Arvinas, Inc. (ARVN) Earnings Call Transcript & Summary

Good morning, everyone, and thank you for joining our call. My name is Brad Canino, senior biotech analyst here at Stifel. And I'm delighted to be joined by 2 members of the Arvinas leadership team to discuss the company's new PROTAC degrader entering the clinic against the neuroscience target, LRRK2. And I would say, for me, it's been an exciting past 12, 18 months as an analyst to see Arvinas bring this technology to late-stage clinical development for breast and prostate cancer patients, really pioneering this new modality and defining the patient populations who can benefit. And now the company is again set to be the first, this time to develop a protein degrader for CNS diseases. So to discuss that, I would like to introduce John Houston, Chief Executive Officer of Arvinas and Angela Cacace, Senior Vice President, neuroscience and platform biology. So thank you for joining us. Now many of you on the call will know John, but I think it would be a great opportunity for Angela to introduce herself and her role at Arvinas.

Happy to, Brad. So I've joined Arvinas 5.5 years ago prior to the IPO to build out the neuroscience platform, and we're really excited about the progress that we've made. Prior to joining, I was at Fulcrum Therapeutics as employee #4 there for 2.5 years. And prior to that, I spent 20 years at Bristol Myers Squibb in various capacities, PhD from Columbia in pharmacology.

Perfect. Thank you, Angela. So for the listeners, this call will be structured as a presentation for the Arvinas team. That will then be followed by questions for myself. And please feel free to send any questions you may have in the Zoom chat box as well or you can e-mail them to me at [email protected]. And with that, I'll hand it over to you, John. Thank you.

Thanks, Brad. And Angela, maybe you could just go to the first slide. This is just the same that goes about any forward-looking statements and may or may not come to pass. So we're going to talk about PROTACs, not surprising because Arvinas is a PROTAC company. And just as a kind of a brief round around what a PROTAC is, which stands for proteolysis targeting chimeras. These are heterobifunctional molecules. One end binds to the ligase, the protein degradation machinery in a cell. The other end of the molecule binds to the specific protein target that you believe is causing disease that you want to degrade. And then the PROTAC brings these 2 proteins together on this slide, point 2, brings them into close proximity. And then ubiquitination occurs, the natural process of E3 dropping an ubiquitin onto target protein. And once 4 ubiquitins appear in that protein, that serves as a signal for that protein to be dragged off to the proteasome, which is the cell's garbage disposal unit, and the proteins are stripped down into peptides and flushed back into the cell. Now the great thing is the PROTAC is released at this point and goes back and does the same PROTACs over and over. So it's an iterative process. One of the first things is it very different from [indiscernible] inhibitor. In fact, there's a number of different things that you look at with the PROTAC versus inhibitor and we look at it from a point of view of a protein knockdown in the cell. It eliminates rather than just inhibiting the protein. It can also disrupt scaffolding function, if you have a protein, say like a KRAS protein that has a lot of other axillary proteins that bind to it. By getting rid of the protein, that's scaffolding function disappear. So really important in terms of changing the signaling process within the diseased protein. We also have the ability because of this being a proximity-based approach to look at tackling [indiscernible] difficult to drug targets, where you really don't need to be binding right into the active site of the protein but you can actually bring the proteins together and that drives the efficacy, as I mentioned before iteratively. And as you'll see, we've been able to drive these molecules to be orally bioavailable, and as you'll hear from Angela, also have the ability cross the blood brain barrier. So really a true therapeutic modality. Here's the current Arvinas' pipeline. Not surprisingly, heavily focused on our major programs, vepdegestrant, ARV-471, which is in a number of different trials for metastatic breast cancer. Most notably, we have our pivotal monotherapy trial, which we have a top line readout later this year. We then have a whole host of other combination trials, really trying to position along with our partner, Pfizer, vepdegestrant to be the endocrine backbone therapy of choice for any other molecule that could be combined with it. So very exciting advances in that program. Similarly, with ARV-766, which is our prostate cancer degrader in planning for Phase III, we'll be going to health authorities in the second quarter of this year with our data as it relates to project optimist work and selecting a dose, a very exciting stage for that program, too. And then behind that, we now have the first of our new wave of programs going forward in oncology and hematology, BCL6, where we plan to be in Phase I this year. And then LRRK2, which is going to be the bulk of the discussion that Angela is going to go through our first ever neuroscience asset, the first of hopefully several from that pipeline moving forward. And then a whole host of other preclinical programs that, over time, we'll be able to discuss in detail. But today is about neuroscience and a very, very large area where there's a lot of need, not many good therapies out there. And greater than 6 million patients [indiscernible] goes with either Alzheimer's, Parkinson's or Huntington's, that's just those alone. We believe PROTACs really offer a great opportunity to provide a disease-modifying therapy. So not just the symptomatic, the blood-brain barrier penetration, which has been a challenge for other modalities, we believe will not be a challenge for PROTACs. So we believe we'll be able to get into those compartments of the brain with the disease proteins as well. And this will be through a drug that will be an easy delivery process, either an oral drug or through IV. So not some of the kind of more invasive procedures of other neuroscience products where you have to be intrathecal. So we believe that the neuroscience and PROTACs in particular, that combination have the potential to change the treatment paradigm for neurodegenerative diseases: the blood brain barrier crossing, being able to target pathogenic proteins in the brain specifically and the fact that we can make these drugs oral as well for helping with patient compliance. And our major programs right now are LRRK2, Tau, alpha-synuclein, aphasic and Huntington. And as you'll find out now, we're ready for our beginning of Phase I with LRRK2 targeting. That's happening very soon, and that will be in human healthy human volunteers. So with that, I'm going to hand over to Angela, who's going to take you through some of the very exciting data as it relates to LRRK2 and then we would be happy to answer your questions. Angela?

Thank you, John. It's a pleasure to be here today to talk to you about LRRK2 PROTAC-mediated degradation as a potential treatment, as John mentioned, for idiopathic Parkinson's disease and progressive supranuclear palsy. And it's really the human genetics and the strong preclinical biology that create a very good rationale for differential biology of the PROTAC LRRK2 degraders. LRRK2 is a large multidomain scaffolding kinase, otherwise known as leucine-rich repeat kinase or LRRK2 as it's commonly called. And so I want to start by talking about Parkinson's disease. As you know, since high unmet medical need, I think we've all been touched by Parkinson's disease, either a friend, family member or caretaker that we know. There are no approved disease-modifying therapies for Parkinson's disease. And it's really the familial mutations as well as sporadic mutations that implicate LRRK2 in Parkinson's disease and actually put the brakes on the lysosomal protein clearance system for these aggregating proteins that accumulate in the disease like alpha-synuclein. And one of the things I want to point out is recent data that has been published by Mark Cookson and his colleagues that shows that in post-mortem brain, there's overexpression of LRRK2 in microglia in the brain. And this contributes to the neuro-inflammation that occurred in the brain as well as mitochondrial damage. And so all of these aspects of LRRK2 dysfunction caused dopaminergic loss in Parkinson's disease and loss of other neurons that are critical to function in disease. And I also want to point out that 50% reduction of LRRK2 improved pathology and neuronal survival in a synuclein Parkinson's disease model. And Virginia Lee and her group were unable to show that kinase inhibitors rescued neuronal loss in that model. And so now I want to redirect your attention to progressive supranuclear palsy or PSP. This is a pure tauopathy. It is a very rapidly progressing disease that's horribly debilitating and leads to death within 5 to 7 years. There are no approved therapies for progressive supranuclear palsy. And recently, the University College London have shown in a large GWAS study that there are genetic variants of LRRK2 that are associated with accelerated progression and time to death. So any time in drug discovery for neurodegeneration that you have human genetics that point to progression of disease. That is an indicator that, that target is worthwhile pursuing. And so we're -- and also the additional evidence really from the eQTL analysis that suggests that LRRK2 has increased in expression in this disease as well. And so what I'll show you is differential data from kinase inhibitors. And as John mentioned, some of the differential data around antisense as well. And so really, we know that these kinase inhibitors and the antisense in clinical trials right now, and we're rooting for those companies to validate LRRK2 kinase inhibition and reduction as a therapeutic approach. So let me start by showing you data that shows that our LRRK2 PROTACs reduced LRRK2 in human microglia. I mentioned that this is a relevant cell type in the disease brain. And here, we're showing very nice dose-dependent reductions of LRRK2 looking at a western blot compared to the housekeeping protein GAPDH. On the right, importantly, we have looked at human peripheral blood monocytes. These are -- and whole blood, and we've been able to show that we see dose-dependent reduction in total LRRK2. So we're looking at target engagement here. And then this translates very nicely to lysosomal pathway reductions looking at phospho-Rab reduction. And so we have potent molecules that we're taking forward into the clinic, as John mentioned. And so we can basically translate our mechanism of action in human blood. Now I want to step back and talk a bit about the disease. I mentioned that LRRK2 mutations put the brakes on lysosomal function, but also overexpression puts the brakes on lysosomal function as well. So here, I'm showing a published data. In gold and in green, you can see LRRK2 overexpression in a transgenic model and then G2019S, the largest familial population, you can see that in a mouse model that there's reduction in liposome number. Reduction in lysosome number has been confirmed in Parkinson's disease patient brain, postmortem as well. So this nicely shows that LRRK2 may be involved in reducing lysosome number. Now importantly, in this study, they were able to show that LRRK2 reduction using genomic knockout increases lysosome number in astrocytes. We wanted to actually confirm that we can see this activity and compare directly pharmacologically to kinase inhibitors from a cell biology perspective, looking at LysoTracker Red, this is a microscope assay. And here, you can see dose-dependent increases in lysosome number and that we're replicating the literature to show that we can increase lysosome number and that we differentiate from kinase inhibitors. So this is in red the Merck scaffold, MLi2, compared to the Genentech scaffold, GNE-7915. And so we were gratified to see these data. Most importantly, we wanted to test the idea that we could actually increase protein clearance in the lysosome. And the way that we tested this is to load cells with a reporter called DQ-BSA. This is taken up by cells in the early endosome. Lysosomes and late endosomes fused to become endolysosomes. In the endolysosome, there's cleavage of BSA releasing the fluorophore. And we can measure this in a microscopy cell biology assays, looking at increases in fluorescence and spot count. And you can see here that we're dose dependently increasing the degradative capacity of the lysosome compared to GNE-7915, the kinase inhibitor, and we have similar data for MLi2 as well. Now I want to redirect your attention back to progressive supranuclear palsy. And these are the data that were published by ED Jabbari at the University College London. I mentioned that this is a very GWAS study. And what they've been able to show is that the SNPs for LRRK2 that's implicated in increased LRRK2 expression increases accelerated time to death by a year in progressive supranuclear palsy. I mentioned that it's a pure tauopathy. So as you know, and John mentioned, we have a tau program, and we're looking to reduce tau using PROTAC-mediated clearance, but we're also studying Alzheimer's induced pathologic tau, and we wanted to test this idea that I just showed you that increasing and enhancing lysosomal clearance may reduce pathologic tau. Here I'm showing you in cells that we're able to in green, dose-dependently reduced pathologic tau in our Alzheimer's disease model in vitro and that we see differences versus kinase inhibitors shown in blue. And so what I also want to highlight and importantly, our preliminary data indicate that LRRK2 PROTAC induced pathologic protein clearance reduction in 2 pathologic tau models. We're looking at the TG-4510 and the PS19 models. These are very dramatic tauopathy models, and we were able to show in preliminary data that we do reduce pathologic tau. So more to come on that. This also indicates to us that the LRRK PROTAC may also have utility in the larger tauopathy Alzheimer's disease. So now I want to direct your attention to our oral dosing of our LRRK2 PROTAC to show you that we reach deep brain regions following oral administration in the primate brain. And we've been able to show this across mouse and rat, but the important thing is, can we measure LRRK2 reduction across the brain? And can we get to regions of the brain that are very important for Parkinson's disease, the striatum, as well as progressive supranuclear palsy, the cerebellum. And this is after growth dissection, we're seeing 87% reduction in the cortex. In purple, you can see that's clearly happening also in the striatum. And then importantly, we're able to decrease 89% of LRRK2 following oral administration in the cerebellum. And folks who have focused on antisense drug discovery, so I have some experience from my time at Bristol Myers Squibb, working with Roche Innovation Center, Copenhagen on locked nucleic acid. And we know after intrathecal dosing that those antisense do not distribute very well to the cerebellum and degrade regions of the brain. And so what's important for progressive supranuclear palsy is that we get to that deep brain region of the cerebellum, the dentate of the cerebellum, which impacts cerebellar gaze and progressive supranuclear palsy. And you can see that we're reducing LRRK2 there. So this is very exciting data in a primate, which is very well conserved across primate. So very exciting. John mentioned, importantly, the catalytic activity of the PROTAC, and this has a huge pharmacologic advantage over inhibitors. And here, I'm going to show you this in action in the G2019S mouse brain. And you can see when we look at the time that has maximal effect for both the PROTAC and the inhibitor to give the inhibitor the best shot at working, the maximal effect occurs at 1 hour and it is transient. But you can see that we see 2 orders of magnitude, greater potency at LRRK2 target engagement in green versus the GNE-7915 inhibitor for phosphophoryn-935 inhibition. And this translates very nicely into 2 orders of magnitude, greater potency at lysosomal pathway engagement, importantly. So what I want to highlight here is that our Arvinas stands the opportunity to show that we can move lysosomal markers in disease. And so we will be studying these and we are studying these lysosomal markers in the brain and also in cerebrospinal fluid, which is how we aim to translate and sample these changes in the central compartment. So I mentioned biomarker changes, and I want to show you the biomarker changes that reinforce our confidence in the PROTAC mechanism of action in the periphery and in the brain. And so on the left, you can see BMP. This is bis(monoacylglycerol)phosphate. This is a lysosomal lipid that has been used clinically and is a clinically validated biomarker. You can see that at both -- all 3 dose ranges that we see reductions in BMP in mouse -- sorry, in cyno urine, and so this is important for us to look at lysosomal changes in the periphery. And then most importantly, we want to translate LRRK2 reduction to cerebrospinal fluid. You can't sample the brain in human studies, but you can sample cerebrospinal fluid. And here, what we're showing you is the beautiful pharmacokinetic and pharmacodynamic relationship that we see in the primate cortex compared to the primate cerebrospinal fluid in blue. So here in green is the cortex. In blue is the cerebrospinal fluid, and you can see the changes that occur in LRRK2 protein measured as increases in plasma-free PROTAC concentration. So we are poised to be able to show in our clinical studies that we can reduce LRRK2 in the central compartment of human CSF. So I hope that I've convinced you that PROTACs are a paradigm shift in neurodegenerative treatment. And so we're excited about the potential there. Preclinically, we've been able to show that we can increase lysosome number in degradative capacity following in vitro studies in cell systems with LRRK2 PROTAC degraders. We've been able to show across multiple models in vitro and in vivo that we reduced pathologic tau. We can show that we degrade LRRK in deep brain regions following oral dosing, and we can also show that we can impact clinically relevant biomarkers in primates. And so the opportunity for PROTAC protein degraders is really great. So there are a few disease-modifying therapies in neurodegeneration. We cross the blood brain barrier and are very different than other mechanisms that reduce pathologic target expression in the brain. We do not require intrathecal hosing nor the IV dosing in the case of the LRRK2 PROTAC. So again, across the blood-brain barrier, we also -- even though we're not showing you here, we can specifically target pathogenic proteins in the brain, including mutant Huntington and sparing wild-type Huntington. Again, potential for oral therapies. We're very encouraged by the progress that we're making in tau for Alzheimer's disease and progressive supranuclear palsy, alpha-synuclein -- for clearance of alpha-synuclein in Parkinson's disease as well as mutant Huntington in Huntington's disease. And we're poised to prove our mechanism of action in the clinic with our clinical trial beginning soon. So very excited about the opportunity here. And I just want to say thank you to the entire Arvinas drug discovery and development team. We are nothing without our colleagues and really a great team to work with. So thank you very much for your attention, and John and I are happy to take questions. Thank you.

Okay. Excellent. Thank you very much for that overview. Look, I think I'm going to split some of my initial questions into 2 parts. One on the asset drug and early clinical questions. And then second part on the development strategy. And like I said, please submit any questions you have through the Q&A box if you have them. Look, you presented a really compelling data on the suboptimal lysosome and tau effects with the inhibitors for LRRK2. Why does a degrader differentiate here?

So the degrader differentiates largely because it's targeting the whole kinase. So the kinase has 2 catalytic activities. It has the Rab GTPAse activity. It also has the kinase inhibitor activity, but it also has scaffolding function. And one of the key aspects of pathology is that it's also targeted and redistributed to microtubules in the disease as well. So there are multiple aspects of scaffolding function that we think contribute. There's preclinical data that differentiates reduction of LRRK2 from kinase inhibition in synucleinopathy Parkinson's disease models. And also there's data in vitro that shows from Steve Finkbeiner that shows that it's reduction of LRRK2 as opposed to kinase inhibition that rescues neuronal loss.

Okay. And then how does the selectivity of your degrader compared to the kinase inhibitors that have been developed? And what tests are you using -- control proteins are you looking at to define that?

Sure. And we've disclosed these data publicly. We've been looking at proteomics with our PROTAC degrader and we actually look at it ex vivo. So we dose the PROTAC in vivo, and we look at how selective our molecule is in the brain. And largely, it's very clean. And so we've seen that LRRK in wild-type mouse brain is the only target degraded in the brain. And in pathology, which we haven't done -- studies then, we're excited to explore what other changes are happening in the brain. But our PROTACs have very clean profile.

Okay. And then talk a little bit about the safety profile of LRRK2 inhibitors and your view of what is on target versus off target, especially in relation to introducing a new highly selective degrader modality here?

Yes, yes. So we've been really following the work that's been done to study, and this is largely work that's been funded by Michael J. Fox to study the lung. So we know that from the knockout animal studies that have been done that the lung and the kidney are target organs for LRRK2 reductions. And so early in the program to convince ourselves hands-on part that we could move forward with respect to impact to lung type 2 pneumocyte enlargement. We did studies in the mouse to induce type 2 pneumocyte enlargement using the Merck scaffold. So they recently published a very compelling argument about kinase inhibitors causing remodeling and collagen deposition. So we have data that shows that we actually induce less type 2 pneumocyte enlargement with full target engagement compared head-to-head with MLi2. So we feel that the LRRK2 PROTAC reduction is differential with respect to inhibition also for the liability in the lung. This remains to be seen and proven out. So we're continuing our toxicology studies, but it suffices to say that we have the space to proceed to move into healthy volunteers.

Okay. And maybe a corollary to that, any competitive view of the ASOs and where they're targeting more direct administration to the brain that is proposed to maybe mitigate some of that theoretical systemic toxicity?

Right. We actually don't have any direct information there. But certainly, direct administration of an ASO should limit peripheral exposure. But I would say that there's also exposure that occurs in the kidneys with those antisense as well. It remains to be seen how well they'll be tolerated and how high you need to dose to see the type of reductions that we're seeing in the brain at reasonably low doses. So we're encouraged about our safety margin, and we'll continue our safety studies and taking this very seriously. We've been certainly looking at collagen deposition in all of our toxicology studies in the lung as well.

Okay. And what is the target for LRRK2 knockdown do you think for efficacy? And you've talked a bit about some of the models you've used to suggest you can safely do that, but what is the actual target do you think?

I mean it's a great question. Certainly, no one knows the actual answer to that question until we go into human disease. But I would say that the disease model data that's out there supports 50% reduction. Human genetics showing twofold overexpression, again, suggests 50% reduction would be beneficial. And I would say that also data from [ Green Myers ] Labs showing that 30% reduction may actually be sufficient. So we're going to explore a dose range that enables us to understand what that might look like. And I mentioned that we impact lysosomal function. We're also looking at lysosomal biomarkers, and we hope to be able to dial in the amount of reduction based on the lysosomal biomarkers and that PK/PD relationship that we're establishing between tau and LRRK2 reduction.

Okay. And before I move into some of the early-stage clinical questions, we did have a couple -- quite a lot, actually, questions come in. To just general one, is the status of the GLP tox studies and anything you can share on the FDA input from pre-IND meetings?

Yes, look, we're not going to share any toxicology information at this point. It suffices to say that we're following the standard toxicology approach that's been taken in the field, and we're paying close attention to the LRRK2-target organ in our studies.

And we have a CTA approval. So...

Oh, thank you, Tom. Yes, we do, and to move into healthy volunteers.

Yes. Okay. Can you say anything about the starting doses? You'll be working with how close that might be to some of the target degradation levels. It's always a question for investors of how quickly will you be at relevant doses for those initial biomarker reads?

So I can't say anything specific about the dose levels, but I can say that we'll be able to prove our mechanism in the single ascending dose with respect to LRRK2 degradation.

And then can you help us understand the scope of the early stage development? And really, I'm trying to figure out what are the key derisking early data readouts for this mechanism that you can provide, even within healthy volunteers and especially those early patient cohorts?

Yes. So we'll be following safety and we're certainly following all of the -- again, the target organ systems for LRRK2 reduction very closely and monitoring those healthy volunteers very closely as well. I would say also that we have all the biomarker assays in place to be able to measure peripheral blood reduction, peripheral lysosomal engagement, central LRRK2 reduction. And I mentioned that we're also developing assays to be able to look at lysosome function as well as other inflammatory mechanisms and mitochondrial mechanisms that LRRK2 may play into. So we're very excited about the work that we're doing preclinically in the primate to help us inform those biomarkers that are LRRK2 mediated.

Yes. Kind of a follow-up question to this, and I think it's going to tie in a lot of the preclinical data that you've shown, but how do you plan to select a dose for this degrader with high confidence? And will this be any easier than some of the challenges that have been experienced with the inhibitors? I mean you've got the very compelling distribution data in monkeys. But how do you ensure that, that translates into human subjects with a deep brain penetration and mechanism of action?

Yes. I think this is a really important differentiator for our PROTACs versus the kinase inhibitors. So I showed you the iterative catalytic activity that we see in the substoichiometric potencies that we're able to achieve in the brain. So we stand the chance to move biomarkers that potentially the inhibitors were not able to move centrally. And so what we're doing is really lining up how much reduction do we need in terms of translating that to biomarker movement for lysosome function, inflammatory function as well as also looking at mitochondrial function and other pathologic proteins. So we believe that we'll be able to use biomarkers to create an educated approach, but we're also using the human genetics to guide us. So we -- as long as we're in a safe dose range, we can test multiple dose ranges that we think would allow us to see efficacy in human disease.

Yes. And now on the blood brain barrier topic, we do have a question coming from the audience. Just about how the PROTAC has an enhanced ability to cross the blood-brain barrier, especially given it's a large complex molecule. How is this happening? And why is this happening?

So we've been able to engineer our protect across the blood-brain barrier. And I would say that we put assays in place. So having worked in neuroscience for years, we have a good understanding of some of the mechanisms that basically inhibit a drug's ability to remain in the brain. And I will say also that as we've translated from rodents, which has a higher number of transporters to the primate that has less transporters, we've been able to see enhanced potency. And we've also been able to really drive our PK/PD relationship. So I mentioned that catalytic activity. It doesn't take much PROTAC to induce degradation. And so we're fortunate that we have this substoichiometric potency that allows us a lot of flexibility to play with as well. So it's been really a journey. I would say we're the PROTAC company. We've put a lot of effort in terms of building our understanding. We've been at it for 5 -- at least since I've joined, 5.5 years, to really build a relationship and understand how to engineer our PROTACs to cross the blood brain barrier. Other companies dabble. That's my answer. [ Works for real ].

Got it. Now as we move into the initial patient cohorts, are there any PD -- or biomarkers for efficacy for PD or PSP. I think, particularly there's going to be a focus on the idiopathic form of PD for...

Yes. I mean there are a number of interesting biomarkers that we've been following that we're pretty excited about. Some are microglia markers that are associated with progression of idiopathic Parkinson's disease. And so we've been working with the Michael J. Fox Foundation and other investigators to focus in on some of those disease biomarkers. As you know, Michael J. Fox Foundation funded PPMI, which has been at least a 10-year endeavor to understand biomarkers, and a lot of the data are coming to fruition in cerebrospinal fluid from idiopathic Parkinson's disease patients. We're paying particular attention to those biomarkers that are linked to disease and linked to processes that we think we can modulate. And so we're looking at those biomarkers in our [indiscernible] studies. And I can't comment, but it's very -- we're seeing some very interesting movement. And so we aim to actually bring in a Parkinson's disease cohort into our early clinical studies to understand whether we move those disease biomarkers as well.

Perfect. And then maybe just some more questions around Parkinson's disease, which I'm starting to learn is a very heterogeneous disease where there is a large -- there's a subpopulation with the LRRK2 mutations that can drive PD. Just talk about what is the lifetime risk of those carriers with the LRRK2 mutation?

Yes. So the mutations in LRRK2 that are the dominant familial mutations are linked to late onset Parkinson's disease. So these patients tend to live longer and their disease process is long. And so we're actually more excited about focusing in on a more recent data around the SNPs that implicate -- that are much more prevalent that implicate LRRK2 in terms of increased expression in Parkinson's disease. And in fact, there's some literature that reducing -- that there are genetics in LRRK2 that reduce risk. And when you look at the cell biology behind those mutations, there's actually a 50% reduction in LRRK2. So we're really compelled by the human genetics for reducing LRRK2 at this stage, and we think we have the molecule to be able to prove the concept.

Yes. Now, kind of broader question here. Once validated in these early-stage clinical studies, how do you contemplate a vision of pivotal development? I think especially in light of the Biogen-Denali example of showing some preliminary target engagement, but having to discontinue that carrier study because of feasibility challenges continuing on only an idiopathic PD, but not really having a strong patient selection strategy. Give me some comments on how you think about that pivotal development plan?

Oh, yes. So we've been working very closely with patient advocacy groups to understand the cutting-edge work that's going on to really stratify the patients for idiopathic Parkinson's disease. But I'll say that our focus really is on this recent data that has come out of the University College London focused on progressive supranuclear palsy. As you know, that is a rapidly progressing disease. And within a year, you can show meaningful changes in disease progression. And so moving the needle by a year and showing genetic link to a target in progression in neurodegeneration, that's where a drug discoverer wants to live, right? And so we are really encouraged by the data that we see for tau reduction. And our aim is to go into a progressive supranuclear palsy, and then potentially, and I'll let John speak to this, our plans in Parkinson's disease long term.

Yes. And then maybe this is a good segue to a question to John. Because given the importance of patient selection in these PD trials, how early would you expect strategic interest to be stepping in, wanting to just take development responsibilities for a complicated pivotal trial design once you've validated this mechanism in early studies?

Yes, Brad, there's no doubt we've expressed this several times over the last few years that at some point, we get to the stage where having a strategic partner or partners could actually be incredibly beneficial for progression of the program. Up until now, we [indiscernible] to those potential interested partners that we were going to wait until we are in the clinic and had a real sense of confidence around PROTACs in humans, and I think we're obviously incredibly close to that and also having line of sight to the rest of the portfolio. So for me, I think we're pretty close to the idea of saying what would be beneficial for moving this asset forward? Is it Arvinas building a neuroscience development and broaden out the infrastructure related to that? Or is it having a strategic partner that has that in play already and can actually help execute those more complex trials. So I think that is something that is going to be ahead of us. Clearly, what we look for is we're funded and in a good position to run these Phase I trials. And I think that will be the type of exciting dialogue we can have in this [ fairly recent ] future.

Yes. But it sounds like, maybe from some of Angela's comments that PSP is a disease where you could contemplate arenas bringing this forward independently. So if a partnership structure is not ideal or the timing is not right, this asset can continue forward. Is that the right way to think about it?

Exactly. We're pretty well funded to move forward with our plans right now. And I think it's when you look into the much broader setting, and we have experience of this, obviously, with our estrogen program and our androgen program. These programs get big when you get into Phase II and into Phase III. Neuroscience is going to be no different. In fact, we'll have even more complexity. But that's definitely kind of a narrower approach so we can continue quite happily ourselves, which we're clearly going to do.

Okay. And if PSP is something you take more of an impendent role and, I guess, do you view LRRK2 as a more proximal target of the pathology of that disease? Is that something that you take on the risk of that clinical development versus something like idiopathic PD, what's the difference?

Yes. I'll let Angela talk about that. We've had a lot of internal discussion about the relevance of the target to each of the different diseases, including Alzheimer's, and it has the implication in terms of our of what we take on.

Yes. And I'll just add to what John just said, I think we're really compelled by the human genetics and progression in progressive supranuclear palsy that implicate LRRK2 and the fact that we can build this relationship, how [indiscernible] clearance in our preclinical model. So we think that it's a reasonable approach for us to go into progressive supranuclear palsy because of the large data set that's been generated out of UCL. So it remains to be seen, but it's something we're encouraged by and the data that we've been collecting in that disease, and we'll be looking at biomarkers in that disease as well. So a lot is known now about neurofilament light chain and other indicators that can give us an early read on whether we expect to impact neuronal survival, neuroinflammation and also mitochondrial dysfunction in that disease.

A question came in on the line to asking if intermediate biomarkers such as fMRI and qEEG be of utility for any of these diseases?

You know, I mean, right now, we're focused more on biochemical biomarkers than imaging biomarkers and progressive supranuclear palsy, the imaging biomarkers haven't been that great. But certainly, you're mentioning connectivity and EEG. They're interesting biomarkers. We'll certainly keep an eye out as we advance our development program. And certainly, functional MRI is another area that is being explored, but has not been reduced to practice in clinical treatment. So -- and of course, those are not approvable biomarkers. So one of our hopes is that at some point in time, the regulatory agencies will recognize neurofilament light chain as a significant, meaningful end point in these very rapidly progressing neurodegenerative diseases.

Got it. John, maybe another question to you on the partnership. Because not only will this be validating for LRRK2, but it will be validating for the brain penetrants and capability of your PROTACs and neuroscience and CNS diseases broadly. What would a potential partnership be ideal to be multi-asset or more structured around LRRK2?

Yes. No, it's a great question. I think we're open to the kind of dialogue as it relates to that. Clearly, LRRK2 is the most advanced program. We've done deals in the past. As you know that we'll be very target specific. Those types of deals where a company hands us their targets, we find degraders and hand them back. They were very exciting at the stage of development of the company in those days, but that's not quite as attractive to us now. We want to build a portfolio. We want to share the risk and the benefit, but then just [indiscernible] an idea of talking to our company about shared programs. And certainly, the programs we have, I'm sure, will be of great interest to those companies as well. So shared programs, shared benefits, shared risk and maybe even asset specific. I think all options are open as we think about what that might be in terms of strategic partnering in the future.

Yes. Okay. And then in terms of structures of how much involvement. You said shared trade benefit, shared risk as we think about 50-50 structures. Is that essentially what you're looking for here to be involved with the R&D even with some of these larger idiopathic Parkinson's disease indications and such?

Well, I mean, I think our experience -- unique experience in developing -- targeting and developing brain penetrant PROTACs, I think is telling you where our strong uniqueness is. Being able to study what these PROTACs look like in the early stages of the development. I think it's going to be a key development we'll build ourselves over the next year or so with LRRK2. But as we head beyond that, when you get to more complex trials, I think, yes, that's shared risk, shared benefit model kicks in quite significantly. We won't get to whether it's 50-50 or some other ratio, but the idea of partnering is the clear thing. We're not looking to sell the assets, particularly, it's more like building a portfolio that allows us to be a [indiscernible] clear in neuroscience in the future.

Yes. It makes a lot of sense. That's all the questions I had today. Maybe though to close, John, you do have another asset entering the clinic as well for a novel oncology target. Maybe if you can just give that a plug as well?

Yes, with the B-cell 6, our next program in B-cell lymphoma with a stage where we're mapping out that Phase I, which will be in patients. So yes, that will be this year. All the plan is going forward, a very exciting new area for us in terms of hematology and very exciting preclinical data that shows that we have some unique characteristics of [indiscernible] them out compared to others. So as I said earlier, this is at [indiscernible] wave of the pipeline coming forward for many years, will be focused on AR and ER and quite rightly, those were the major programs for us. But now we're starting to see neuroscience peering and the next wave of oncology targets behind B-cell 6. We have [indiscernible] read KRAS programs that are moving forward fairly rapidly as well. So an exciting next stage for the company, not only for the big pivotal data for our ER degrader, [indiscernible] and also planning for ARV-766 in prostate cancer for this next wave of new targets. So hopefully, a lot to talk about in the coming months and years.

Yes, indeed. Well, I really appreciate you taking the time this morning to go in deep on the emerging neuroscience pipeline and platform at Arvinas. This is a wonderful conversation. Angela, John, thank you so much for joining us. And thanks, everyone, for joining and listening.

Thank you.

Thank you, Brad.