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

Great. Good morning, everyone. My name is Jess Fye. I'm the large cap biotech analyst at JPMorgan, and we are delighted to be continuing the conference today with Denali. Little change from last time we were here in person. We're not going to switch rooms for Q&A. We're going to go seamlessly into Q&A after the presentation. You can raise your hand and someone will bring you a microphone or you can enter your question electronically on the portal, I'll send it to an iPad up there, and I can ask the management team. So with that, let me pass it over to Denali's CEO of Ryan Watts.

Thank you, Jess. It's great to be back in person. It's great to see so many familiar faces, friends collaborators and friendly competitors looking forward to dive into some data today for our programs. It's such an exciting time to be in biotech. Actually, it's a very exciting time to be in neuroscience in biotech, both rare and common neurodegenerative diseases. And so let's just dive right in my disclaimers and talk a little bit about the past and the future together. So the first point I want to make is around our portfolio. In the last 7.5 years, we've brought over 10 molecules into the clinic. We have 7 active clinical programs, 3 in late stage. And in fact, in 2022, it was a big transition year for us to bring multiple late-stage programs into the clinic in Parkinson's, Hunter and in ALS. In terms of the future, we look forward in the next 3 years to complete 3 to 4 late-stage programs. In fact, this year, we'll initiate another late-stage program in ALS with ultimately our goal of bringing multiple molecules to patients and delivering these medicines through our commercial organization. Let's talk a little bit about our platform. So we have invented a platform for crossing the blood-brain barrier, what we call the transport vehicle technology. And in the last several years, have validated this with at least 2, now 3 programs in clinical testing, and we will be entering a fourth program into clinical testing using the transport vehicle technology this year. But our goal in the next 3 years is to expand our TV platform, including to antisense oligos. And so I'm happy today to share some new data on our ASO crossing OTV or oligo transport vehicle. Ultimately, our goal is to solve the blood-brain barrier for large molecules using this TV technology. Notably, Denali also has a small molecule effort. In fact, we're about half and half, half small molecules, half biologics. But similar to the challenges with the blood-brain barrier with biologics, small molecules require also key engineering and we have now a robust small molecule portfolio. We'll continue our investment in discovery and in fact, we've now published a number of papers later this week. We'll have a paper come out on TREM2. And we're very excited to talk about the mechanism of our ATV:TREM2 using the transport vehicle technology, and we'll bring 3 additional NMEs in the clinic over the next 2 to 3 years. Our goal here is to break open the science in neurodegeneration but also have platforms to solve the blood-brain barrier. And I'll end with my introduction around strategic partnering. It's been a big part of Denali, and it will continue to be a part of Denali. We have great partnerships, both bringing in technologies but also working with partners to advance, especially our late-stage portfolio. Here, we'll be selective about how we evaluate our new partnerships. But ultimately, we want to be a partner of choice around blood-brain barrier and neurodegeneration. So this is our focus. It hasn't changed. It's been, again, 7.5, almost 8 years. In fact, it was JPMorgan 8 years ago, was the genesis of Denali, and we're focused on both rare and common degenerative diseases with a specific focus in lysosomal stores diseases. Our scientific principles are what we call the degenogene pathway. So these are genes when mutated that cause neurodegeneration similar to the oncogenes in cancer. Brain delivery has been a major focus over the last 7.5 years. And our biomarker-driven development strategy, you'll see today, I'll share some new data from our programs using biomarkers to assess dose and patient population. And then in terms of our business principles, we have a broad portfolio, again, now 3 soon to be 4 late-stage programs integrated global capabilities. We have sites in Zurich, Salt Lake City and here in the Bay Area and then strategic partnering, again, being a focus of the company over the last 7.5 years. So here is our portfolio and the way that we've -- that we're displaying the portfolio is our large molecules in orange and our small molecules in blue, and today, I want to focus mainly on the development stage portfolio and some of the data on these programs, but we also have a very large discovery stage portfolio. But let's start first with the large molecules and the transport vehicle technology. Before I get to that point, I want to outline the portfolio in terms of our 3 areas of focus in terms of indications or disease areas, lysosomal storage diseases. You now say we have a late-stage program, pivotal study known as COMPASS study for DNL310. We'll be bringing a second enzyme into the clinic. In terms of our rare diseases, we have 2 ALS programs and 1 FTD program. And one of those ALS programs being led by Sanofi is already in a large clinical study Phase II study. And then in terms of the common degenerative diseases, Here, we have made progress in Parkinson's disease with the first LRRK2 inhibitor to enter a potentially pivotal study, both the Phase IIb as well as a Phase III in idiopathic as well as LRRK2 carriers in Parkinson's disease and then our 919 program for Alzheimer's disease. Another way to look at this is around our commercial build. So this is also a very exciting time. As we've transitioned into late-stage development, we've also started building out our commercial capabilities. Our initial focus will be on Hunter and ALS as we build that internally and expand our med affairs as well as our commercial teams in this area. And then in terms of our co-commercialization, we're focused on the larger diseases, such as Alzheimer's and Parkinson's. And right in between is ALS, where we have both a partnered asset as well as a wholly owned asset. So let's talk about the transport vehicle technology, and I'm just going to provide a quick introduction here. I know some of you are familiar with it, but others may have never seen this before. So our approach to getting large molecules across the blood-brain barriers by utilizing natural transport mechanisms that are required to transport iron in particular or the transparent receptor. And when we founded Denali, we wanted to build a platform that was highly modular, not just to get antibodies across the blood-brain barrier, but also to get enzymes, other types of proteins as well as antisense oligos. And so what we do is we engineered the Fc portion of an IgG as shown on the left-hand side here on this slide to bind to the transparent receptor. When this binds, it then is naturally transported across blood vessels and into the brain. The question is how robust is this pathway for getting large molecules into the brain and how widely applicable is the technology to other types of modalities. I'm going to show a fair amount of clinical data really substantially the point that indeed the transparent receptor is a robust pathway to the CNS, and we hope will open up many opportunities in terms of large molecules, treating CNS diseases. I'll just end by saying that the mechanism for this is essentially through endocytosis. And so transparent receptor is expressed at very high levels on blood vessels to get iron into the brain and the idea is that you naturally hitch a ride and get across the blood vessel into brain. But this is a key point because these blood vessels express transparent receptor, especially the capillaries. So it's the entire central nervous system. And in fact, we have about 400 miles worth of blood vessels in the human brain. So there's a huge surface area to get molecules if you can naturally transport with the iron transporter. There is a nice little video describing this actually on our patient side, so I encourage you to go take a look at it and describing the technology. So in addition to getting antibodies, as I mentioned at the beginning, across the blood-brain barrier, we're very excited about getting enzymes, proteins, and then I'll share some new data on our antisense oligo technology or the OTV as we call it. So here's the portfolio is drawn for the different sub modalities. 3 of the 4 are in clinical testing now with enzymes, proteins and antibodies, and we are rapidly advancing our oligo technology to the clinic as well. So let's focus first on DNL310 or ETV:IDS. So this particular molecule is a iduronate-2-sulfatase similar to Elaprase that's engineered across the blood-brain barrier using the transport vehicle technology. Very excited to show the data on the right-hand side, which was recently presented at SSIEM and this is basically patients treated with ETV:IDS. In fact, patients are on either sulfate and then basically switch to ETV:IDS. And what you can see is that the CNS levels as measured through the CSF dramatically drop. In fact, all patients are normalized or near normalized. This is unique in the field, the robustness of this normalization. I'd like to highlight 1 or 2 points. With continued dosing, we also see a reduction in immunogenicity to IDS, which is a well-known challenge with enzyme replacement therapy. In addition to that, we have several patients that had very high levels of antidrug antibodies. And in these patients, we could actually back-calculate the minimally effective concentration for reducing heparan sulfate in the brain. In fact, it's about 1.5 mg per kg. This actually gives us insight into the capacity for transparent receptor at the blood-brain barrier. And I'm going to show you more data from a second program using the transport vehicle technology, further validating that there's robust transport across the blood-brain barrier. So this data shows both rapid and sustained normalization of heparan sulfate. We're excited to present additional data at World coming in February with this ongoing Phase I/II study, and our focus now is really around recruiting and rolling and dosing our COMPASS study, which is a Phase II/III study for ETV:IDS. The next molecule to enter the clinic using the enzyme technology is ETV:SGSH for San Filippo. And similar to what we've shown for IDS, we have a robust pharmacodynamic response. And I think importantly, when we see reduction in brain, we see a one-to-one relationship with reduction in CSF as well. So when we measure CSF heparan sulfate, we essentially confirmed brain exposure with our technology. So this program, the key update here is submitting the IND in the first half of this year and then advancing in the clinic. We'll share a pretty significant data package at World on the preclinical data for this program in February. Let's now transition to our protein transport vehicle for progranulin, also known as DNL593. So this is the second clinical data. This was presented towards the end of last year essentially showing now a different molecule robustly crossing the blood-brain barrier. And similar to what I've shown with SGSH in terms of the pharmacodynamic response, but we actually know with DNL593 is that brain concentrations are equivalent to CSF concentrations for progranulin. And this is just showing data from healthy volunteers that with increasing dose, we see increasing concentration of progranulin in CSF which we think will be sufficient to rescue the lysosomal defects caused by progranulin loss of function. So this is now a second program essentially validating transport vehicle and in particular, transparent receptor for robustly crossing the blood-brain barrier. We'll have a final data set that we'll be presenting later this year, and we are currently recruiting Part B of this study, which is FTD granulin patients. I'll now turn to 2 Alzheimer's targets. I know Alzheimer's is a key topic right now, and I'm obviously very excited to work on Alzheimer's disease. It's something that we focused on from the beginning of Denali. And the key here is how would we approach Alzheimer's disease. And these 2 programs, one is targeting TREM2 and the other one is targeting a beta. And let me focus first on the TREM2 program, which is currently in clinical testing in healthy volunteers. So this is new data that will be published later this week. This paper is in press, basically comparing in Alzheimer's models, so plaque bearing models the difference of treating with a standard anti-TREM2 antibody versus an ATV-enabled TREM2 antibody. Again, the ATV is the antibody transport vehicle. So we would expect increased concentrations of drug and brain, but we see something actually pretty unusual with the addition of ATV, which is the enhanced potency of TREM2. And so what you're looking at here is basically a gene expression profile. These are clusters. So every dot on these graphs represents a single microglial cell. So Alzheimer's mice treated with control, then Alzheimer's mice treated with anti-TREM2 and then treated with ATV:TREM2. And what you see is that the majority of microglial cells are in a homeostatic state or in what are called disease-associated state or a DAM state. The vast majority of microglia completely changed their state when treated with ATV:TREM2, and part of this is the potency of targeting TREM2 when you add transfer receptor to this. And what you see is a shift away from the homeostatic and DAM state to primarily a metabolic state and a cell cycle state. Now just a reminder that TREM2 loss of function is a risk factor for Alzheimer's disease or cause it for Alzheimer's disease and the idea here is that we can robustly activate TREM2 using the ATV technology. We plan to report our first clinical data for this program later this year. So we're very excited that we continue to dose escalate and healthy volunteer studies with ATV:TREM2 program. The next Alzheimer's program I want to focus on is ATV:Abeta. So obviously, a lot of interest in targeting Abeta with biotherapeutics. And here, our differentiator is using, again, the transport vehicle technology. And what I'm showing you is a whole mouse brain using iDisco. So it's a way of essentially clearing the mouse brain and looking in 3 dimensions, where does the antibody distribute. What we noticed, and we've seen this actually for multiple therapeutics is that standard antibodies primarily distribute near vasculature or perivascular distribution. This is shown on the left side image of the anti-Abeta. So in other words, systemic injection, vascular localization. However, when treating with ATV:TREM2, we're crossing the capillary beds. We're not using this CSF, ISF perivascular distribution, but rather we're using -- we're going straight across capillary beds. And what you see is a very broad distribution focused primarily on parenchymal amyloid plaque. And so we see this as a potential to differentiate from standard anti-Abeta antibodies that have a preferential binding to perivascular amyloid. So we continue with this program. In fact, Biogen has the ability to opt into this program. And I should have mentioned with TREM2, we're in partnership with Takeda and Takeda indeed has opted into this program as well as the progranulin program, and we are now moving those programs forward in collaboration. So now I'll focus on the expansion of our TV technology to antisense oligos. And I'll summarize what I'm going to show you in terms of data. And the take home here is that using the OTV technology, we can get antisense oligos, distributed broadly throughout the CNS. There's a huge potential in this field, what we call the universe of possibilities in terms of the targets to go after. A lot of significant interest in various CNS targets in which we can modulate gene expression, primarily knockdown, but also, in some cases, upregulate. So I'd like to show you data in nonhuman primates and a little bit more extensive than what we have had presented publicly before. And so let's start here. So what we've shown before are these cross-sections through the brain, looking at the difference between an intrathecal delivered molecule versus a systemically delivered antisense oligo using the OTV. On the left-hand side, I'll just comment that we picked the dose. We maximized the dose for intrathecal delivery that is near sort of that causing high limparalysis. And what you can notice -- what you notice immediately is that there's very high concentrations of ASO in the spinal cord as expected. This is a lumbar intrathecal delivery. But as you look at deeper brain regions, look at the CNS and then across the brain, including cerebellum, basically, what you label is the region of cells adjacent to the cerebral spinal fluid. And you can see that as you go throughout the brain. On the right-hand side is delivery using the OTV technology. So again, an antibody with a single ASO fused. In this case, we're using MALAT1, which is actually a reporter ASO, so we can measure both where the ASO is going, but also the potency, the ability to knock down gene expression. And what you immediately see is broad distribution, all cell types across the CNS. So now if we zoom in at structures within the brain, one thing that you'll notice is that for the intrathecal delivery, you primarily, again, focus on labeling cells exterior. So this is very important data. And I think probably underappreciated both for ASOs, siRNAs or any large molecule when you actually deliver intrathecally you're not going to get broad distribution throughout the CNS. And it depends on the size of the animals. So many studies are done in rat. And then as you scale to monkey and then you scale to human, it's a bigger challenge. In fact, human brain is about 18x larger than the cynomolgus monkey brain shown here. But what you see with the OTV is essentially all cell types labeling. Now on the right-hand side, looking at Cortex Triad, cerebellum, and even in white matter where it's largely a cellular, you see endothelial cells and some oligo tender sites also labeling with ASO. And I should just comment that the white labeling in the previous slide in this slide is where the actual ASO goes, and we can see that through immunohistochemistry. So now let's talk about the potency. And so there really -- there are 3 groups of animals in this slide. The white bar graph is basically the control. That's the baseline expression level across brain regions of MALAT1. And then we have either intrathecally treated animals or we have animals treated with the OTV. And the take-home message is, when you look at the right-hand side, you see about a 50% reduction in gene expression across all brain regions. It's basically what we've observed through immunohistochemistry is that you get this broad distribution of ASO and potency across various cell types. And in fact, in mouse models, we've shown that we can knock out or knock down gene expression in all cell types, neurons, microglia astrocytes and beyond. On the left-hand side, you see through intrathecal delivery, primarily spinal cord reduction in gene expression as expected and also shown by the immunohistochemistry. So today, we're actually announcing our first 5 targets to go after using the OTV technology. So there are 2 in common neurodegenerate diseases and probably the targets that everyone would expect alpha-synuclein as well as Tau. So MAPT and SNCA are the genes that regulate Tau and alpha-synuclein expression. These are fantastic targets. We know that reduction of about 20%, 30% or 40% can be highly protective in most of the models and we look forward to advancing these programs. We also are moving forward with UBE3A. ATS as well as an epilepsy target, which we have identified, but will not disclose at this time and then DMPK. I failed to mention that in addition to CNS distribution, we also see very good muscle knockdown and peripheral knockdown of gene expression using the OTV technology. The advantage of going after using OTV with DMPK is that we can also target CNS expression as well. Okay. I'll now end by focusing on some of our small molecule programs, which are in late-stage development. Let's start first with the LRRK2 inhibitor. So as far as we know, this is the only small molecule inhibitor for LRRK2 in clinical testing. And this was a big milestone year. 2022 is a big milestone to actually begin our first full efficacy studies in both idiopathic as well as LRRK2 carrier studies. This gene was actually discovered in 2004, so there's some insight in how long it takes to crack the code for some of these targets. The mutations are actually kinase activating and then, of course, we're using a kinase inhibitor that's engineered across blood-brain barrier, a small molecule. These programs now the Lighthouse and LUMA study, which are both LRRK2 carriers as well as idiopathic are currently enrolling and Biogen is leading the operations around these clinical programs. Here, I'm going to show you data that we just presented at end of last year or so in December. This is the first data in ALS patients treated with an eIF2B activator looking at the ability to inhibit the integrated stress response. So our eIF2B program is one of the most advanced programs. This is a highly competitive space. And we recently announced that we are moving this program into the HEALEY platform study this year. So this, again, will be a large study focused on efficacy. But what you can see is both the low and high dose robustly inhibit expression of integrated stress response genes in this ex vivo [indiscernible]. These are from patient samples in the ALS study. We plan to report out the final 28-day Phase Ib data mid-2023, and now it's all about kicking off the HEALEY study and enrolling that study. In terms of our RIP kinase program, we don't spend a lot of time talking about this program. We have a fantastic partner in Sanofi for this program. But this is actually the first time presenting this data on the lead program, SAR820. It was formerly known as DNL788. So this is the CNS crossing RIPK inhibitor. And what you can see is at all doses, a very robust and sustained pharmacodynamic response using this RIPK inhibitor. Now this program has now expanded to a number of indications enrolling right now a Phase II study in ALS. This is a large study, 260 patients. Soon an MS study will kick off, again, being led by Sanofi, a lupus study with the primary completion mid-2023 and then recently an ulcerative colitis study that has kicked off. With those last 2 indications, it's with our peripherally restricted RIPK inhibitor. So again, a fantastic collaboration with Sanofi as we search for efficacy across multiple indications. So in summary, this next year is around clinical execution, advancing the fourth program into late-stage clinical development continue to execute across our portfolio, including key data readouts for some of our earlier-stage programs and then our TV expansion, and I highlighted the OTV but also bringing in a second enzyme, which will be our fourth TV-enabled program. And then I think excitingly, getting ready for a commercial launch. It's focusing initially on Hunter as well as ALS. And so our commercial readiness will be a key focus for Denali. And with that, we're well capitalized, very excited for the coming year. But I want to thank really 2 groups of people. And first, and I guess when your portfolio gets to a point where it's advanced to patient studies, you start to hear a lot from patients, from families and from caregivers, and it's the thing I love the most about my job. It's a fantastic experience to be able to engage with patients who are on our trials or who want to be on our trials, and I'm grateful for them and the sacrifices they make to be on our trials. And then second, for everyone at Denali here in South San Francisco, but also in Salt Lake City and Zurich, we have a great team, and thank you for all your hard work. And with that, we'll take questions.

So as a reminder, to ask a question, you can raise your hand and someone will bring you a mic or you can submit questions via the portal. Maybe I will start. The kind of push into OTVs is really evident. How do you make sure that the O part like the oligo is optimized? I think there's reasonable buying on the TV part at this point, but what about the O part?

Yes. It's a great point. There are 2 points of optimization. One is the transport vehicle itself and making sure you have the right affinity, which we've done a lot of work in animal models over time. And there, we have selected a lead OTV, the IgG, we'll call the IgG core which we have a stable cell line. We're an IND-enabling stage with that so we can produce the OTV. The ASO, there are many opportunities to invent in this space and to continue to improve the platform. So at this point, what you'll see those 5 targets for most of those we have advanced ASOs, some lead ASOs, and it's a combination of just understanding the potency but also the sequence and how it's basically how stable it is in systemic circulation and its ability to knock down. And ultimately, it's the pharmacodynamic response that drives that. But you're exactly right, there's a huge opportunity for invention. I also just note that the actual image we show is the image of our OTV. So it's a single ASO linked to the IgG, and that's not by chance. We've looked at many variations in that regard.

Maybe switching to DNL310. Is there any update you can provide on the pivotal Phase II/III study? When do you expect to complete enrollment for the neuronopathic and non-neuronopathic cohorts?

Yes. Carole?

Yes, sure. So that study is actively recruiting right now. There's been a lot of enthusiasm from the community. We currently have 10 sites activated in 5 countries and anticipate bringing on 17 countries for a global Phase II/III study.

When do you expect complete that enrollment?

So we haven't provided guidance on that from clinical trials. We expect that study to complete at the end of 2025, which is really reflecting a 2-year treatment period for the neuronopathic cohort, which is cohort A and a 1-year treatment for the non-neuronopathic cohort. I think it's very important to understand the design of that study, which really enables us to gather data that will enable DNL310 to replace standard of care for both patients that have only peripheral disease, but then most importantly, the majority of the patients, more than 2/3 of them have neuronopathic disease. And the neurologic symptoms really are the most unmet medical need, and we expect to see superiority compared to standard of care Elaprase.

So for those neuronopathic patients, I think you allow for a blinded treatment switch from week 48 to 72. Can you talk about the purpose of the switch and the criteria for the switch? And how should we think about any impact that would have on the primary endpoint?

Yes, it's a great question, and it's something that we put into the design of our study also in consultation with patients and patients families. And so the blinded switch is to enable patients to make that switch should they feel that they are declining and not responding to the treatment allocation. The reason for allowing the blinded switches, we're able to then keep the patients in the study and get data all the way to the 96-week endpoint. We don't expect a lot of patients to switch in the study. We have a 2:1 randomization, which means the majority of the patients will be receiving active therapy, which is also very important to patients and families.

I'll just add one other point, which is kind of interesting from the slide that I presented that a handful, although it's very few patients are actually not well treated with either sulfate because of very high antidrug antibodies, right? So even their peripheral heparin sulfate is not reduced. And what we can see because we have the ability to dose much higher than either sulfate that we can essentially eventually normalize those patients, right? So I think the key here is that a patient that goes on the trial has the ability to have an effective drug. That would maybe one population, but you'll see it's 2 patients in 27 that kind of met that criteria.

Yes, it's a great point. And I think these -- the physicians are always monitoring patients based on urine GAGs and we know that our therapy is able to reduce those urine GAGs to essentially normal levels. And so for patients that are in the trial knowing that they have a 2:1 likelihood of having active therapy, we don't anticipate, again, many incidences of blinded switches. So we don't expect really that should impact the primary end point and our analysis.

Yes. And that data also drove -- the data in Phase I/II also drove our decision around the dose level to really capture all patients going with the higher dose, even though we know the minimally efficacious dose is about 1.5 mg per kg, we selected 15 mg per kg to be able to capture all patients, especially those that mount a pretty robust immune response.

Regarding the age range of, I think, 2% to 6% for the non-neuronopathic cohort, what was the rationale behind enrolling younger patients?

Yes. So we really wanted to be able to intervene on patients close to the time of diagnosis. I think as most people know, this is a very progressive disease where patients essentially gain development until milestones normally until about the age of 2, and then they subsequently lose this, losing the ability to speak, losing the ability to in many cases, toilet even ambulate. And so starting early is going to be very important, particularly as newborn screening will likely be much more prevalent in this disease over time.

I think Jess is looking for answers from the audience. Every time you look up for questions. You can do answers and questions. Anyone, there's got to be one question. Right there. There we go. Sorry, Jess. I'm moderating now. Jess, I have a question for you.

Can you comment on the affinity of your transport vehicles for glia versus neuron a little bit on how that distribution and the uptake happens?

Yes. So just to restate the question around affinity and cell type specificity.

Yes.

Okay. So the affinity for each one of our TV is engineered specifically for that target. So I can just give, for example, ETV:IDS, through our experience, about 300 nanomolar is the ideal affinity to give very good biodistribution in CNS, but also periphery because remember, we're targeting periphery as well with IDS. Notably, we've seen no difference between cell type specificity with affinity. So you can dial the affinity up or down, but you get the same distribution. And I think really, really importantly is the ASO data the ASO data tells us because when we look at like the different cell populations, that you get equal knockdown across microglia, astrocytes, neurons, oligodendrocytes, right? But TFR is very important for that. Not all BBB targets will enable the ASO delivery, but we've confirmed that indeed TFR will drive that. And so we have done those affinity experiments, and I don't think we're disclosing the exact affinity that's optimized for the ASO, but for every modality and even target, it's different. So for example, TREM2 were slightly lower affinity because there we're looking for a sustained exposure in the CNS and therefore, you get a better sort of PK profile. That's a great question. Thanks.

For DNL343, can you talk about the potential advantages of being part of the HEALEY platform trial?