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

Good morning, everyone. Thanks for joining us. We're pleased to have Denali Therapeutics with us this morning. I'm Salveen Richter, biotechnology analyst at Goldman Sachs. And from Denali, we have Ryan Watts, Chief Executive Officer. And with that, Ryan, I'm going to turn it over to you to make opening presentation, and then we can move it into Q&A.

Great. Thank you, Salveen. Excellent to be here today. Looking forward to presenting. I'm going to share my slides now and spend some time on 3 of our programs today, starting with the blood-brain barrier technology, moving on to LRRK2 and then to RIP kinase. And so just quick disclaimers here. Just a reminder that Denali is focused on defeating degeneration. And so we have a number of ongoing or recently completed studies in rare neurodegenerative diseases; ALS, Parkinson's and Alzheimer's disease. The company is built on 2 platforms, what we call the degenogene platform. So these are genes when mutated that cause neurodegeneration or a major risk factor for neurodegeneration. Within that biology platform, we have 3 biology teams; lysosomal function, glial biology and cellular homeostasis. We also have built blood-brain barrier technologies, including small molecule, biotherapeutics and gene therapy. And today, I'll focus on the small molecule programs as well as the biotherapeutic platform, known as the transport vehicle. In terms of our portfolio, we have a number of clinical stage programs. I'll focus today on 3 of them; LRRK2, IDS -- LRRK2 for Parkinson's disease, IDS for Hunter syndrome. Both of these are in our lysosomal function biology area, and I will give an update on RIP kinase, which recently we announced yesterday, the transition from our 747 to another molecule, DNL788, and I'll provide some data and rationale behind that decision. Beyond that, we also have introduced a new AAV program. So our focus on AAV is basically engineering either the proteins that are expressed by -- or the genes expressed by the AAV and the subsequent proteins that cross the blood-brain barrier or AAV capsids that can readily cross the blood-brain barrier, again, consistent with our BBB technology platforms. This particular AAV is targeted towards Parkinson's disease. Also, we have now transitioned both progranulin and TREM2 into IND-enabling studies using our transport vehicle technology to, again, transport proteins and antibodies across the blood-brain barrier. Also announced yesterday the advancement of our RIP kinase program for peripheral indications, the completion of healthy volunteer studies and now planning for additional, now, patient studies across multiple indications in inflammatory disease. This program is being led by Sanofi. In terms of our goals this year, our main goal is to select a lead LRRK2 inhibitor to move into a Phase II/III trial. We will be doing that in the middle of the year with the totality of the data we have for both of our molecules, DNL201 and 151. We will establish biomarker proof-of-concept in patients for our transport vehicle technology using the enzyme transport vehicle and in Hunter syndrome, and I'll spend some time on what the expectations are there and what we're trying to achieve. We have an -- we had an ongoing Phase I study for DNL343, which is an eIF2B activator. I won't discuss that program today. It's been delayed by COVID, but we plan to initiate that study again soon. Our ultimate goal is to enable patient study this year, and we'll see, based on COVID delays, if that will be possible. And we've completed now the ALS and Alzheimer's studies and just recently read out those studies, I'll show some data today, and we've made a decision to move to our backup compound DNL788. And again, I'll provide some detail. Finally, the proof-of-concept for ETV:IDS, we'll read through more broadly for the proof-of-concept for the blood-brain barrier technology, the transport vehicle. And now I'll provide some details on that. And in fact, just recently published 2 papers in Science Translational Medicine, outlining the blood-brain barrier technology. Just a note on the COVID impact. As I'm sure many are impacted by this, just to note, our on-site and remote operations are nearly at full productivity levels. We've been able to continue to do experiments, even though we're based here in San Francisco Bay Area. Of course, biotechnology is deemed essential, and we've continued to work in the labs. Enrollment of our DNL151 as well as 343 clinical trials have been paused due to, again, COVID. We're able to do -- to complete a number of arms for both of these studies, and so have initial data. However, we need to continue to dose escalate, for example, for 343. Our key 2020 clinical readouts and decisions remain on track, those I outlined in the goals, and then we have a strong balance sheet with just over $600 million in cash at the end of Q1. So let's start first with the transport vehicle technology and to go into some detail here. So just a reminder that the blood-brain barrier is a major obstacle for therapeutics, specifically biotherapeutics, but also small molecules in terms of the ability to cross vessel walls and get into brain tissue. This is because the brain involve the blood-brain barrier to protect us from toxins and also to maintain a tight microenvironment for neuronal signaling. What we have done is we have engineered the Fc portion of an IgG, and I'll outline this in the papers that we just published, to bind to the transferrin receptor, which is highly expressed on the blood vessel walls in order to transport molecules across the blood-brain barrier. The first of 2 papers published back-to-back by Denali scientists outlines the brain delivery of therapeutic proteins using an Fc fragment blood-brain barrier transport vehicle in mice and monkeys. So I'm just showing here some of the data. Just a reminder that what we were able to achieve is basically engineering the Fc portion to bind the transferrin receptor. On the upper right-hand corner is the solved co-crystal structure of this interaction. What I'm showing on the bottom is robust brain uptake in nonhuman primate. It's actually 25 to 35 folds across all brain regions that we measured. And you can see by imaging, basically broad biodistribution of the antibody transport vehicle. So this first paper used antibodies as a proof of concept. The second companion paper, brain delivery and activity of a lysosomal enzyme using blood-brain barrier transport vehicle in mice utilizes Iduronate 2-sulfatase fused to the transport vehicle, so an Fc fusion, which is a standard biotherapeutic approach. And what I'm showing on the bottom right-hand side here is basically rescue by imaging of GM3 and GM2. These are lysosomal markers, and you can see robust rescue with ETV:IDS where IDS sulfatase did not rescue. So I think the key with our BBB platform or the transport vehicle platform is its broad modularity. And so the first example that we've -- we're pursuing is, again, ETV:IDS for Hunter syndrome. However, the transport vehicle can be applied to antibodies. Our lead program here is TREM2, which is an agonist antibody for TREM2, can be applied to other proteins. And here it's progranulin for FTD. By the way, TREM2 is for Alzheimer's disease. And recently, we've established preclinical proof-of-concept that we can knock down gene expression with systemic delivery of ASOs fused to the oligonucleotide transport vehicle, here establishing greater than 70% gene knockdown. So we see broad utility. We, in 2018, actually entered into a partnership with Takeda based on the blood-brain barrier technology and 3 named programs, which include TREM2, progranulin and Tau using the transport vehicle technology. We see its utility more broadly, and I'll get to that at the end as we think about the other therapeutic areas in which we could utilize this technology. So what I'm illustrating here is actually a molecular animation of ETV:IDS. So on top in yellow is Iduronate 2-sulfatase, on the bottom is the Fc fusion. And you can see down at the bottom, one of the 2 Fcs binding to transferrin receptor, binding in a way that does not block iron interaction with transferrin receptor. The human brain has about 400 miles worth of blood vessels, and these blood vessels are aligned with various transporters for iron, for glucose, for essential amino acids. Most biotherapeutics establish a steady state of about 1,000 molecules in blood to 1 in brain. And here, we can boost that by 30-fold by utilizing active transport using the transferrin receptor. So you can see in this molecular animation binding to transferrin receptor on that apical domain. It's then internalized, brought into blood vessel walls and then what you see is broad biodistribution throughout the central nervous system after the molecule is transcytosed across the vessel wall. Importantly, in these studies and in preparation for entering clinical trials for ETV:IDS, we took it one step further and asked where does the enzyme actually go after systemic delivery. And what we see is that the enzyme is taken up into cells, likely either via the transferrin receptor or the mannose 6-phosphate receptor, which is the receptor for the enzyme as shown here. This is critical because the enzyme is injected systemically like Elaprase, rescues peripheral disease, but also can rescue central disease by crossing the vessel wall, being brought into cells and then into lysosomes and basically processing the substrate as illustrated here. So just a reminder, DNL310 is now -- has now cleared IND, and as we are at the point now where we're gearing up and enrolling these studies with the goal of getting initial biomarker proof-of-concept by year-end, that will be essentially short-term dosing, looking at CSF biomarkers. Hunter syndrome is caused by a mutation in IDS, which then leads to an accumulation of glycosaminoglycans or GAGs. These are heparan sulfate and dermatan sulfate. That ultimately leads to neuroinflammation and neurodegeneration. As I'm going to take you quickly through some of the data that's presented in the paper and basically point out that IDS compared to ETV:IDS has equivalent efficacy in the periphery, but only ETV:IDS shows robust reduction in brain and rescue of lysosomal function. We then ran an experiment where we could basically dissect the brain and look at the various cell types; neurons, astrocytes and microglia. And across all cell types, we can reduce the substrate GAGs. This is after 4 weeks of dosing in the IDS knockout, and here you can see anywhere between 80% to 95% reduction across all cell types. When you zoom in on a single cell using super-resolution microscopy, what we can see basically is the human IgG, which is ETV:IDS and LAMP2, which are lysosomes and the co-localization of ETV:IDS with lysosomes within neurons. This is a neuron because we've labeled it with NeuN in green and then the cell -- the nuclei is in blue. In addition to that, when we do chronic dosing, so 13 weeks of dosing, not only do we reduce GAGs in brain and CSF between 50% and 75% depending on what you're measuring, we also can completely block neurodegeneration by measuring neurofilament. This is actually the bar that we've set for the acute dosing in the clinic, basically a 50% reduction in GAGs knowing that, through chronic dosing, will lead to basically block of neurodegeneration. So our Phase I/II study is a biomarker proof-of-concept study. Obviously, the primary endpoint being safety in addition to a 50% reduction in CSF GAGs in an interim readout, again, short-term dosing, 4 weeks of dosing. We'll then continue to dose for 6 months and look at other biomarker endpoints, including lysosomal as well as neurofilament. So the transport vehicle technology have illustrated its utility for Hunter syndrome and enzymes. And just to highlight again, we can deliver antibodies, proteins or antisense oligos. We've applied the transport vehicle also to a beta such as aducanumab or to HER2 and have seen, again, 30-fold increased uptake, improved immunodecoration in terms of a beta and also improved efficacy in terms of HER2. But as shown here, these are our lead programs. So we see a broader utility, obviously, for the transport vehicle. And the data in Hunter syndrome will be critical for basically validating the platform in humans. Now switching gears, I'll focus on LRRK2. And just a 2 broad comments. First is we believe LRRK2 has broad therapeutic potential. Part of this is driven by the fact that genetics suggest many lysosomal-related proteins and LRRK2 inhibition improves lysosomal function. We have DNL201 and 151, which are both clinical stage inhibitors, and our plan is to select between these 2 molecules. It's been shown that, in fact, in Parkinson's disease, LRRK2 is activated in sporadic Parkinson's disease, not linked to necessarily LRRK2 mutations. Of course, those carrying LRRK2 mutations also have about a twofold increase activity of kinase. When we inhibit LRRK2, even in Gaucher patient fibroblast, we see a 4-fold increase in lysosomal function. And so broadly speaking, we believe inhibiting LRRK2 can have broad therapeutic potential. Just recently, 2 weeks ago, a paper was published in Nature Medicine, showing that LRRK2 loss of function in humans is well tolerated. There's no, as we can tell, adverse effects on lung or kidney, which is areas in which the lysosomes are actually enlarged when you inhibit LRRK2 or in LRRK2 loss of function. I think, importantly, we can achieve greater than 70% inhibition at trough to see even greater than that, and these molecules are well-tolerated. So just a reminder that LRRK2 mutations increased kinase activity, which leads to hyperphosphorylation of Rabs, which is one of our biomarkers and subsequent dysfunction of the lysosome. And this can be measured again by various lysosomal markers, similar theme to what I was sharing in Hunter syndrome. This ultimately leads to lysosomal dysfunction and neuronal degeneration, and in particular, dopaminergic neuron loss. As I've already highlighted, there's substantial rationale for LRRK2 activation in sporadic Parkinson's. Thus, we're pursuing both mutation carriers with hyperactivated mutations as well as sporadic Parkinson's disease. We've now completed DNL201, both healthy volunteer as well as patient studies, and we've shared that data at the beginning of the year. We have ongoing studies for 151, both in healthy volunteers as well as patients. We've completed several of the arms in the patient study, and we would like to continue to dose escalate because we have not found a dose-limiting toxicity. And I'll share some of that data now. So for 201, what we see is robust inhibition, both at the low and the high dose, looking at target engagement, pathway engagement and as well as rescue of lysosomal function. Directionally, when you inhibit LRRK2, BMP levels go down. When you have a mutation in LRRK2, BMP levels go up. And so the goal is to bring that back to wild-type levels. And we can achieve that both with the low and the high dose. Subsequently, we measured this, the first study ever run in patients with a LRRK2 inhibitor, and we had a subset of LRRK2 carriers as well as sporadic. And we focused on biomarkers that were LRRK2 carrier specific. Interestingly, these biomarkers end up being lysosomal in nature, so maybe not surprisingly, linking LRRK2 to lysosomal function. And so we identified a subset of biomarkers that were elevated in carriers relative to sporadic, and these biomarkers are reduced by inhibition of LRRK2. We've also presented data on DNL151 healthy volunteer study. Again, very robust target inhibition, greater than 75% inhibition, looking at both target engagement as well as downstream pathway engagement with Rab. And subsequently in terms of lysosomal function, we see, again, reduction in BMP back to the levels we want to achieve in terms of relative elevation in the mutation carriers. In terms of the safety profile, DNL201 was well tolerated at the low dose. And at the high dose, we saw an increase in incident of moderate adverse events, including headache and nausea. We believe this is related to an off-target effect of 201, specifically phosphodiesterase, which we do not have in 151 and the reason we brought 151 into the clinic. And in fact with 151, we have not identified a dose-limiting toxicity, and thus, the desire to continue to dose escalate both in healthy volunteers as well as patients. In terms of next step, we've hit our target engagement and biomarker goals for both molecules, both in healthy volunteers and patients for 201 and in healthy volunteers for 151, and we'll soon read out data for 151 in patients. We'll select one of these molecules to move forward into a Phase II/III study. We've already been preparing for these studies with a partnership with Centogene in terms of genotyping Parkinson's patients and basically gearing up for that study. So now I'm going to turn our attention to RIP kinase program. A brief introduction to the target itself. So RIP kinase, I think the simplest way to describe it is that RIP kinase-1 is downstream of TNF receptor-1. So the goal here is basically an oral anti-TNF, at least as it relates to the RIP kinase pathway. When RIP kinase is activated, we see an increase in inflammation and necroptosis. And necroptosis is a necrotic cell death, similar to apoptosis, but is initiated when RIPK1 is activated. So the goal for the RIPK program was to develop a suite of inhibitors that would target both peripheral inflammation as well as central inflammation. And indeed, the peripheral inhibitor, DNL758, is being led by Sanofi and the central inhibitor, we're codeveloping with Sanofi. So just a reminder of the study designs for the Phase Ib studies for DNL747. These are unique studies, in that we treated patients, both Alzheimer's and ALS, for 29 days, and then we have placebo for 29 days or vice versa, placebo for 29 days and then treatment for 29 days. The reason for this is that we could follow biomarkers as well as safety on and off drug, increase the power for us to see changes in biomarkers that are related to RIP kinase and are elevated in the disease state. In terms of the topline results, the molecule is very well tolerated, up to 29 days. Major -- sorry, the majority of adverse events were mild or moderate. In fact, no severe AEs, no discontinuation. There was 1 SAE, but that was during the placebo period. It was well-behaved in terms of plasma PK and CSF/unbound plasma ratio, meaning great brain penetration, and we'll show some CSF biomarkers. And we had robust target engagement of RIPK and partial correction of disease-relevant CSF biomarkers, and this is important in terms of our decision-making for this molecule. So here are some of the data. I'm going to set the context by showing data on the left-hand side, which we've presented previously in healthy volunteers and then on the right-hand side in Alzheimer's patients. And what you can see is a robust inhibition profile. This was given at half the lowest dose, and you can see that the lowest dose here was -- showed robust inhibition as did 2x and 4x. And the reason for choosing this dose is we had preclinical chronic tox data that we wanted to dose at a lower dose. And what we achieved was in the window of what we wanted to achieve. So we had 83% target inhibition at trough and up to 94% at max target inhibition. That being said, we have a number of biomarkers we've identified that are downstream of RIP kinase-1 that are elevated in the disease setting. And here, we're focusing on the Alzheimer's data. A reminder that Denali that we lead decision-making in Alzheimer's disease, and thus we're going to focus in on this data. And what you can see is that we've identified 2 biomarkers. This was presented previously at our R&D Day, what we call biomarker 1 and biomarker 2 that are disease-related, elevated both in MCA -- MCI and Alzheimer's disease, and in a dose-dependent fashion are reduced by RIPK inhibition. And what you can see is that we were able to reduce 1 of these 2 biomarkers. In fact, this level of reduction, 25%, is equal to the level of elevation in Alzheimer's disease. However, the second biomarker, we did not achieve this level of inhibition. And there does seem to be a rightward shift in the biomarker. So in summary, the Phase Ib dose study partially corrects 1 of the 2 biomarkers, and higher exposures may be required for efficacy, and thus, we had a decision. And based on the preclinical tox, we'd have to increase the duration of dosing in humans, plus then dose escalate, and our decision based on timing is basically to go to the backup compound, DNL788. So in summary, GLP preclinical tox demonstrated evidence of immune-related hematological findings. And in the chronic tox, we saw it at lower doses and longer duration. We've completed now the healthy volunteer study as well as the AD and ALS study. And in terms of DNL788, the preclinical tox of comparable duration just demonstrated no evidence in immune-related hematological findings. As a result, we've made the decision to move to DNL788 in terms of timing. It's essentially the same as opposed to longer duration studies with 747, and we plan to start that healthy volunteer study in early 2021. We've completed the IND-enabling tox studies, and we'll be ready to go. I think importantly, in terms of the target itself, DNL758, we've completed GLP preclinical tox, and we see no immune-mediated toxicities. And we've completed the Phase I healthy volunteer study and are now preparing for patient trials in multiple indications. Thus, we know that RIPK as a target is achievable, it's just identifying the right molecule. And just to pause for a moment, and as we've stated previously, for us, the bar is very high to advance in Alzheimer's disease. We want to make sure that when we move a molecule forward that we have robust target engagement, we can test our hypothesis and that is really behind the decision to move to DNL788 rather than continue with 747. So with that, I'm going to end what we plan to deliver throughout the rest of the year. So in terms of LRRK2 selecting between DNL201 and 151 for ETV:IDS, establishing biomarker proof-of-concept in patients, we'll continue with the healthy volunteer study for 343 as soon as those are initiated, and we hope to be able to enable a patient study that will be dependent on back -- getting back into dosing at higher doses. And I think importantly, we've now completed the ALS and Alzheimer's studies. I have just read out those studies, and I have made the decision to move to the backup compound, DNL788. And then finally, and I think related to ETV:IDS to establish TV platform, proof-of-concept in humans is critical for the platform. But also we've now initiated IND-enabling studies for both progranulin and TREM2 and happy to go into more detail on those programs if there are questions. So with that, I'm going to hand it back to Salveen and answer a few questions. Thank you, Salveen.

Thanks Ryan. So maybe to start, so you actually talked about a new viral vector today and your entry into gene therapy. Could you just expand on that for us and help us understand which disease areas? And how are you going to bring that into the portfolio, for what time frame?

Yes, absolutely. So one of the -- at the very beginning of founding Denali, we had basically made the decision to develop the company around 2 platforms; the degenogenes and BBB technologies. We built a biology team around blood-brain barrier and then a set of engineers, and the engineers are chemical, biotherapeutic, and then about 1.5 years ago, we hired several AAV engineers. And the way we're approaching AAV is twofold. And this first program, actually, the protein itself is engineered across the blood-brain barrier and then we use gene therapy to express this in liver. And as a result, we can rescue both peripheral, so any defects in the periphery, but also in the brain, and the molecule can steadily cross the blood-brain barrier. We're going to be very excited to share more data about that program. We've established actually proof-of-concept in models. And our plan, probably early next year, we'll give more details on the time lines. Now interestingly, you can move very rapidly in the gene therapy space. We'll be using standard AAV capsids in terms of liver expression. The second effort around AAV I see in the future for Denali, which is actually engineering the capsid across the blood-brain barrier. I think the challenge there is getting levels sufficient to be able to infect many cells. There are several companies that are trying to do this. And I think for us, we're going to take a very deliberate approach in trying to identify capsid that was broadly impacting. So in many ways, we're using what we learned from the transport vehicle technology and applying that to AAV, and it's just a different form of delivery. So rather than injecting protein once every week or once every 2 weeks or once a month, we inject an AAV and the protein now is engineered to cross the blood-brain barrier, and it's essentially expressed by the liver. That's a delivery type technology with liver expression. So I would just say stay tuned for that data in terms of both its proof-of-concept and in terms of the timing. We're working out details on timing. And again, we're -- I'd say that generally, you can move pretty rapidly once you have the right vector and the right AAV capsid.

And then secondly, on the blood-brain barrier platform. So we've seen supportive data continue to emerge over time. When you look at all of this in totality, what is it that gives you the confidence here that you're going to see all this preclinical work really translate to that efficacy result you want to see in humans?

That's a great question. So a couple of answers, both from our data and from other people's data. So I started working on the blood-brain barrier in 2006. So I've been at it for a while and realized that what is needed is an industrialized platform, most of the work that have been done and the literature just asked, can a molecule get into the brain, but not really how much, for how long. And what we've seen with invention of the transport vehicle, is that we can have sustained pharmacodynamic response and all of the downstream biomarkers being corrected. So not only to reduce GAGs, but we rescue lysosomal function, and we reduce neurofilament to wild-type levels, which is a very big finding, and that's obviously what we want to translate into humans. That being said, there are 2 companies who have entered clinical studies with transferrin receptor based technologies. One is JCR Pharma, which is a high affinity bivalent antibody. We've actually made a JCR Pharma like molecule and looked at the differences in biodistribution. And I think the simple conclusion for us is that those high affinity molecules get trapped in blood vessels, but some does get across. And so I think there's some validation that you can get some into the brain, but you could maximize that clearly. In addition to that, Roche has what they call the brain shuttle that's been tagged to gantenerumab, and that's currently in Phase I studies right now. Our approach, again, both of those approaches, both gantenerumab as well as JCR Pharma, the antibodies have full effector function, meaning that they can activate the immune system. We believe that you have to have an immune silence molecule when you use transferrin receptor. So I think that's important for translation. The nonhuman primate data, I'm confident, again, is translatable. But that's why I think, Salveen, this Phase I data will be critical to show that at the doses we've selected, we get reduction in brain, showing that it is, in fact, translatable to human. So there is some precedent in humans. We have, of course, a large safety package that goes into the IND filing as do our other competitors. So I think it's really now about how much do you get in, for how long, and can this really be a platform used broadly for biotherapeutics. And we think the transport vehicle has that ability.

Great. And then when you look at the Hunter syndrome program. That's going to read out end of year where we're looking for proof-of-concept here. Can you just walk through the basis of why you're looking at a target greater than 50% reduction in GAGs at 6 months?

So let me give a sequence of events to what to expect for Hunter syndrome. Basically, there is short-term biomarker data. This is an interim readout in which we want to show that the platform is working, and we get sufficient GAG reduction that we think will lead to translatable endpoints. And so I showed a slide that actually would refer to our figure 8 from the second Science Translational Medicine paper, in which you can see CSF GAG reduction of greater than 50% leads to brain reduction of greater to 60%, 70% leads to complete rescue of the lysosomal defects and neurofilament, again, importantly, neurofilament. So step 1 will be that short-term, let's say, 4 weeks of dosing in humans, validating the platform. We then -- that study is a 6-month study. Our expectation is that at 6 months, we should be able to read out now some more Hunter related biomarkers, which are the lysosomal biomarkers as well as neurofilament. And then step 3 is obviously rescue of cognitive decline and neurological deficits. So step 1 is essentially short-term GAG, step 2 downstream markers and step 3 -- now step 3 may come in the Phase III. But as you know, in rare disease, these are -- these studies rapidly morph towards approvable end points.

Can you just maybe on that question of approvable endpoints, do you think you could use reduction in GAG and neurofilament and others as surrogate endpoints versus kind of more functional endpoints here?

So these are the exact conversations we're having with regulators, and the question is how validated are the biomarkers. And I think interestingly, probably the more distal you get, the higher the probability that it has, meaning clinical meaningful readouts. So in other words, neurofilament is very distal. It's related to the degeneration of the nervous system. And so there's probably a higher -- there is a higher probability that regulators will view that maybe as an approvable endpoint. But at this point, we have no definitive answer from regulators if either GAGs or neurofilament or any biomarkers for that matter will be considered approvable. But that's exactly the mindset, again, step 1, step 2, step 3. And remember, it's a rare population. And so there are challenges using cognitive endpoints with the heterogeneity in a small population, but that's -- we're doing a lot of work around the design for that study as well.

And Ryan, can you just remind us how many patients and over what time point and -- how to think about the doses in terms of what we'll get when you see year-end data?

Yes. So we haven't disclosed the exact dose levels. And just again a reminder, and we're careful of this because of competitive pressure from others working in this space. We have -- the goal is to enroll 15 to 16 patients. It's a 6-month study with the interim proof-of-concept readout after 1 month, and then the 6-month data would basically be the totality of the biomarker. And the idea is that likely 3 dose levels across those patients.

Great. And just for the platform itself, what would be the second program that likely moves forward here?

Right now, both TREM2 and progranulin are neck and neck. They also have excellent biomarkers, some of which we've identified that are proprietary that regulate -- they're related to lysosomal function, for example. We had published a paper at the end of 2019 on TREM2, showing that it regulates cholesterol metabolizing enzyme, which is actually really fascinating because TREM2 loss of function, microglial cells get these large lipid accumulations, which were first described by Alzheimer's by Alois Alzheimer in 1906. So it's one of the 3 pathological features. And what we can do with the antibody is basically activate the signaling cascade, activate those downstream molecules, and we can actually read that out in a clinical setting. And so at this point, TREM2 as well as progranulin are neck and neck. We're essentially in IND-enabling manufacturing and then GLP studies. And then by -- and what's great is that all -- considering IDS and TREM2 and progranulin, they're all 3 different classes of molecules using the transport vehicle. One is an enzyme, the other is an antibody and the third is a protein fusion, not an enzyme or antibody. And so we can actually see now validation across different classes. And so obviously, for us, antibodies represent a huge opportunity to use the transport vehicle, example maybe being aducanumab or HER2 for CNS metastases, but the goal was to take basically a lead program in the subclasses of the transport vehicle to then validate basically that therapeutic format.

And then with the RIPK1 update that you just provided, can you help us understand how the ALS indication played out versus the Alzheimer's indication with regard to biomarkers as well as safety?

So as I think some may or may not be aware, Sanofi leads decision-making in ALS and we lead decision-making in Alzheimer's. And as a result, we are not disclosing the biomarker data from that study. But I think the simplest way to describe it is that the target engagement was essentially identical in Alzheimer's and ALS, and the biomarkers moved basically in a similar way in Alzheimer's and ALS. But what's happened in the field, and I think that the leader in the RIPK field or the previous leader in the RIPK field was GSK. They moved a small molecule into the clinic. They actually moved that molecule back to research, created a new formulation, and what you see there is that they were basically going at t.i.d. and trying to achieve greater than 95% to 99% inhibition at trough. They have data in peripheral inflammatory disease. And I think the conclusion is that the bar is much higher. In addition to that, there has been data published in the patent literature on RIPK inhibitors, again, needing to achieve extremely high levels of inhibition to rescue, for example, EAE, an animal model for MS, and MS is one of the indications that Sanofi is interested in. I would say that the levels of target inhibition that we achieved would probably lead to partial, and we don't know, maybe robust efficacy, but it's the wrong experiment to do. And I think having been in the Alzheimer's field for a long time, we see a lot of these experiments where suboptimal drugs given at suboptimal doses run a large Phase II or even Phase III studies and then have basically equivocal data, and we don't want to do that. We know that it's a serious investment in Alzheimer's to take that next step. So even though we had correction of 1 of our 2 biomarkers, and we had to make a decision, should we go forward at that dose into an efficacy study or should we step back, bring another molecule that doesn't have basically that limitation. We also debated taking 747 into more chronic safety studies in humans because that would be the path as well. And that's where we lined up the time lines and realized that actually moving to 788 we don't really lose much time. There's maybe about an 18-month difference. And we have a molecule that we would -- doesn't have the same safety profile. Now of course, we don't know -- what we don't know about 788, and we're going to go into the clinic, and we'll get that healthy volunteer data. And ideally, it will act like 758 and allow us to dose even higher and have more robust target inhibition.

And a final question here, Ryan, as you look to your LRRK2 program and that moving into Phase II/III, what will we get a sense in terms of -- or will we get a sense in terms of functional results there? In addition to LRRK2 inhibition, will you look to add sporadic patients as well into that study? And then any clarity there on the -- from the FDA in terms of what would be your regulatory endpoint for instance?

So I'll start by saying, the great thing about LRRK2 is we know we have a molecule that can go the distance. We have a molecule that can enter Phase II/III with DNL201. In many ways, we're just waiting to see if 151 is better. And I think the theme is we're always trying to do the best we can because once we enter those studies, they're long, they're expensive, and we're looking for clinical endpoints such as UPDRS, in that study, right? So we've made the decision to basically pursue both carriers and sporadic in parallel. In part, the evidence is growing in sporadic Parkinson's that the lysosome generally is dysfunctional and inhibiting LRRK2 can be beneficial. We want to design those studies and power those studies so that we can see clinical endpoints such as UPDRS. We'll continue to validate the biomarkers that we're working on, the lysosomal-related biomarkers. We've identified a set of LRRK2 dependent, and we're exploring sporadic, more broadly lysosomal biomarkers. But in reality, we have a molecule that we can test the hypothesis. And the best way to do that is to look at clinical endpoints such as UPDRS, right? That means relatively large studies, ideally in treatment-naive patients. But we also realized that when we enter into those larger studies and efficacy studies with LRRK2 that every LRRK2 mutation carrier should have the ability to take this -- to take a LRRK2 inhibitor because it's a smaller, rare population. So I think what you should expect is pursuing both in parallel and doing the best we can to power both. I think it will be obviously easier to power a sporadic study because there are many more patients and essentially clinical endpoints, specifically motor function.

Great. So with that, thank you very much, Ryan. Really appreciate your time today.

Yes, likewise. Too bad we can't be with you in Southern California. It's one of our favorite conferences. Steve and I love -- absolutely love being there. But you know what, Zoom will work for today, and hopefully next year.

Hopefully next year.

Okay.

Thanks, Ryan. Take care. Bye.