque reduction, ultimately better outcomes in terms of cognitive benefit and specifically safety. What we've done here is we've applied the Transport Vehicle technology to antibodies targeting amyloid. On the left-hand side shows basically our ability to reduce plaque.
It's about two to three times better than a standard Aβ antibody given at the same dose. And in the next graph, we're measuring the amount of free oligomeric Aβ. And this is the first time we've shown this data, but basically we can capture the vast majority of oligomeric Aβ in this particular mouse study, given at the same dose as a standard Aβ antibody. The reason why we believe this is the case is because we have about five to 15-fold more concentration of antibody in brain.
So not only can we have more robust plaque reduction, but we capture what may be forms of toxic amyloid beta. In addition, we see a reduction in ARIA. And the argument around this is that these molecules cross capillaries as opposed to accumulating in the perivascular space. And even though we can have better plaque reduction, we see less ARIA.
We think that this is actually translating more broadly into the clinic with others that are using brain shuttle technologies for amyloid beta-targeting molecules. I think most importantly here is the safety profile. By engineering the Fc in such a way that the molecule, when bound to transferrin receptor, is immune silent, but when bound to amyloid plaque, is immune active. It's basically an on-off switch, this cisLALA mutation.
We can basically negate the effects on these immature reticulocytes that express high levels of transferrin receptor while still maintaining very robust plaque reduction. We see this as a potential best-in-class approach for Aβ. In addition to this, which is using transferrin receptor in parallel, we continue to advance our CD98 platform looking at Aβ as well as other targets for antibodies. Now I can basically summarize where we are.
I think what happened in the last year, our goal was to accelerate and to expand. The acceleration we're observing with our actual programs in terms of filing and preparing for our first commercial launch. Our expansion includes the introduction of GAA and GCASE as new IND-enabling programs, in addition to MAPT, SNCA, and Aβ, and IDUA. So we have a very robust IND-enabling portfolio. We also have a robust clinical portfolio with both advanced and earlier stage programs.
We continue to look forward to data in our LRRK2 program in partnership with Biogen. I think maybe my last point is that these discovery examples are not just written on the slide for fun. We actually have data around all of these therapeutic areas, including our oncology efforts where we actually could advance two additional molecules into the clinic.
The challenge is we can't do it all today. And so we have a great opportunity to use the Transport Vehicle technology to enable brain uptake and broad distribution of our molecules. So with that, let me highlight our 2025 priorities. So priority number one, prepare to launch. Priority number two, continue to expand the ETV franchise and prepare for IND and CTA filing. We plan to bring one to two molecules into the clinic per year beginning this year. We have a pool of about nine IND-enabling ready programs.
And part of this is the plug and play. And the question will be the sequencing of these particular programs. That's part of the expansion of the ETV franchise. And we're very excited to be advancing, and I'd say leading the blood-brain barrier field, a lot of exciting work being done more broadly in the field. For someone like myself who's worked in the field for 20 years, it's fantastic to see where the field is today and the progress being made, especially with the clinical data being generated. I'll just end by saying that each of these photos on the right-hand side have very specific meaning and have very specific experiences.
I think a lot of times in biotechnology, especially in these types of conferences, we just talk about the value we can create. Obviously, the value for investors, the value for your employees, but most importantly, the value for patients. I've had an incredible privilege to interact with a number of patients, especially in the rare disease space, and realize that there remains a huge unmet need. It's our responsibility to bring medicines that can actually really transform their lives. That's what we're seeing right now with the Transport Vehicle. I think with that, we'll take questions.
Great. We're joined up here by the company's Chief Commercial Officer, Katie Peng, Chief Medical Officer, Carole Ho, and I believe CFO and COO, Alex Schuth. I guess just to start out, with Tivi, you previously talked about a potential early 2025 BLA filing. Where does that currently stand, and how confident are you in approval?
Yeah, so Carole.
Yeah, so that is on track, and we're currently summarizing all of the data for the filing. I would say that also with this recent announcement of breakthrough designation, we are quite confident about our success and path forward for the Tivi program for filing this year.
Can you recap the market size both in the U.S. and ex-U.S., and maybe talk about how investors should think about or kind of envision the initial launch ramp?
Katie.
Yeah, so the overall market opportunity, we use Elaprase as an analog. It's about $600 million-$700 million. And for the U.S., for this disease area, it's about 30% of that total market looking at Elaprase today. In terms of ramp, I think Ryan mentioned we've been laying the groundwork already with our medical affairs team. We believe Tivi has the option or the potential to become the new standard of care in MPS II. And we've engaged with almost all of the prescribers, and we've identified the centers of excellence.
And right now, in terms of pre-launch, we have high awareness of Tivi and the data. And we know that not just the prescribers, but the community is extremely excited about this potential launch. In terms of launch uptake and how we think about it, we're focused on awareness, specifically understanding the differentiation of our data, as well as payers' ability to cover and improve, as well as our patient support programs. Those are the things we're working on to ensure we have a strong launch uptake.
Just to follow up on that a little bit, I feel like a lot of people talk about how rare disease patients can be sticky with their existing treatment. But on the flip side, I kind of wonder, who leaves their child on the old product? Can you just kind of expand a little bit on how you guys think about that kind of push and pull?
Yes. So as you're probably aware, two-thirds of the patients have some CNS symptoms. And so the current standard of care does not address that. This is why there is a lot of excitement about the potential of Tivi coming to market. In addition, we believe, because even today, even the CNS patients are being treated with Elaprase. We know where the patients are. At launch, more than likely, these patients will be switching to the better product.
Maybe I'll just add one other point. The trial, the majority of patients in the Phase I, II trial and even in the Phase III trial have been on Elaprase and switch, right? There's that experience of switching to Tivi, tividenofusp alfa, which is part of the and the data, as you look at it, that initial data point is often on standard of care. It's a little bit unusual from that perspective.
What about the possibility of pursuing an accelerated path to approval outside of the U.S.? Where does that stand?
Yeah, Carole.
Yeah, so the equivalent of accelerated approval in Europe is the conditional marketing authorization approach. And at this time, there has not been consensus for using a biomarker to support accelerated approval in the EU. However, I think similarly, it's worth noting that with the emerging science, we really had to convene with the community along with the FDA to really understand that science and support this path forward, which happened in 2024. There are similar efforts ongoing now in the European market as well.
Yeah, and I think that those efforts are really catalyzed, obviously, with the success of what happened with the Reagan-Udall Foundation meeting. Also, a large portion of our COMPASS trial is enrolled in Europe. And so we have built a lot of connections in Europe. We have a site in Europe that really drives the clinical trial enrollment. And so we have every plan to advance the program in Europe as well, and broadly the ETV franchise.
Okay. What about manufacturing? Where do you guys stand with kind of commercial manufacturing readiness? How many patients could you support at launch? And what's the right way to think about gross margins for a product like this?
Yeah, so in terms of manufacturing, actually last year, when we didn't feel like there was necessarily an accelerated approval path, we made the proactive decision to just continue full speed ahead for manufacturing and preparedness for commercial launch. And we've been working with Lonza for that. So we're in a very strong position at launch in terms of material. In addition to that, we've built our own manufacturing facility. That will not support the commercial launch of the Hunter program, but it will support the rest of our portfolio.
We began manufacturing in that facility at the end of last year. I think as you look at the expansion of our portfolio, the intent of that facility is to reduce the cost to be able to produce many different products at scale. I think that that's an important piece. The other thing that's interesting about the enzymes, and I think maybe not recognized historically, the cost of goods is very high for enzyme manufacturing. The difference is all of our enzymes are Fc fusions.
Therefore, we can use a traditional Protein A column to purify. You don't need many, many columns to sort of uniquely purify the enzyme. That's dramatically reduced the cost of manufacturing for every one of these products. Also improves the stability that Fc provides both the ability to capture and the stability of that product. We really like that part of, I mean, it ended up being not the original reason we designed it that way, but it's very much advantageous from a manufacturing perspective.
Is that to say that if we kind of think to the future, we might have multiple of these products, we could think of the company's gross margins as being higher than what you would otherwise think of our traditional enzyme business?
No, I think with respect to the cost of goods, we expect them to be in the normal range for an enzyme. We expect under about 20% of sales. This is for the first product, which is manufactured by Lonza. As Ryan mentioned, as we scale up, as we potentially bring in manufacturing for other programs in-house, we do think that that number could actually go down over time.
Okay. What about the COMPASS trial? When do we expect that to read out? And should we expect the data both from the neuronopathic and non-neuronopathic patients at the same time?
Carole.
Yeah, so we've completed our target enrollment of the neuronopathic patients at the end of last year as we projected. The non-neuronopathic patients, they have a shorter follow-up time of one year, so they are not on critical path. So we would expect both cohorts to read out at the same time.
And when is that?
Yeah, so we completed our targeted enrollment. We have 15 countries, 30 sites that we're currently working through to understand patients that may still be in screening, and then we'll make a decision and communicate timing.
Maybe switching to Sanfilippo and DNL126. Can you just highlight, and you kind of blazed past it in the presentation a little bit, can you highlight some of the data that you recently announced for that product?
I'll let Carole answer that. She's probably as excited as I am to talk about the data.
Yeah, so the data that we shared, we didn't share specifics. It's a very competitive environment, but we were able to achieve normalization in that program, and based on that, we have actually expanded that study now from two cohorts to five cohorts to enable us to generate the data to potentially support an accelerated approval pathway similar to the pathway that we've taken with the Hunter Tivi tividenofusp program.
Just without giving away all the details, how do you think your data set compares to Ultragenyx?
Yeah, so Ultragenyx, just so everyone's aware, is a gene therapy that's IV administered. We have seen a greater percentage of reduction in our Hunter program, which is the data that we've shared. And again, we've seen very similar results with our MPS IIIA program, which we have not shared. So from a perspective of CSF HS reduction, we do think we can exceed what you see with gene therapy. And again, that's very similar to what we've seen also with the degree of reduction that we see in the MPS II tividenofusp program compared to gene therapy.
Okay. What's the size of that market for Sanfilippo Type A? Maybe in the context, how does it compare to Hunter, for example?
Yeah, so it's really hard to know the exact epidemiology because there's not a standard of care treatment today. So the patients have to be identified. But we think the market is roughly similar size or slightly smaller than Hunter syndrome.
Okay. Has the FDA signed off on heparan sulfate as a surrogate biomarker that could support accelerated approval for that product?
Yeah, so after the Reagan-Udall Foundation meeting, there's been very much a shift in the consensus on heparan sulfate being a surrogate biomarker. And the feedback that we've gotten from the FDA, and I think you can see this from other competitors that have released press releases as well, the FDA is accepting that as a surrogate biomarker to support accelerated approval.
So I know Tivi's been in development for a little while now, and you got the breakthrough designation there. Could we see that happen for 126 sooner? And how much do you need to go ask the FDA and kind of use that as kind of a pathway to kind of encourage that push for the biomarker-based approval?
Yeah, it's a great question. We do think that it is likely that CSFHS will be used as a surrogate biomarker for the 126 program. Also from the precedent that's been set with Ultragenyx, where they have gotten agreement from CBER for CSFHS to be used as a surrogate biomarker. Regarding breakthrough designation, there is actually a requirement that there also be clinical data that provides a reasonable likelihood that the product is going to be better than standard of care.
That's why we're very excited to have achieved that breakthrough designation status. We are currently the only program that has shared data really showing normalization in the vast majority of patients studied with respect to CSFHS, as well as with neurofilament, which we think is a very important biomarker demonstrating effects on the disease biology and brain health.
Maybe stepping back, thinking about the ETV platform more broadly, what's your criteria for choosing targets? And how does kind of market opportunity factor in versus surrogate biomarkers and things like that?
Yeah, so I think the selection of Pompe and Gaucher/Parkinson's disease reflects that we are very interested in applying the technology to broader markets that still have a clear unmet need. Though in that case, there's also clear biomarkers, right? So we definitely, we look at both the breadth with which we can apply the technology, but the speed with which we can prove it based on the biomarkers.
So both play a significant role. What you haven't seen is that we're picking, there are many smaller, even smaller than Hunter programs that we'd love to apply our technology. And I think as we perfect the manufacturing and reduce our cost of manufacturing more broadly, you could see us going after some of these really high probability, but maybe smaller markets. But for now, I think the next step is to go a little bit larger with Pompe and Gaucher.
Right. And on Pompe and Gaucher, what's the right way to think about time to IND?
Yeah, so what we're guiding towards is, as you saw those six programs that are IND enabling, essentially any one of those can be filed in the next 12-24 months. Two or three of them are in even more quickly than that. And so that's where we've left it out. We actually have to sequence some of these programs simply for just resource requirements. You'll see INDs this year and next year and the year beyond, but we haven't decided which order and therefore we're not disclosing which ones first.
Okay. Maybe on DNL343, you guys put out an update on that product and the results from the Healey trial recently. Are there any analyses you're kind of holding out for that would make you more optimistic about a path forward with that product?
Yeah, Carole.
Yeah, so just to recap, the top line that we provided, which was provided by the Healey, which is the Mass General organization that ran the study, and we have a collaboration with, it was the 24-week top line data for the key primary and key secondary endpoints. We do still expect data on neurofilament as well as active treatment extension longer-term data that will be forthcoming in 2025.
Certainly all of that data will be very important in interpreting the totality of the data. I think something that is well known in the field and I think has always been a concern, but balanced with patients' need for clinical trials, is six months a relatively short time to see changes in ALS. I think increasingly it is appearing that you may need longer durations of treatment to be able to demonstrate a benefit. We certainly are interested in looking at both the neurofilament data as well as the active treatment extension data.
I don't know if we're going to come to the answer right here, but with a disease that progresses as quickly as ALS, how do you guys reconcile kind of the ethical questions that come along with randomizing a control arm for longer than six months?
Go for it.
Yeah, I mean, that's a complex question. I mean, I think just generally, first of all, I think we do need longer trials, which is challenging for patients to be randomized to a placebo or standard of care, which is not very effective for that long. I think earlier diagnosis is also extremely important so that we can get these patients into trials earlier when their disease has not progressed as much.
And I would just add that that exact balance is part of the reason why Healey is six months, because all patients, as you know, no one wants to be on placebo. It's the same for all of the rare diseases that we're working on. It's sort of the battle of what we believe and what the FDA and others believe could be ethical and acceptable in the field, so I mean, there's novel ways to think about designing clinical trials where, let's say, everyone crosses over at six months.
Challenge then, are you still powered to see an effect at a year? I think the best example in the field is there is a medicine, Tofersen, that had the ability to robustly inhibit a biomarker, neurofilament, similar to the neurofilament data that we shared today, but at six months it wasn't obvious that there was a clinical benefit. At least it wasn't statistically significant, so there, you know a drug that works, it has a clear mechanism, took really a year. I think that that's what's going to happen, I think, with these platform trials. We have to step back and ask, what is enough time to see a separation in some of these effective medicines?
What about the OTV programs? I know you've got kind of a lot to juggle and prioritize. So when could those enter the clinic?
Yeah, so very high priority. We're advancing two OTVs in parallel, SNCA and MAPT. We have a third one where we have an ASO candidate as well that is not quite in IND-enabling stage, but they're on the same path as the ETVs. Again, in that sort of 12-24-month, actually 6-24-month period, depending on sort of how we sequence them. But very high priority. I think the key there is if we get it right once, we can apply that across many oligonucleotides.
And so we've spent extra time engineering that program, as we've discussed two years ago, and we think it's time well spent to have what we hope is a best-in-class oligotransporter that we can then take more broadly. This is the one platform that is really plug and play. And I think the reason for that is each enzyme has sort of its unique biology. I think we've been very happy to see the similarity between Sanfilippo and Hunter, but obviously GCase, we had to engineer the enzyme to improve it. Antibodies each have their unique biology, but oligonucleotides, we would probably be able to hit a threshold of potency, and they all behave very similarly. And so the platform is, I think, very powerful, and it's important we get it right, hopefully being the first to prove that.
Can you elaborate a little bit more on what you were taking extra time to optimize?
Yeah, so we actually highlighted this, I think, either mid-last year or even beginning of last year. It was around chemistry in the oligonucleotides themselves. In the last year, we've sort of perfected that for the targets, and we realize those principles are the same regardless of what the sequence of the oligonucleotide is. Also, its breadth across different types of oligonucleotides. We've shown that the TV platform can work not just with ASOs, but siRNAs, and we're just seeing it has incredible utility.
Maybe lastly on the ATV:Aβ product, I think really interesting preclinical data you flashed up. How should we think about timelines there? And just given the kind of size of that market, is that something that you would take all the way independently?
Yeah, it's a great question. Obviously we have a lot to do, and we'd love to do it all on our own. We've been in the past, partnerships have been very important. They remain very important to us and something that we will definitely consider. In terms of timelines for Aβ, we have our clinical candidate. It's in that bucket of IND programs.
And so it's again, how do we balance resources as we manufacture? We will begin manufacturing essentially all of these products ourselves. And we'll sequence the manufacturing. Many of these we've actually started manufacturing externally, and we'll bring them in as we produce clinical material. But this is now on the fast track. Now that we have full ability to really, we have full ownership of our Alzheimer's portfolio. We have continued to advance both TfR and CD98, but as I presented the TfR data today, that's maturing very nicely.
We see clinical proof of concept with others' program, with another program, and yet we think there's room for improvement. Sometimes there's more confidence in transferrin receptor because we also have our own clinical data. So we will see which one wins as the data plays out. But we're looking in the, again, six-month to 18-month timeframe to get into the clinic with that program.
Great. Lots to look forward to. Thank you.
Yeah, thank you.