speaker-0: Hi, my name is Jennifer Smith Parker, Director of Insights at Biospace, and you're listening to Denain Shared. In this episode, you'll hear from Randy Thiel, president and CEO of Rvinus. We explore what it takes to rebuild and refocus a biotech pipeline after a major inflection point, from outlicensing and strategic pivots to expanding into new therapeutic areas through the lens of Rvinus's approach to platform driven growth and portfolio design. Randy, thank you so much for joining this episode of Denatured. It's a pleasure to have you. If you can go ahead and introduce yourself, that would be great.

speaker-1: Jennifer, thank you so much for having me. ⁓ really looking forward to the conversation today. Yes, I'm Randy Teal. I'm the CEO of Ar Venus biotech company out of New Haven, Connecticut. And we're well known for being the first company in the protein degrador space. So we were founded back in 2013 really to bring the idea of protein degraders or ProTec degraders, and I can talk a little bit about that technology, to bring those and try to create drugs out of those. ⁓ and so the company's been around for over 10 years at this point. We very recently crossed a important milestone of getting the first drug using our technology approved by the FDA. So a really massive milestone for us. I've been at the company as the CEO for only for about four or five months, but had a much longer history of the company of about eight years coming up in strategy, business development, and a few other roles along the way. I have a a history in the industry both across biotechs. I was at our Alexion before this as head of strategy. And also a consulting and basic science background, which I try to bring to my role here as CEO. You know, a little bit more on the company. We make Protect degraders, which are a way to link a disease-causing protein that we want to get rid of to the body's natural machinery that degrades unwanted proteins in every cell. So it's a pretty simple idea and pretty powerful. And so along the way we've moved from being a pr company focused in oncology to a company focused on oncology and neurology. I know over the course of the the conversation here, we'll get into multiple aspects around the pipeline. There's a lot of things we could talk about, but I know we really want to focus on one specific area because over the past year we've done something I think pretty unusual, which is to pivot ourselves from a lead program, which was nearly commercial, like I said, now approved, to being a company focused on earlier stage, phase one programs. That we will now rely on going forward to to create value for patients and our other stakeholders. We made a decision on the program that was just approved called VEP Degastrent that another company would take that forward. We licensed it to Rigel, and they will now take it forward to commercialize it with patients. Whereas we've shifted a bit and moved our capital back to moving forward our phase one programs across oncology and neurology. But really looking forward into into how we executed that pivot over the last year.

speaker-0: Perfect, Randy's. So to start off, when a lead asset is outlicensed or discontinued, what separates companies that successfully reinvent their pipeline from those that stall at the inflection point?

speaker-1: You know, I would say ⁓ I think two different things and probably both have to be in place. One is, you know, it if you're transitioning from one thing to another thing, it doesn't matter if it's programs or other places in life. If the item or the thing that you're transitioning to is great, it certainly makes that tr transition a lot easier. And so certainly a lot of what the transition is from an initial program to the next programs will be dependent on how much progress you're able to make with the second ⁓ set of programs. I think the other thing though is how quickly can you do it? Which is really is how short is that transition, which is another way of saying if you have had a lead asset that's been outlicensed or partnered, which is something that we've now had at our Vincent will talk about, we had a number of programs already in place to take the place of the first asset. And to put some more specificity on this, our lead program for a long time was a program called Dep Degastrent, which is a degrader of the estrogen receptor useful in breast cancer. And we had a long-term partnership with that with Pfizer. For a number of reasons, we got to a point where after its first approval, which was a huge milestone for us, we decided to outlicense the program again and allow another party to come and bring it to patients while we were able to reallocate our capital back to the early stage pipeline. So what we worked on very hard over the past nearly year is to explain why it made sense to do that. And it certainly helped to pivot to our next wave of programs, which we've really now done. We've got multiple programs in phase one. It helps to have had those ready to go. to pivot from. So it'd be a different story if we had decided to not take VEP forward to to get it to patients as a commercial company, if we didn't have programs ready made to to pivot to. So the programs have to be good. You have to be ready. Otherwise I think that to use your words, you can really stall out at that inflection point.

speaker-0: That makes a lot of sense. And you very nicely started off by talking about the breadth of ⁓ therapeutic indications that our Venus does do. So thinking about that, the decision to broaden his pipeline beyond its initial focus, particularly moving into neurology and additional oncology indications.

speaker-1: Right, right. So so in order to have that next set of programs to pivot to, that was a feature that we had decided on a long time ago. Not because we thought there was a pivot in the future, but because the original strategy that Arvinus had, you know, I think it's important to remember our Venus was the first company established in protein degradation. So we were the first company to take the technology and really try to apply what had been, as our scientific founder called ⁓ A parlor trick of getting two proteins to interact with one another to try to take that forward and make drugs out of it. And as the first company in the space, we didn't have anybody to follow. And so we made a decision quite early on that the first programs we would focus on would be programs where the targets were very well validated, where we understood quite well if we were able to degrade that target, we knew what would happen. If we had chosen targets at the very start that were undruggable to start with or very unvalidated. And it hadn't gone according to plan, we wouldn't have known whether the problem was the technology itself and the degradation, or whether the problem was the degradation was fine. We just didn't know what would happen when we degraded the target. So while our first targets back in 20, you know, going back all the way to the mid-2010s, were very well validated: estrogen receptor for breast cancer, androgen receptor for prostate cancer, we made a decision very early on to move beyond. well validated targets and beyond oncology to other areas where we thought that a protac degrador, which is what we work on, would have a big impact. So I mentioned I joined in 2018 and I joined in the spring. By the time we got to the fall of 2018, we had already hired a head of neuroscience and were building out a team to take protac degradors into neurology because at that point we had already established preclinically that we could get protac degraders to be orally bioavailable and turn them into drugs. Again, preclinically And so we wanted to aim at the next horizon, which was getting a ProTech across the blood brain barrier and be relevant for neurology. So that was a very early step. We we knew we wanted to start with well validated targets, but we knew as soon as we got that done or far enough along that we would want to branch out. And so we we did that well in advance of ever actually pivoting to those programs as what we would consider to be our leads.

speaker-0: I think continuing on that and about the neurology particular indications here, so how do you balance leveraging existing platform expertise with the need to build a new biological and clinical insight?

speaker-1: Yeah, it's a great question. ⁓ because whenever you start a new target, a new disease area, you have to you have to build out the capability to test your drugs at a very early stages all the way preclinically into the clinic. The assays that you might use are going to be different. The disease knowledge that you have is going to be different. So I always think it's helpful to build on something you know well and then add on something that you don't know so well. So go I'll go back to neurology again. That's an easy one. But we had established a way. To ensure that we could design pro tact degraders that were orally bioavailable, we knew how to do that well. What we had to add on was the ability to engineer a protect degrador to cross the blood brain barrier. And I haven't described this yet, but the essence of what our technology does is instead of a traditional drug, which is usually an inhibitor of some activity of a protein. That's what most most drugs that people would think of do. They inhibit some activity of protein. Instead of inhibiting activity, what our technology does is eliminates the protein that you're trying to get rid of. So instead of inhibiting a disease-causing protein, we're eliminating it. And it does that by linking a protein of interest, like the androgen receptor, which I mentioned before, to the part of the body in a cell that is responsible for degrading proteins. Nearly every cell in your body will have a machinery for degrading proteins that are no longer needed. All a protact degrador does is link that machinery to a target protein of interest that we would like to degrade. And that in the body essentially takes care of the rest. And so we knew what we were building on chemically from an ability to create drugs that could be taken by mouth orally. And we needed to expand into neurology. So to do that, we had to design the drugs differently. We also had to build out the assays differently. We had to build in bring in people with new expertise. And we've tried over over the years to really specialize in those two areas, oncology and neurology. Those are pretty broad areas. Those those can cover a lot. But with that as a background, there's a lot of solid tumor knowledge that we learned from prostate cancer and breast cancer that we went on to apply to K Rast driven tumors and things like that. So so I think there is new, but we always try to blend in the old at the same time. And by old I mean what we already think we are, you know, experts in.

speaker-0: the way you answered that say starting with your your baseline of what you know and then adding on to what you don't know to that. So that's

speaker-1: It it applies to a lot of things in life. Start with start with something you know well and add on something you don't.

speaker-0: So that so that does segue very nicely to the next question of a that our our Venus has built a strategy around a pro proven mechanism. And what's a framework for deciding which new indications are the right fit for that mechanism?

speaker-1: Yeah, and it it's a good point. I think that we, you know, as you know, when I joined the company, we spent all of our time externally. And I whether it was with scientists, whether it was investors, anybody else, explaining what a pro tact degrador did, what I just did for you, explaining what it worked, and convincing people that there was a chance that it would work. ⁓ and there were a lot of people that didn't believe that would be the case. Now that we've focused on neurology and oncology, that's the first part of the Venn diag diagram that we're looking for. We're looking to move forward in those areas. As we look at targets, we want to find targets that are driving disease that have significant unmet need. We're not ⁓ you know, we're not we do have some rare disease targets, but we're not only looking at rare diseases. We're looking for where we can make a significant difference for patients. We're not a Me Too company. I want to go places where we can actually make a step change in what a therapy looks like for a patient. And that's often found by what is the unmet need that patients have? Is the is the area is is the disease well served already? If it is. Not a place where you probably need a new technology. If it's not, ⁓ then that might be a place we go. So so we look at the level of unmet need. Two, I would say we want to make sure that the d target that we're looking at really drives disease. We want to know that the target we're looking at, we can make a very strong case that if we hit that target, we'll we will impact disease. And I think I could go back to the old targets, the original targets of AR and ER, very well known to drive those diseases. That's why we chose them. But then I might fast forward to Some of the programs we have now, like a BCL six degrador called ARV 393, we know that B cell development and B cell really misdevelopment can cause hematological disorders. We know that by degrading BCL six, we can prevent some of those problems from happening because what happens with BCL six is it's involved in B cell maturation. It's supposed to turn off when that's done. If it doesn't turn off, then you might get hematological diseases from overactivity of that protein. So we know that if we can degrade that protein, then that doesn't help, which might lead to being able to address disease better, longer, be able to be relevant in a resistance mechanism that other drugs run into, that sort of thing. And then I think the third piece that is important to highlight is as a smaller company, it's important to have to be able to get to a proof of concept in a reasonable amount of time. We are not a company that has billions of dollars of revenues coming in that we can then allocate to our research engine. We have to make sure that as we pick targets and we determine that they are the right targets to hit the disease, we have to be able to get to some proof of concept to to reinforce where we're going, to make sure that we have the conviction to make to take the next step, to make sure that our investors have the conviction to take the next step with us.

speaker-0: So when you're looking at your portfolio on that aspect and you're balancing at let's say the early stage level between risk, novelty, probability, a success, how do you think about that after a major pipeline shift like you've noted?

speaker-1: The short answers a lot. And I think as a company that is really founded as a platform company where we have shown the ability to take a technology and get to an approved product, but we want to do that again and again and again. And having a product, not a product, but a technology that could be used in so many different places for so many different diseases, finding a focus and a through line is important. But I actually think that the diversity of the pipeline is important to us. And what I mean by that is. As you balance the risk around the target, maybe I'll just look at our three clinical programs we have right now as sort of the examples of that. I mentioned maybe I'll start with the two I didn't mention yet. We have a target, LARC II, which is relevant for neurological disorders, neurodegenerative diseases like Parkinson's or progressive supernuclear palsy, where LARC II is involved in a pathway that results in the pathogenic proteins forming aggregates. It's a target that is not proven in the clinic. There are no disease modifying therapies out there. There's no there's no clinical evidence that hitting LARC II will affect the disease course. That's never that's never been shown. We believe it will, but that's never been shown. At the other end, we've got a program that degrades a form of antigen receptor called polyglutamate repeat angen receptor for a disease called Kennedy's, or spino and bulbar musculatrophy, which is a muscular degenerative disease. Where we know that polyglutamine AR causes that disease. The disease is caused by aggregates of poly QAR. So we have very high confidence that if we hit and degrade poly QAR, we will impact the course of disease because that's what's driving the disease. So those are sort of at the bookends. In the middle is the program I mentioned before, which is the BCL6 degrader 393, where we have very strong conviction that hitting the target will affect disease. In fact, other companies have hit it and have seen some very early signals of efficacy. ⁓ but at the same time, it's not nearly as validated and as direct a driver as poly QAR is in the rare Kennedys disease. So we have a mix where you've got programs where it's less clear. We have good reason to believe, but it's never been proven before. But the opportunity to impact patients with neurodegenerative disorders is tremendous. To the end of the other end of the scale where you've got very high certainty that if you hit that target, you'll affect disease. And in the middle, and I like having that mix. I like having the mix of risk reward. And when I say reward, I mean benefit to the patients that we can serve, where all of biotech is a risk. We gotta choose how we're going to take them. And so as a company, we've tried to balance those and make sure that as we reinvent the pipeline, we have shots on goal that range from smaller and surer to larger and less sure. But that's the business we're in. Like that that that's what we want to do. In order to to impact the most patients, sometimes you have to take big swings and we will figure out where the right swings are for us as we move forward.

speaker-0: So when you're reorganizing a pipeline, as you mentioned, I mean obviously that's gonna involve a lot of different people involved in that too. So what are the biggest leadership challenges in re reorienting an organization around an earlier stage pipeline and how do you keep teams aligned and motivated through that transition?

speaker-1: know, if there is anything that ⁓ that proverbially or really keeps me up at night as a CEO, it's this. It is this question, right? It's because we have gone through a a dramatic shift in the past year. We've gone from being a company that was poised to become a commercial company with the first ever ProTec, to being a company that has the first ever approved ProTec, but it's been licensed to another party to take forward to patients. And our future and value inflection and strategy is now focused not on a marketed product. But on phase one assets. And that's a big shift, right? It's a big shift that to some people can feel like a step backwards. I don't see it as backwards at all, right? I see it as we've all set out with the mission that we're going to create therapies that will benefit patients. Well, within a few months, we will have a therapy out there in the hands of another party benefiting patients, like goal achieved, right? And at the same time, we can reallocate capital to go do it again with other programs. And some of those we will expect to take all the way and become a commercial company. But in the meantime, you can see it as a step back from marketed to phase one. The way I think about it and the way a lot of people are thinking about it, Arvinus, is every time a company grows and expands over time, it grows in ways that you look back and you say, I'm glad we did that that way. I think it's also fair to say that when companies grow and change, they also take on some characteristics that people might say, hmm, if I was going to do it again, I might do it a little differently. And I think that moving from a nearly a commercial stage company to a company that's focused on its phase one assets is a really fun opportunity to learn from what we've done and the successes that we've had, but also learn from things that we might do a little differently, just in terms of how we run the company the the next time around. And for people that come to biotech, like people that move from pharma to biotech, which most people do, like a lot of people are coming from big pharma, they're antsy for that. They're eager to think about how can we do things differently, how can we do things better. How can we be more agile? And so it's a breath of fresh air for a lot of people. And that's what we're really focused on. But it is a journey. It's a change in how you do things. And so how you do that and make sure that the we bring the organization along to see it as a positive shift and to grab onto the positive aspects of that and be excited about what comes next. That's something I think about every day.

speaker-0: You mentioned the outlicensing aspect and I definitely want to dig into that because we've seen a lot more of the strategies in pharma generally, I think over the past couple of years. We know it can be a strategic lever internally. So how do you think about the long term value of outlicing and shaping a more resilient pipeline?

speaker-1: Yeah, coming having grown up on the strategy and BD side of the house, I certainly would never describe outlicensing as a setback. To me, it is it is a function of when you have a platform, and I mean a real platform, there's lots of companies out there that describe themselves as platform companies that have a couple of assets. But if you have a technology that you can really use anywhere where a disease is caused by a protein that can be degraded, right? Whether the protein's overacted, whether it's mutated. If you have a a function like that that a degrader can go to, it means that, you know, the sky is the limit. It means that you can create Protects. And if the platform is truly repeatable, you can you can probably do that faster than you can develop things on your own. Right. Because when you go out to raise capital, biotech gravity would say that you are raising based on your lead program. And that might not be enough to support many programs. So I have always thought and expected and it is And it is the case, right? That we will produce from our research team more programs than we will choose to take forward all the way to market. Whether that means that they are partnered after phase one, like Vep Degastrant was with Pfizer, you know, five years ago, whether it means that they were partnered, you know, just at the start of phase two, like other programs. I'm really focused on making sure that the programs that we create, their value gets maximized. And sometimes that's going to be by us. Sometimes that's gonna be by somebody else. We outlicensed our AR degrader, Lux Degalutamide, two years ago to Novartis. And they've now got it in multiple combination studies. And ⁓ we expect them to be gearing up to be running phase three studies. Now, could we be doing what we're doing with our four phase one programs and also running a castrate sensitive prostate cancer study? Wow. I'd love to tell you yes. Right. I'd love to tell you yes. ⁓ But I think that it is much more likely that we're able to benefit more patients in more ways faster by creating protagonist, which some of them we take forward all the way, and others we look for partners to say, look, we could do it, but you can do it bigger and faster and you can impact more patients than we can. And we think at the end of the day, that's how we create value for everybody, all of our stakeholders.

speaker-0: Yeah, and I think as I said before, I think more farmer companies and biotech companies are seeing that. They really understand the value of

speaker-1: Yeah, it's not it's not either or, right? It is not you outlicense programs or you don't. Right. We've had partnerships that have ⁓ been really important over the course of the company to get drugs to patients. Like we've now licensed Veb Degastrant to another party, but it was the partnership with Pfizer that got it through its registrational studies. Pfizer ran the registrational studies, right? So there's a lot that ⁓ That we can do as part of the biotech and pharma ecosystem. We don't have to do everything ourselves. ⁓ we can focus on what we're really good at. We're making great at making protect readers. We are great at getting them into the clinic. We're great at getting them through the clinic. That doesn't mean we have to do that for every program we create. And I definitely believe that we can create more value over the long term by creating multiple programs that multiple companies, especially us, can be taking forward.

speaker-0: So looking back, are there specific strategic or operational decisions that proved critical to move quickly and confidently after its lead asset change course?

speaker-1: I I actually think it was one of the most difficult things we did that turned out to be the most valuable, which was when we decided last summer that the path forward for VEP was going to be in the hands of a new partner, we announced that publicly. We said that we are going to go out and find a new partner. And again, as someone who grew up in on the BD side, I do not like doing that. I don't like calling a shot, right? And saying that we're going to go do this. But I will say that by doing that, what it enabled us to do was 100% align our external message and communication with our internal message and communication. Because if we hadn't done that, we would have been looking for a partner internally, while on the outside, been giving a varied message. And so it really forced us to be very clear about what we needed to do. And that is probably the key to why we were able to shift the focus for the company internally and externally to the earlier stage programs, the phase one programs that. that we will now rely on for the milestones and catalysts and data coming, which which there's a lot coming in the next year. ⁓ I but I think that even though it was it was painful to me as a BD guy to announce that we wanted to go get a deal, I think it was critical in actually making that pivot. So ⁓ things turn out the way they should, I guess.

speaker-0: Perfect. Well, thank you so much, Randy, for speaking with me about Arvinus' pipeline and its strategic shifts at ⁓ outlicensing. It's been a fascinating discussion. And if you'd like to listen to more episodes of Denatured, please turn to biospace.com. Thank you very much.