I'm Andy Baron, Senior Biotech Analyst here at Leerink Partners. It's day one of our Global Healthcare Conference in beautiful Miami, beautiful background, beautiful weather, and we're very happy today to have Arvinas. We have Angela and Randy. Thanks for joining us.
Thank you.
Thank you for having us.
Great. For those who don't know Arvinas, maybe you can start, give us an overview of the company.
Thank you again very much for having us down here, Andy, it's great. I'm Randy, I'm the CEO, and Arvinas at this point is, I think, a really great opportunity to look at, as we look at the next year, we have a number of programs that are in phase I already. We make PROTAC degraders. We've been around since 2013. If you're looking now, we're a company with four phase I programs in a range of disease areas. We have the capital to move them forward, and we've got data coming up for all of them in the relatively near future to make decisions about what we take forward. Like I mentioned, we've been around since 2013. People know us as the PROTAC company, and we certainly do make PROTACs.
The great thing about this situation we're in now is in addition to having the programs and the capital, we also have a strong platform and foundation to build from, in that we've already had pivotal phase trial readout positive last year for vepdegestrant, our ER degrader. We also have a program called Bavdegalutamide that's with Novartis, that we outlicensed to Novartis, which really I think sets a strong foundation for us. The programs that we have now in the clinic are a LRRK2 degrader in neurodegeneration. We have a KRAS G12D degrader for solid tumors with mutated KRAS. We have a BCL6 degrader called ARV-393 in hematology.
Just announced in the past couple of weeks, we also have ARV-027, which is a polyglutamine repeat AR degrader, which will be used in, for patients with SBMA or Kennedy's disease. It's in healthy volunteers now, but we'll get to patients in the future. With those coming up, we have a lot of opportunities to show that the pipeline that we've created based on the strength of our research pipeline can really be differentiated. I think at this point, that's what I'm trying to convey as I step into the CEO role, is that we have spent a considerable amount of time building the pipeline, and now what we really need to be known for is the ability to create differentiation for each of the assets.
As we look at the data that come out, we'll make sure that we are investing in the right places, and finding opportunities, even in the situation where everything is successful, that we're able to progress the pipeline, perhaps with the help of others, in places that they're better suited to do so. It's a great time to be looking at the company since I think we've changed a lot in the past year.
Okay. Well, I know we're gonna focus predominantly on the pipeline and the, you know, the assets that you guys are gonna move forward. Vepdeg was a success in phase III, so there is value there obviously. We did have some news today from persevERA. Does that surprise you?
Not particularly. The thesis for an ER degrader, like our PROTAC ARV-471 or vepdeg or the SERD from Roche, we've always thought that an ER degrader will work anywhere that ER is driving disease, and I think we showed that with our pivotal data, right? We had a positive endpoint in the ESR1 mutant setting, and this is in second line plus breast cancer, and we didn't hit the endpoint in the all comers or in the wild type patients. The reason we believe that is that in late line patients that are still driven by ER typically have ESR1 mutations. If they don't, it doesn't mean they don't have other mutations, it's just that there's other factors that are driving disease.
Last fall, Roche showed that their SERD worked in the adjuvant setting, which again is nearly all wild type ER, but the patient tumors are driven by ER and so the drug worked. Today the data were not statistically significant when partnered or combined with palbociclib. Whether that's because of the way the trial was designed or the ability to differentiate from palbo by itself or with fulvestrant, we don't have more information than you do. I suspect that as has been the case, ER drugs will work where ER is driving. The question there just may be the design and how its ability to separate from the control.
Yeah. To that point, I was lucky enough this morning to have a panel with Richard Pazdur, you know, from the FDA, and I asked him on the heels of that news, you know, why doesn't the FDA promote more non-inferiority trials? He was, you know, his response was, "We are very open..." Or when he was there, they were very open to non-inferiority trials if they're run prospectively that way and they control for all the variables. It is interesting-
Yeah
Be ause I do think, I mean, everyone says, "Oh, the trial failed," but the reality is it didn't fail. Well, the trial statistically didn't meet.
Right
Superiority, it's at least as active as fulvestrant, which is obviously active in patients.
Yeah
Y ou know, without ESR1 mutation. You know, it is interesting to think about running those trials. I know there's complexities, he did caveat and say it's not easy to run a non-inferiority trial. There's a lot of variables. There's a lot of difficulty making certain assumptions. They all have to be prospectively defined up front. I thought that was very interesting.
Yeah.
I guess my thought was the FDA really didn't like non-inferiority trials in cancer, but he said that they're very open to that.
Well, to round out the Arvinas story on ER, you know, we've said that with our partners at Pfizer, we're looking for a new partner to commercialize and develop the drug further. We have decided to focus our resources and capabilities on the earlier line pipeline, but, we're making progress on that partnership. I hope to have it done by the PDUFA date in early June. Going forward for us, it'll be an important financial asset, but we will spend our resources in building capabilities internally to focus on the other phase I assets going forward.
Okay. Where do you think, before we jump into each of the programs, where you guys were the pioneers and have been and still are the, you know, for degrading, you know, as a class of drugs, you know, what have you learned about where degraders, you know, can exert the greatest benefit over the other options that are out there?
The VEP story was not about a degrader versus another degrader. It was about a PROTAC degrader versus a SERD, which is a different mechanism which got to better degradation. I think the question going forward is when we look at each program, I would say I think less about where does the platform differentiate and I think a lot more about where each program differentiates. It's not about, for me, it's not about the platform being better than another platform. There's going to be a bright future for PROTACs and for inhibitors and for antibodies and for ASOs and for everything else. The question is program by program, where do we differentiate?
As we go through the programs today, we will definitely talk a lot about how ARV-102, which is the LRRK2 degrader, how it differentiates from the inhibitor that's out for LRRK2 as well from another company. When we talk about KRAS and G12D, we'll talk about the reasons that that PROTAC can differentiate from another degrader in the space and also from another inhibitor in the space for KRAS.
I think there's going to be important features of each part of that story for where and why we think we could be better, whether that's durability, whether that's the depth of degradation, whether that is overcoming amplification, or and those are all KRAS points, or whether it's going back to LRRK2, the ability to degrade the LRRK2 kinase, which is not just a kinase, but also has other functions that won't be affected simply by inhibiting it. In each of the areas, we're going to be very focused on the programs that we have showing differentiation more so than thinking about the platform as it were.
Right. Okay. Fair, fair enough. Right. I mean, in the breast cancer space, you know, degrading a constitutively active receptor makes sense too.
Yeah.
You know what I mean? You know.
It makes sense, right? We would argue that we think our data were differentiated, right? That's why we think it's important to get that deal done and get the drug to patients and physicians in the case that it's approved. However, we just made the decision that instead of focusing on building a commercial infrastructure to launch a drug that for us would have been launched several years before the next potential launch, we think it makes more sense to invest in the pipeline and allow someone else to bring that drug to patients.
Okay. Why don't we start with an overview of the PROTAC approach versus other methods of degradation?
It's probably a great time to bring in Angela.
Sure. Other methods of degradation. Our PROTAC method of degradation, right? This allows us to really iteratively degrade. It leads to substoichiometric potencies. In terms of degrading, let's say, in tumors, right? Removing oncoproteins in what we call an iterative mechanism really overcomes many of the resistance mechanisms that inhibitors have. We're very excited about that. What it allows us to do also is optimize the molecules much more effectively than, say, a molecular glue mechanism, where you're really optimizing an interface with two different proteins. We have two different ligands that we're optimizing, so they're separable domains of the molecule. More straightforward for us to optimize. We also understand the rules of PROTACs to, you know, basically optimize the oral bioavailability of those molecules and now crossing the blood-brain barrier.
The advantages of PROTACs versus other degraders, including genomic degraders, right, like antisense, which degrade RNA, really allow us for oral administration all of the bioavailability and penetrance that small molecules have. We can do everything a genomic molecule can do, except we're orally bioavailable, which we think is a huge advantage, particularly in the brain.
Right. I understand.
Without intrathecal administration.
Right. For also for chronic situations, I think.
Exactly. For chronic administration.
Okay. why don't we start with 102, going into neurodegenerative diseases.
Sure.
What's the properties of that molecule and what have you guys seen that gets you so excited?
Sure. We can start with the target and why we're tackling it with degradation versus inhibition.
Great.
Randy's point. LRRK2 is a very large, multifunctional protein, so it has 3 different domains. It has a scaffolding function, it has a GTPase function, and it has a kinase function. All 3 of these functions contribute to neurodegeneration. The scaffolding function contributes to the lysosome-mediated clearance, the GTPase contributes to the neuroinflammation properties of the protein, and then the kinase domain contributes to the endolysosomal function. All of these properties lead to pathologic accumulation of proteins. We aim to remove the entire protein, and this will lead to clearance of these pathologic proteins, whether it be tau, alpha-synuclein. In our case, we're interested in going after progressive supranuclear palsy as well as Parkinson's disease.
You know, you've probably most familiar with Parkinson's disease because mutations in LRRK2 cause late onset Parkinson's disease. These mutations are spread throughout the entire protein, and they all cause lysosomal stress and activation of this toxic gain of function of LRRK2. By removing the protein, we would impact all of those pathologic properties. We're encouraged by that. Increased expression of LRRK2 is associated with pathologic progression in progressive supranuclear palsy, which is a pure tauopathy, and it's a very rapid progressing neurodegenerative disease, devastating. People die within 5 to 7 years. It is also a movement disorder, so it's a terrible disease.
What has been shown is that LRRK2 elevation again causes this increased progression and clinically meaningful progression, meaning that, more recently, University College London professor has shown that, you know, a 20-point scale, within 1 year you can measure this progression. We can actually be able to, you know, study this in 1 year and reduce LRRK2 and potentially clinically meaningfully potentially move that disease. That's our goal. That's why we're excited about this. That's our aim, is to study that. In terms of what we've shown in phase I, we've shown three things. We've shown that we cross the blood-brain barrier in healthy volunteers. We've shown that we dose dependently reduce LRRK2 in the cerebrospinal fluid.
We've shown that we engage the LRRK2 pathologic proteins that are increased in LRRK2 Parkinson's disease. All of the proteins that are driven by LRRK2 variant Parkinson's disease that increase are now coming down when we treat with ARV102. It's just, you know, very confidence boosting that we're impacting those proteins. That has not been shown for the inhibitor. We already differentiate from the inhibitor.
Are there data, preclinical or clinical from anyone showing that by decreasing LRRK2, you can either stop progression of the disease or reverse the progression of the disease?
In preclinical studies, there are data that show that if you reduce LRRK2 with an antisense oligonucleotide, that you can impact progression in a Parkinson's disease model with the antisense, but not with the inhibitor. You can rescue dopamine neuron loss in the substantia nigra, and you can reduce alpha-synuclein pathology. We're compelled by those data, and we're also, you know, compelled by our own data that show that we can increase lysosome number and increase degradative capacity of the lysosome compared to the inhibitor. We can reduce PSP-mediated induced pathologic tau in our models, and we can also reduce lysosomal pathologic tau in two different in vivo tauopathy models in the brain and acutely. This is the toxic neuronal toxic tau.
Why would a inhibitor not, if it stops LRRK2 production, why would it not have the similar effect to a degrader?
It doesn't stop LRRK2 production. It inhibits only the kinase activity.
I see.
That's the difference.
Okay.
We would be actually inhibiting.
You're getting rid of the LRRK2.
Or degrading LRRK2.
I see.
Yeah.
Okay.
That's actually the difference. Thanks for pointing that out.
You still have the inflammatory response.
You have inflammatory response.
What was the third component? The GTP binding? I think was the.
Correct.
Okay.
You have all of those aspects.
I see.
Of pathology that are still going on. You're, you know, hopefully, I mean, we're rooting for Biogen and Denali to see some impact of kinase inhibition. We don't see impact to the lysosomal function o ur preclinical studies.
Ah.
I see. Okay. You know, do you think, I mean, two separate diseases with some similarities, but do you think that what you see in Parkinson's disease is gonna, you know, be applicable to supranuclear palsy and vice versa?
We do think that the endolysosomal and neuroinflammatory marker changes that we'll see, will actually translate. Because these diseases really are, you know, a spectrum of endolysosomal disorder and leaky lysosome disorder in terms of neuroinflammatory and pathologic protein accumulation.
Okay. Interesting. Very, very exciting.
We'll be showing data next week at AD/PD, aiming to show similar biomarker changes that we showed in healthy volunteers. The goal there is to show in, you know, we showed in healthy volunteers on average 25 years of age. Now we'll be showing in patients that have neurodegeneration, which are sporadic Parkinson's disease patients on average 60 years of age, that we're degrading and retaining, reduction of LRRK2 in the brain, and that we're also engaging that LRRK2 pathologic, Parkinson's disease pathway engagement in the CSF. That's our goal.
Okay. You wouldn't expect to see a reversal of the disease?
Not within 28 days of treatment, just that we're, you know, encouraged that we'd be seeing these biomarker changes.
Okay.
I don't know if you wanna add anything, Randy?
I'd just add in terms of what's coming up, right? We have the PD patient data next week at AD/PD. We'll be looking to start a phase Ib trial in patients with PSP by the middle of the year or so. All stars aligning, data coming through, conversations with the agencies, we have the potential to start a phase II registrational study by the end of the year. We've got a few hoops to jump through before we get there. That's where we're looking to go. Looking forward beyond that, Parkinson's is also something that we're looking at. The risk-benefit will have to be a bit different than for PSP, given that a patient with Parkinson's could be treated for, you know, has a disease that could last well over 20 years, whereas PSP unfortunately is more like 5- 7.
Even beyond that, not really part of our development plans at the moment, but there are other tauopathies out there like Alzheimer's that could be relevant because the same pathway is implicated. Reducing LRRK2 in patients with Alzheimer's could at some point be shown to impact pathologic tau there as well. That's getting quite a bit ahead of ourselves.
Yeah.
You didn't say that you wouldn't eventually see a reversal. Is it thought that you would see the disease reverse or is it just going to halt the progress?
I mean, our goal is to halt the progress, but, you know, I mean, halting is our goal. You know, remains to be seen what's possible.
Yeah.
Yeah.
Okay.
So far nothing has done that.
Nothing has done that.
Yeah.
In progressive supranuclear palsy or Parkinson's disease.
Okay. How do you know how much LRRK2 you have to degrade to get a benefit? I mean...
Right. You know, based on the human data, there's twofold elevation in cerebrospinal fluid of LRRK2, and then in postmortem brain, there's also twofold elevation of LRRK2 in microglia. Our goal is to reduce by 50%.
To normal levels.
Yes.
Yeah.
Yeah. In homeostatic levels.
Do you see that, animals, like when in the preclinical?
Yes, we do. We see that if we reduce, by 50%, we clear, pathologic tau.
Okay. Remind me, I'm sorry, remind me again how much you showed in the healthy volunteers.
We showed that we reduced, greater than 50%.
Okay.
Yeah.
Okay.
Yeah.
Well, that's encouraging.
Yeah. Yeah.
Okay.
Stay tuned for next week and Parkinson's disease patients.
Okay. Now let's switch to G12D. That's more my wheelhouse.
There we go. Talk about oncology.
It's a little more comfortable. I mean, I used to do neuro, but I don't do it anymore.
There we go. Sure
Obviously other programs in G12D. There's obviously pan-KRAS.
Yes.
There's pan-RAS.
Yes.
Multi-RAS, whatever, you know, which, whichever you wanna refer to. You know, what's gonna be the advantage to a degrading approach, you know, based on when we started the conversation? Like, why... I think I know what you're gonna say...
Yes
I'd just like to hear what.
I do too.
Yeah. What do you think? There are other companies, I think, that have G12D programs or maybe G12C. I don't cover them.
Right. Right.
Maybe I can jump on the, on that sort of illusion there, and then we can go into the detail.
Sure.
You're right, Andy. There are many other companies with programs in KRAS, whether that's pan-RAS or G12D, and we, in general, agree with the idea that having multiple agents could be helpful. We have 806, which is in the clinic now, which is a G12D agent. We also have a pan-RAS coming along pre-clinically. A bit like RevMed has a G12D, and they also have a pan-RAS, not KRAS. Our thinking, in general, is that, you know, differentiating this a little bit from the 102 story we just had, KRAS is a situation where the target is very well validated, and there's a lot of competition. Here in particular, we know that we're not coming first.
We think that the program that we have and the programs that we're developing could be differentiated, but we'll need to show that, both versus a pan-RAS inhibitor as well as the degrader from Astellas as well. Maybe in terms of why that could be the case, I'll let Angela elaborate.
Thanks, Randy. Certainly removing the oncoprotein verse inhibiting is a huge advantage, right? We're binding to both the on and the off state, taking the oncoprotein out of the driver pathway.
Yep.
For oncogenesis is our goal. What we've seen pre-clinically is that is a big advantage in terms of proliferation and pathway, right? We're 25-fold more effective at, you know, inhibiting proliferation than the clinical compounds that we've tested, including, you know, adagrasib, you know, zoldanrasib. All of those compounds we've been able to show this. The other advantage is that with the inhibitors, what you see is compensatory upregulation. You see amplification as a major mechanism of resistance for the inhibitors.
Of G12D?
Of G12D.
And, and other-
Others.
Meth.
Right.
Yeah.
Correct. You know, we are degrading, and so we don't see that, at least in our pre-clinical studies, right? We don't know what our mechanism of resistance will be clinically, obviously. We're early. You know, from the standpoint of pre-clinical work, we overcome that upregulation, that compensatory upregulation. The other advantage that we have is that, you know, from a pathway perspective, right, we also aren't, you know, inhibiting, you know, cyclophilin. Some of the molecular glue mechanisms that inhibit cyclophilin will have an effect on the inflammatory pathways. We've also observed that the N and the H RAS inhibitor, you know, pan RAS approaches, also inhibit T cell activation and, you know, have cooperative effects on EGFR inhibition. That's also not a great direction to go to from a safety perspective.
We think we'll have an advantage there also. You know, we'll be reporting out data.
Right
I'll let Randy talk about the status there.
Our trial of ARV-806, which is the KRAS G12D degrader, has enrolled pretty rapidly. It only began late last summer, we've said data this year, but given that it's already fully enrolled, we'll hope to get that as quickly as possible, meaning you won't have to wait till December for that. I think in the first data update that we give, it's going to be a standard dose escalation, right? We've got patients that start, and you're going to end up having a range of patients that start below the predicted efficacious exposure and then, and then ranging upwards. We definitely are looking forward to getting those data out during the year so that we can get a first sign of what a differentiated asset could look like.
Mostly pancreatic?
Yeah.
Yeah.
it's all comers G12D. statistically, yes, most likely to be PDAC, but we'll have other tumor types as well.
Okay.
Yeah.
You know, I think one of the things you guys probably learned with Vepdegestrant is the importance of combination.
Yeah.
Oh, absolutely.
Absolutely.
I mean, you know, how do you think that the G12D molecule will combine?
Very well.
It seems like there's gonna be combination strategies in PDAC also.
I mean, preclinically, we've been looking at combination opportunities. We've publicly disclosed combinations with anti-PD-1. We look superior versus adagrasib. We're not inhibiting T-cell function. We're also, you know, seeing that we do produce MHC as well. In general, we think we're going to be very combinable. What, you know, Astellas has shown with their degrader is also very promising. We've shown that we're 40-fold more potent than that degrader preclinically. They're running right up against their liver tox issues, so we think we'll be superior there as well. But it does show that that molecule's very combinable and has really nice efficacy profile. It bodes well for a degrader in the space.
Yep. Okay. I know we're under five minutes.
Sorry.
BCL6, 393. You wanna just give us an overview of that, what you're planning to do?
ARV-393 is a BCL6 degrader. We have it in phase I studies right now with patients with both B-cell and T-cell lymphomas. The good news from that program is that we had disclosed late last year that even at doses that were below those that we had predicted would produce an efficacious exposure, we had some responses from patients with both B-cell and T-cell lymphomas. We've also seen good degradation of BCL6, which is great, as it's a very rapidly resynthesized protein. We have the phase I escalation ongoing now. We'll have data from that in the second half of the year. We've already seen some data from a competitor BCL6 program, which we were gratified to see shows that degrading BCL6 has had some impact.
I think BMS showed north of 50% response rates, which we think is great, right? This is a undruggable target. When we started this program, no one had degraded BCL6 before, and so we like the validation that that provides, and we'll look forward to getting those data out in the second half of the year. At the same time, for development for that program, we will include both monotherapy and combination approaches. To that end, we'll be starting a combination trial with a bispecific here in the next few months, as that'll be an important development point as we try to move into earlier LBCL.
Okay. Let's see if there are any questions from the audience. Any of the other... Yeah, you have other assets too. Anything else you wanna highlight?
I'll highlight the other two that will, that are and will be in the clinic this year. Right? ARV-027 is a polyglutamine repeat AR degrader. AR is something that we have a quite a strong history of degrading, so we like our odds at producing a orally bioavailable and efficacious and tolerable degrader there. It's planned for eventual use in patients with SBMA or Kennedy's disease, which is a neuromuscular disorder that leads to muscle wasting. A rare disease, something like 5,000- 6,000 patients in the U.S., although, as with many rare diseases, we'd expect it may be underdiagnosed since there are no disease modifying therapies that are available. That just started in the clinic, exciting program for us.
The other one that will go in in the second half of the year is ARV-6723, which degrades HPK1. That one, another oral degrader, which we think could be pretty exciting for various IO uses, both as monotherapy and in combination. A lot of potential combination uses that you could think of for that. The most important thing will be to get it into the clinic and show some initial monotherapy activity, but that will really round out our programs over the course of the next year. No data for ARV-027 or ARV-6723 expected in 2026, but we have to wait till next year for that. Plenty coming across the first three programs that are in the clinic now.
Yep.
Yeah.
Starting next week.
Yes, starting next week.
Okay.
With 102 .
102, yeah. Yeah.
All right. Well, congrats on the progress.
Thanks.
Thank you very much.
Thanks for joining us.
Thank you.
Yeah. Thank you for having us.