Analyst at Jefferies, and I'm pleased to introduce the management team from Denali Therapeutics. CEO Ryan Watts is with us and going to give an introduction with some brief slides, and I've got a whole lot of questions afterwards, and we'll have a nice dialogue after your presentations. Thank you.
Thank you, Mike. Actually, I don't know how brief my presentation will be, so I'll try to move quickly. I guess the feedback I got is it's like a mini JP Morgan presentation, but you know.
What bank is that? I don't know what you're talking about.
Yeah, exactly. What is that? What is that?
Never heard.
Great to be here in London, especially at this conference. This is my first time here. I know Alex, my Chief Operating Officer and co-founder, has been here many times, and we're looking forward to connecting with many of you over the next several days. So just quickly, Denali was founded to do two things.
First, cross the blood-brain barrier, and then second, defeat degeneration. Obviously, the second is a long-term goal that we're going to be at for years and years, but the first is, I think we're at that point in time where I'm going to show data today. You've seen data from us and from others that crossing the blood-brain barrier is actually achievable now in humans, and it will enable a new, I guess, era of medicines using our blood-brain barrier technologies.
We're focused on rare degenerative diseases as well as more common diseases like Alzheimer's. You'll see throughout the presentation, our first set of molecules that are really on the path to approval are going after some of these rare diseases, lysosomal storage diseases in particular, and then we'll end with several of our programs in Alzheimer's disease. This is the team.
I won't spend much time introducing the team here. Alex is here with me today. When we founded Denali, we had three major areas to focus on: what we call the degenerogenes, genes when mutated that cause neurodegeneration, blood-brain barrier delivery, and then ultimately biomarkers to prove the technology. Now what I'll say is biomarker-driven approval.
At first, we just thought we'd use biomarkers to show that the medicines were working, but now we're in an era where biomarkers may actually be used as accelerated approval endpoints as surrogate endpoints. This is our portfolio split in two. There are large molecules. Those are the programs in orange here.
Similar to the lanyards, you have the orange and the blue. The blue is actually our small molecule programs, and I'll highlight each of these programs in succession now. Another way to look at the programs is PEEK2 and PEEK1. So the PEEK2 programs I'll end with, these are the Alzheimer's programs. Those will be entering the clinic in the next basically six to 12 months, so maturing very rapidly, and then the PEEK1 programs are programs that have read out or are reading out now and are really the near-term value drivers, including our enzyme replacement therapy portfolio.
So what is the technology? So it was described in the late 1980s that transferrin receptor is a potential path to the brain, but it's taken multiple decades to engineer brain delivery using transferrin receptor, which is an iron transporter. The take-home message is that in order for iron to get into the brain, it's actively transported through the transferrin receptor, as are many other important metabolites a nd the idea here is you can hitch a ride a nd the way that we've approached this is the second-generation approach.
The first generation is using traditional Fabs. So you'll see the vast majority of BBB platforms are using antibody or antibody Fabs. But rather what we did is we engineered the Fc portion of an IgG. And this is actually very important, obviously well-known therapeutic approach using Fc fusions.
This allows us to build tolerance, allows us to have fantastic PK, but also incredible modularity, taking different types of cargoes across the blood-brain barrier. These are two of the key papers that highlight the invention of the technology, the transport vehicle using transferrin receptor in 2020, and then applying this to a new receptor, CD98, which we won't discuss in detail today.
What happens when you cross the blood-brain barrier using these technologies? And I think this has actually become very relevant as we talk about the Alzheimer's antibodies at the very end. On the left-hand side is a traditional antibody dosed in a mouse. These are whole mount images, and what you can see is that you have a very bright vascular, perivascular stain. We believe this is related to probably some of the safety findings that are being observed with the anti-amyloid therapies.
When you use a transferrin receptor technology or a CD98 receptor technology, in this case, the transport vehicle, you get an even distribution throughout the central nervous system, and you don't get this perivascular accumulation. And that's because the antibodies are crossing the capillaries directly through receptor-mediated transcytosis.
So using this, I'll show actually on the left-hand side and the right-hand side, transferrin receptor is the ideal receptor to deliver enzymes, and on the right-hand side are oligonucleotides such as ASOs or siRNAs that can be delivered also through transferrin receptor. The middle programs, and in particular the antibodies, is where we compare head-to-head either CD98 or transferrin receptor to find the optimal receptor for crossing the blood-brain barrier. So I'll focus now on the PEEK1 programs.
The first is our Hunter program, in which we're planned to basically replace the standard of care, which is idursulfase or Elaprase, which is an iduronate-2-sulfatase, which basically is delivered systemically but does not readily cross the blood-brain barrier. The goal here is to now give IV therapy with an idursulfase that's fused to the Fc that binds to the transferrin receptor and readily crosses the blood-brain barrier. Here's now a mature data set over the last four years of data collection in Hunter patients. The first thing that we observed is we're the first and only technology to not only cross the blood-brain barrier, but to normalize substrate. So we get a 90% reduction, 90+ percent reduction in heparan sulfate, which is the substrate for iduronate-2-sulfatase. That leads then to cellular rescue.
This is GM2, GM3, and glucosylsphingosine, which are lysosomal biomarkers , and I think most excitingly, we also now see rescue of neurofilament. In fact, all patients have normalization of NfL. In fact, younger patients have a more rapid normalization, and even older patients that can be as old as eight, nine, or 10 years of age when they go on therapy and have had neurodegeneration for many years, we see that we can halt neurodegeneration and NfL levels are now normal.
We recently announced top-line data for the next enzyme, which is SGSH, and basically similar to what we saw in Hunter syndrome, we have the ability to normalize substrate. This is also heparan sulfate. Based on these data and on interactions with the FDA, we've expanded our clinical trial. We've added three more cohorts, so that's now 20 patients. The initial data is in eight patients.
We've expanded that trial, and the goal is to find a path to accelerated approval for this program as well, hopefully with not nearly the same size as the Hunter trial, which we basically use to validate the technology. Important, this program has also been selected for START, so we've had many interactions with the FDA, including in-person meetings where we were defining the phase III design for this study, which would be a confirmatory study based on accelerated approval in the phase I/II data. So in addition to those two programs, the third clinical stage program using the transport vehicle technology is for progranulin. This program has been, I think, generally challenging to enroll. We often screen over 30 FTD patients before we identify a single progranulin mutation carrier.
That being said, we've been able to show in healthy volunteers an increase in progranulin levels, actually about 25x the levels needed to rescue the granulin deficiency. We're now enrolling cohort B2 with the goal of getting proof of concept and then observing the competitive landscape and being prepared to advance into a larger trial based on those data, so in summary for the enzyme franchise, in fact, I added progranulin into this franchise. We'll be launching, we'll be filing our first BLA early next year for Hunter syndrome, and then maturing the data set for Sanfilippo, finding an accelerated path for that program, plus kicking off a phase III study.
And then we've selected two more enzymes that are in IND-enabling studies now, one of which we'll file in mid next year, an IND, and we'll now bring a number of molecules forward using the enzyme transport vehicle technology. So let's talk briefly about the PEEK1 small molecule program.
So we made the decision earlier this year to focus entirely our discovery efforts on blood-brain barrier crossing technologies using the transport vehicle technology. That being said, early days Denali, we had a number of small molecule programs. In fact, we spun out our preclinical small molecule portfolio, but we have three programs that are still active, some of which we lead independently. So this one, the eIF2B agonist program, we at Denali are leading this program.
This program is in a HEALEY platform study, which has been completely enrolled, and in fact, the six-month portion of the study was complete in October, about mid-October. It will now be in HEALEY's hands to determine the timing of the release of the top-line data for this particular program. The mechanism here is basically inhibiting the integrated stress response by activating eIF2B, returning cells back into a normal state of protein translation.
We show that we can do that with biomarkers in the clinic, and we look forward to that data in the coming months. The second program is our LRRK2 inhibitor program. This is a target we've worked on for many years. LRRK2, when mutated, is a risk factor for Parkinson's disease. The mutations increase LRRK2 kinase activity. This is the most advanced program targeting LRRK2 in the clinic.
Basically, we have a robust, over almost 200 patients, not patients, but healthy volunteers have been treated with LRRK2 inhibitors, and now we're in a very large phase II-B study that's being led by Biogen known as the LUMA study. This study is essentially a one-year endpoint study. We continue to enroll that study. Then we recently announced a second study, a phase II-A study, a BEACON study that's focused on biomarkers of LRRK2 and of neurodegeneration. The goal for this study is a shorter study where we can see some evidence, not just of activity, but ideally of halting neurodegeneration using a subset of biomarkers, and that study is actually kicking off just now. Let me talk briefly about the PEEK2, and I know that I'm obviously moving rapidly here because I'm looking forward to Mike's questions.
So the PEEK2 programs using the transport vehicle technology, I'm just going to focus on the Alzheimer's programs, but we have a number of other programs, including smaller indications. So this is probably the one program that we received the most questions about in recent days, in part because of the progress of the blood-brain barrier technologies enabling antibodies to amyloid beta, such as trontinemab, and also recent acquisitions in the space using these types of technologies. And we've been working for, of course, a number of years enabling antibodies for Aβ and other approaches to target Alzheimer's disease. And what I can say is that we've selected a lead molecule.
What's unique about this lead molecule, and I think very important, is it's engineered to be immune inactive when bound to transferrin receptor through these mutations that are called the cisLALA mutations, meaning that we will not affect immature reticulocytes. We should not have an effect on red blood cells, as have been seen with other technologies. So it's immune silent when bound to transferrin receptor, but when bound to amyloid plaque, we get robust plaque reduction.
What I'm showing you on the first graph here is immunodecoration using this ATV:Aβ molecule compared to a standard Aβ antibody. The center graph is about two- to three-fold better plaque reduction than the same Aβ antibody given at the same dose. And then I think importantly, a reduction of MRI findings that are similar to ARIA in this particular mouse model.
So what we see is with the standard antibody, about 10 out of 11 animals develop these ARIA-like imaging abnormalities. However, one out of 11 at the same dose with the ATV: Aβ technology. And the question is why? And I think what we've observed, and I mentioned this in the three-dimensional image I showed earlier, is that standard antibodies localize in this perivascular space, which is also where you have high amounts of cerebral amyloid angiopathy.
We believe that's part of the reason you have this increased risk of breakdown of the blood-brain barrier. And using the TV technology, you get an even distribution throughout the brain, as shown on the far right-hand side, meaning that as the antibody crosses capillaries, it will engage with plaque more broadly as opposed to concentrating around these perivascular spaces.
We believe that this is probably one of the main drivers for this decreased risk of ARIA. It appears that this is also playing out in the clinic with clinical competitors that are using blood-brain barrier technologies. I'll end now talking about oligonucleotide transport. So if I go back in time here and just comment broadly, we have an ETV franchise, which is an enzyme transport vehicle franchise.
We have an antibody transport vehicle franchise, which is led by the Aβ program. And then I think the real future of brain delivery is oligonucleotide transport. We recently published work showing that this is actually achievable. We know that many others are now working on these types of technologies, and the goal here is systemic delivery of an oligonucleotide, either ASO or siRNA, that modulates gene expression in the brain. And standard approaches have used intrathecal delivery.
We're using, of course, the OTV, which is taking a full antibody and fusing either an antisense oligo or siRNA and modulating gene expression in brain after systemic delivery. This is one image from the recently published paper in which you can see a non-human primate brain. On the left-hand side is traditional intrathecal delivery, where you can see the spinal cord with very high concentrations of ASO. This is labeling the antisense oligo.
On the right-hand side is basically even distribution throughout the spinal cord, as well as all the brain regions, including deep brain regions. And what you'll notice is that the deep brain regions are not targeted using the intrathecal technologies, and so this opens up a number of targets within the central nervous system. Our most advanced program is targeting MAPT and MAPT codes for tau. So this is also an Alzheimer's program.
What we've learned with this particular technology is, if you take just a standard ASO, link it to the OTV, you can get modest reduction of transcript in brain shown on the left-hand side. But through proprietary modifications, we're able to achieve very robust reduction of ASO on the right-hand side. This is actually using the exact same sequence, and so we believe this is very important to the technology as further enhancement of either the chemistry or the linker of these either siRNAs or oligonucleotides, different types of oligonucleotides to transport vehicles. I'll make one other comment, which is interesting, is that also having a full-length antibody in some ways is ideal because of stability and driving increased brain uptake. So let's look ahead, and then we'll answer a question. I think we're at a point now where the platform has been validated both preclinically and clinically.
We're on our way for our first BLA filing for Hunter. This year has been actually a pretty incredible year as we've seen the FDA embrace surrogate endpoints, specifically in rare disease and specifically in MPS disorders and heparan sulfate. We're preparing for our first commercial launch as part of this. We have our second enzyme, which we've also achieved proof of concept with heparan sulfate, and we want to get that on the accelerated path as well in Sanfilippo. And then more broadly, just executing on our portfolio. We're also excited now, I think next year, to bring a number of new molecules into the clinic using this transport vehicle technology.
We believe in the next two to three years, we have between six and nine INDs that are really lined up using the transport vehicle, building out the enzyme franchise, the antibody franchise, and then ultimately the oligonucleotide franchise. And with that, I will pause and we'll take questions, and I'll go sit down next to Alex and Mike.
Fantastic. So let me talk about some of the near and medium-term things and then maybe a couple on the longer term. So just to reiterate, you believe that you will, you're on track to file the BLA in Hunter syndrome, and that could be a priority review, and we could have a PDUFA date sometime second half of the year. Is that correct?
That's correct. Okay.
And that is based on regulatory. So first of all, you could be your commercial launch company next year.
So that's important, but that is based on regulatory discussions to be able to file on that type of open label, single-arm package. We have Peter Marks here on Thursday, so I'm going to ask him some questions on this. But you believe that there is a market shift in the dialogue around being able to follow that type of regulatory path for other programs such as Sanfilippo. So can you tie those two together? So could Sanfilippo be pretty quickly following that so you could have two drugs in two years?
Yeah. So I think that is definitely the goal. I think maybe an important point. So Peter Marks, in my opinion, helped lead the FDA into the future of using these biomarkers as a potential path for accelerated approval. But importantly, he leads CBER, not CDER, and all of our molecules are actually under CDER leadership.
So it's a different leadership. What really shifted the mindset at the FDA was this Reagan-Udall Foundation for the FDA meeting that went into great detail around the relationship of heparan sulfate to neurological damage and heparan sulfate levels and CSF in brain and their correlation. And that really set the stage.
Now, importantly, Sanfilippo, Hunter, Hurler, Scheie, those are all heparan sulfate-driven diseases. And one thing that's really fascinating about the MPS diseases is that heparan sulfate is both necessary and sufficient to cause neurological damage. So there are some MPS diseases where heparan sulfate is not elevated and you don't see this neurological damage. And notably, there are gene therapy competitors that are being regulated by CBER. That's really the questions for Peter, where heparan sulfate is also being used as a surrogate, and that includes Sanfilippo.
And so that's why we believe we have not had that conversation yet with the FDA, but there's every reason to believe that essentially Sanfilippo will be similar, if not identical.
So Hunter follows the path where obviously a gene therapy company, REGENXBIO, is in the process or completed the filing. And that coordination with CDER has supported your ability to file as well.
Yeah. I mean, the other, well, first of all, they haven't filed yet, and their interaction is with CBER, and ours is with CDER. So we probably will file at a very similar time as REGENXBIO.
And then following that path, Ultragenyx, I think, is going to file in Sanfilippo with gene therapy at some point soon.
That's publicly disclosed.
And again, to mirror that, and you have FDA START designation actually formally in your work.
That's right.
That obviously sets up a path to more clearly, visibly be able to follow shortly after once you've completed your 18 or 20 patients.
Yeah. That's correct. And I think the question we get, and maybe you'll ask this as part of this dialogue, is what is the future like with gene therapy and with these enzyme replacement therapies? And I think what's interesting is that, so in particular with REGENXBIO, the gene therapy is delivered directly to the brain. And we have not seen evidence yet that they get sufficient delivery of enzyme, let's say, to the liver. And as you know, with these enzyme replacement therapies, even in Sanfilippo, but most certainly in Hunter, there's peripheral manifestation of disease. So most patients will need to be on an enzyme replacement therapy to rescue periphery.
So are they going to be on an enzyme replacement and then get the gene therapy directly administered too?
Yeah. That would be the right now what we're seeing is that they're delaying the standard of care, delivering the gene therapy to the brain, delaying as long as possible. But there's almost no world in which you don't need enzyme replacement therapy because you have enlarged liver and spleen, and those are not effectively treated by a gene therapy that's delivered directly to the brain.
All right. I will go ask directly then what their opinion is on that.
Yeah. I think their opinion is that they're delaying the standard of care. I mean, basically they've said we've been waiting to put some period of time.
Okay. And then in Sanfilippo, same idea there, or is there that's peripheral?
Yeah. So Sanfilippo is a little bit different in the sense that Sanfilippo is largely a neurological disease, but there are interestingly elevated heparan sulfate in the periphery, and there are some changes to liver and to spleen. But what's notable about Sanfilippo is that there is no standard of care because it's largely central nervous system. No one has developed a standard enzyme replacement therapy even to treat the more modest peripheral disease. But we believe, and in fact, we're seeing this in our trial, there's elevated heparan sulfate in the periphery in these patients as well. And so we believe that there's both peripheral and central disease to be treated. And this is the dynamic that's a little different with gene therapy is like how effective, and also organs divide, cells divide over time and dilute. And so durability is a second question.
Well, I would just say just even comparing side by side, the CNS data is not as robust for gene therapy.
That's right.
And we don't have time to go through the distribution, but the overall effect.
Yeah. Just heparan sulfate alone is very differentiated in Sanfilippo. I think the other is, as similar to what we showed with the intrathecal delivery gene therapy that's delivered directly to the brain, will not evenly distribute throughout the brain.
Let me ask a question that is a little bit the elephant in the room. There is significant nervousness about RFK. How does that idea of Peter Marks and the FDA ultimately impact things? Now, Moderna was asked about this for vaccines.
Yeah, yeah.
And it's a relevant question about how embedded things are beyond just Peter Marks, obviously.
Yeah. I mean, I wish I had the crystal ball.
I think I'm probably the last person who can predict the future. That being said, we've seen a significant shift a year ago. If you asked me this question a year ago, the FDA, in my opinion, needed to correct course, and now we're seeing that. So we'd love to see that continued momentum. I think one advantage we have is we're working in rare diseases that are severe. There is no homeopathic or diet that's going to treat these diseases. They're going to need enzyme replacement therapies or gene therapies, and that unmet need hasn't changed. And so let's see how things play out over the next several.
Yeah. More that if someone who has been seen to be a spearhead towards these efforts, more as a figurehead, and Sarepta has been obviously thrown into this picture too, that if we'll ask him on Thursday, but he obviously is very committed to everything. That's right. That this idea on Wall Street that some of the sentiment may shift is much more deeply embedded than just Peter Marks.
Yeah. I think a year ago, what you had was Peter Marks and his ideas, and you had the rest of the FDA, including, by the way, the review divisions under Peter in CBER and certainly CDER. CDER wants to be independent, and they have acted independent. The Reagan-Udall Foundation meeting gave them the opportunity to review data and independently make the decision that now was the time to consider heparan sulfate. I don't think it was a pure just alignment with Peter's view, and I think that's actually really important.
But they are fully bought in on obviously the surrogate nature of the data. It's predictive and the data are strong, and that should follow obviously with additional. It's not just about Peter.
That's right. That's right.
Last question in the maybe 60 seconds I have in Alzheimer's, which is a huge market opportunity, and we've been seeing despite Leqembi's lackluster launch, pretty promising data by Roche just presented. We saw AbbVie do a deal north of $1 billion for a BBB transparent product. What are the ramifications for you, and when would you be in the clinic on your Aβ product?
Yeah, and Mike, we've discussed this before.
The nature of the lackluster launch is really two things: a perception around safety and specifically around ARIA, but equally a perception around efficacy. How efficacious are these anti-amyloid therapies? And the way I look at both of those is that the efficacy probably largely has to do with the timing of intervention.
If you think of how an Alzheimer's patient is treated, if they have any mild cognitive impairment, they've had amyloid plaque for almost two decades a nd so we have to get to a position where we are clearing plaque as a preventative measure, no question about it, that we start to develop plaque at age 60, we remove plaque for a year, we delay the onset of Alzheimer's for a decade. But in order to do that, you need to be, and the drug needs to be safe.
I think the story that I told here is that the biggest concern right now is around vascular integrity in the central nervous system in the context of anti-amyloid therapies. These are brain bleeds, these are hemorrhages, they're vasogenic edema, ARIA- H, ARIA- E. What you've already seen with the data presented by Roche is a leftward shift in that safety, meaning that there's less ARIA, and as a result, there may be less associated risk. I think we need to drive towards that prevention paradigm with safer anti-amyloid therapy. Our plan, as I mentioned before, in the next year to advance that molecule into the clinic that has that shift in safety, but that robust plaque reduction. Fantastic.
Thank you guys very much. Look forward to the updates and appreciate it.
Yeah. Thanks. Thank you.