Thanks again for being here. I'm Brian Abrahams, one of the senior biotech analysts here at RBC Capital Markets. Our next featured company is Regeneron, since I picked up coverage of the company, I've been getting more and more questions about what's going on in Regeneron's pipeline. Of course, I get a lot of questions on EYLEA and Dupixent, people are, I think, more and more interested in learning about the R&D engine. We're really pleased to feature today, I think a different aspect of Regeneron than many people get a chance to see and understand. We have with us Aris Baras, who's the Senior Vice President of Regeneron's, the Regeneron Genetics Center, as well as Christos Kyratsous, the Senior Vice President of Research, and Ryan Crowe here on stage as well, who's their Vice President of Investor Relations. They're going to walk us through a little bit more about what goes on behind the scenes at Regeneron that enables them to maintain one of the broadest pipelines in all of biotech. Thank you so much for being here and joining us. Thanks, Brian. Just a quick, forward-looking statement. Just wanna remind folks that remarks made today may include forward-looking statements about Regeneron, and each forward-looking statement is subject to risks and uncertainties that could cause actual results and events to differ materially from those projected in such statements. A description of material risks and uncertainties can be found in Regeneron's SEC filings. Regeneron does not undertake any obligation to update any forward-looking statements, whether it is as a result of new information and future events or otherwise. I think Aris and Christos can have a little open, and then we'll go to your questions, Brian. Thanks for having us. Great. Well, maybe just to kick things off, can you start by telling us more about the Regeneron Genetics Center? How does it work? What are some of your overall responsibilities? Absolutely, Brian. Thanks for having us. Thanks for coming out, to meet with us and hear from us about our genetic medicines efforts at Regeneron. Brian, maybe I'll take a moment, I'll start. Christos will, you know, add and finish up. Talk about two things, the Genetics Center, we don't mean to confuse, and also genetic medicines. Two different things that we talk about at Regeneron, and we want to raise awareness for them as well. Briefly about the Genetics Center, something we've been doing for a very long time, the last 10 years or so, large scale human sequencing, very simple goals, looking for identifying new targets, genetically validated targets that have much higher probability of success in drug development. That was the initial goal, and we've been very productive in terms of the number of new targets we've discovered at Regeneron and advanced them across lots of different modalities and programs, antibodies, genetic medicines. Since the initial efforts, we've also added to that, where it's not just target discovery, and we'll get to this, you know, later today, but also how we can use genetics to guide the development of our existing programs. You know, a really simple and great example, we use genetic mutations, genetic variants that many of us have, and we've sequenced millions of people, so we've got lots of data on this, as surrogates or mimics of what a drug is doing. You have a drug that blocks a target. We've got thousands of people that have a mutation that is basically a knockout of that target. We can look in real human data to see what the prediction is, what the effect is. Is it gonna have a benefit on heart attacks or asthma or COPD? That's the basic gist of it, how we've been using genetics, at a scale that doesn't really exist in our industry. We'll talk about examples. This is distinct from, but leads in nicely to genetics medicines, where Christos also has been at, you know, Regeneron. We've been, you know, I guess we're now the old-timers. A funny story. About 12 years we've been at Regeneron. About five years ago, maybe even, you know, longer than that, we really started to kick off efforts beyond antibody technology platforms. Specifically what we talk about in genetic medicines are things like siRNA, our big collaboration with Alnylam, gene therapies, CRISPR-based editing, and, you know, other enzymes and approaches that are being used today. You know, I'll just say one last thing and Christos, you know, take it away from there. The reason why we made a big investment and made it a priority area for us about five years ago when we started doing this. Couple things. We really believe in technology platforms. We invest heavily. You know Regeneron as a company, as a technology development company. Antibodies, traps, been prolific in that over the last 30 years. We like technology platforms that are not a single product opportunity, but they can be multiple product opportunities from the platform. Number two, we also like in genetics medicines, they have a lot of features that antibodies have in terms of their precision, their specificity. In contrast to a great field, medicinal chemistry, small molecules, very hard to get really specific inhibitors or activators. Just like antibodies, we can get really specific blockers or sometimes, you know, agonists. Because of these being genetic medicines and a lot of sequence-based, it's very precise. You can design a sequence to inhibit something with siRNA or to deliver a gene, obviously, right? Those are some of the hallmarks of why we like these genetics medicines platforms and why we've invested so heavily in their development at Regeneron. You wanna add to that? Sure. Thanks, Aris, and thanks, Brian, for the invitation. Very happy to be here. Two things to add. One from the technology development side, it's a very nice synergy between antibodies, what we've been traditionally doing for the last 20 years or so, and genetics medicine, meaning that you can take antibodies and specifically target genetics medicines, other viruses or siRNAs or other components, and we can talk about that in a bit. In terms of technology development, it's a very nice follow-on story for what we've been traditionally doing with antibodies. The second thing I wanna add is by expanding our modality portfolio to genetics medicines, that gives us a very vast array of modalities to choose from. From the traditional protein therapeutics, mostly antibodies, again, we've been working on those for several years now, to siRNAs, CRISPR, gene therapy, you name it. We can let the biology areas at Regeneron do their work. Then choose the best modality for your indication, the best modality for the disease. You're not restricted to the single modality you have available. We have the entire array to choose from. This is a huge point, John. I have 30 seconds here. You know that Christos always talks about correctly, we are not stuck to a certain modality. Yeah. Whatever we think is the best modality, or if you need to take multiple shots on goal for a fantastic target, we can do that given the different modalities that we have. The other point that we always make is precisely because we have a very productive genetics and biology effort at Regeneron, we have lots of targets we've uncovered. In the past, through protein therapeutics, we really could address, you know, predictions are a quarter or a third of the human genome because those gene products are secreted or available as antibodies. Now we can really access a lot more target space through this. We should also add, this is a big research and technology development effort, but it's also a big drug development effort. These efforts over the last five years have led to, we have now six programs in the clinic. Happy to talk about these, all the way into proof of concept studies and late-stage development and a very rich pipeline now coming from preclinical development into the clinic. Got it. No, that's great. You mentioned, with some of these modalities, you mentioned siRNA, and I know you guys alongside your partner, Alnylam, recently reported proof of principle data from an APP-targeted RNAi. I'd be curious if you could tell us maybe a little bit more about what those data mean for your approach, both for this program itself and then maybe even bigger picture use of RNAi to get at neurodegenerative neuropsychiatric diseases. Maybe if you could also kind of weave in the next steps for this program and your confidence in the overall safety? Yeah. Thanks for that question. Obviously, we're really excited about what's going on. Yeah. In siRNA in the brain, in central nervous disorders. The data, as many of you heard from Alnylam the last time around, they did a very nice presentation with some data from the human study and also some of the background data from the preclinical development, the primate studies. It's early days, right? You know, we have to remind everyone this is the first. Yeah. First time, you know, we're getting siRNA into the brain in human studies. Honestly, this really exceeded, you know, our expectations in terms of what the potential, what the possibility is, right? Emphasizing it's early days, but up to 90% silencing was seen in the highest doses tested there. That's quite profound in terms of the potential of this technology and platform. There's lots that still has to be done. You alluded to that we have to complete studies in terms of the, you know, the single dose cohorts, and they're advancing to multi-dose and really establishing the safety profile of that platform. You can remember, you know, decades ago when they were first developing siRNA technology in the liver and how far that has come, right? You know, there's nothing more we can say on that front other than, you know, we have to continue this development with our partners, with Alnylam, but so far everything looks, you know, really hopeful. To your point about potential, if this all holds up and we can get, you know, as it looks, a really profound platform in terms of silencing of target genes in the brain and hopefully have the type of safety profile that siRNA has had in liver, the possibilities are fantastic. We know a lot of great targets for neurodegenerative diseases that affect very large patient populations without really any treatments, effective treatments available. The discovery pipeline through genetics and a lot of other work is really rich in that space. This could unlock, you know, a big opportunity in drug development in CNS. Two things to add here. Yeah. Aris, you talk about the level of knockdown about 90%, but let's also not forget the durability, right? You get multi-month durability so far. Okay, we don't know exactly how long it's gonna last for. The studies of course, are ongoing, which is really exciting. A single dose can knock down expression for more than 90%, for about 90% for multiple months. One more point I wanna make about safety here. First of all, when we, our partner, Alnylam announced we're designing a lot of the preclinical toxicology studies, we had no idea how the platform is gonna perform in humans, right? So you have to guess a little bit about your dose, guess a little bit about the frequency of dosing and things like that. You also wanna push the system, so you sometimes you wanna see toxicity in your animals so you can understand your margins, right? It's always a data set that is hard to explain unless you have the totality of the data and you combine all this preclinical data with the emerging human data. I think that's exactly what we are planning to do now with Alnylam, look at everything collectively and assess how we're gonna be progressing forward. There's a partial hold here in the U.S., the studies are still recruiting as well in the world, which also shows how different the regulatory agencies sometimes see the same data set in different ways. This is not a black and white thing. This is the very first time you see biology and technology like that translating in humans. It's actually unknown territory, right? That Alnylam is trying to carve here, which is really exciting. You mentioned at the beginning, you know, some of the targets that have been discovered through your efforts. HSD17B13, I think was one of the more interesting targets that was deriving from your efforts that you were able to really go from target identification to proof of concept in humans very, very quickly. Can you talk more about that program, I guess, where you are now with regards to the ongoing phase II and continued dosing work in phase I, what you're looking for, in terms of histological benefits to guide next steps? I guess how you're thinking about the NASH space overall, because it's. You sort of have this interesting element here where you have a very novel target that no one else is going after. It's a field where there's some regulatory and commercial uncertainties, but there seems to be, sort of growing momentum as things move into late stage and mature. Where does this fit into your prioritization? What are the next steps here? How excited are you on this program? It's a major priority for us. Favorite question, so thank you for that. You know, one of the things we love to do, you know, back to the Genetic Center, is one of the things that was new in the field about 10 years ago was look for these protective genetic mutations. Really, genetics has before that been mostly about what genetic mutations cause disease, right? Pioneers in the field, you know, examples in heart disease and some infectious disease had done the opposite. They had discovered mutations that make you almost superhuman. They protect you from certain diseases. 10 years ago, we started on a big campaign to not find one or two of these, but to find dozens of these. We have done that now, and you're highlighting one of the early stories. We focused a lot on NASH because of, as you said, the big opportunity there, right? No treatments. It's now the major cause of liver cirrhosis and liver transplant. Unfortunately, it's been a graveyard of drug development, but we're starting with these protective genetic starting points. We know in humans, when these genes are knocked out, they have a tremendous benefit, reducing your risk of getting NASH, or if individuals have NASH, they dramatically reduce your risk of progressing in NASH. HSD was the first, but I also want to remind folks, we have a very complementary portfolio with our collaborators at Alnylam. We're leveraging the siRNA approach in the liver for the most advanced program, HSD17B13. The next one is PNPLA3. It's a different mechanism, very complementary. The third, which is we've talked about, is in the latest stages of preclinical development, moving quickly towards the clinic, is CIDEB, which actually had the biggest effect we've ever seen in terms of reducing risk of NASH in our genetic studies, published information. Back to your question about HSC. We did finish the early human studies. There was a phase I study and then a 1B that Alnylam reported out on last year in NASH patients. Not powered, obviously, for these types of things. It's a phase I study, but we got a sense, an early sense of being able to look at not only kind of dose and target silencing, but importantly, some early biomarkers. They were seeing numerically lower transaminases, liver enzymes, biomarkers of that. We've now started the proof of concept phase II studies, where, yes, we're absolutely looking at biopsies, looking at elements of inflammation, fibrosis, you know, the core type of information that we'll need to advance drug development there. Just to round it out, PNPLA3 has also started clinical development, and there the opportunity will be similarly to look at in the phase I, also to get a component of that where there will be patients with fatty liver. There, the mechanism is looking at liver fat, where we hope, you know, we would expect to see very, you know, there's been some competitor data there, some large reductions in liver fat, pretty quickly through that pathway. Good. Well, looking forward to seeing those data. You talked at the beginning about, you know, being modality agnostic and all the different, the growing suite of modalities that are enabling you to interrogate and explore these novel targets that are coming out of the genetics efforts. Can you talk a little bit more about the modalities, the new modalities that you're most excited about? I'm curious to maybe go maybe a level deeper. I mean, it sounds like the RNAi efforts are in full force, and, you know, obviously have antibody technology. Tell us more about what else you're excited about, what's novel beyond some of the ones that we're already kind of seeing in the clinic. Sure. First of all, I wanna mention that for all these modalities, we see them more as a, you know, all of them are evolving first, right? You can see siRNA, for example. It was something that we've utilized quite a bit in the liver. You can very efficiently deliver siRNAs to the liver. Now with Alnylam, we were able to unlock CNS as a new space, which is an entire new area. Our collaboration with Alnylam is also expanding to the eye, so we have another tissue that we are hoping that we're gonna get data in the future and we are able to unlock. You can see the modality evolving into other extrahepatic tissues by different types of targeting. CRISPR therapeutics are similar. A couple of years ago, with our partner Intellia, we announced, we published that we were the first to actually deliver systemically these CRISPR components, knock out a gene in the liver, in hepatocytes TTR very, very efficiently, and reduce levels of circulating TTR by more than 90%, about 90%. CRISPR is currently systemically administered. CRISPR components are mostly targeted to the liver. Unlocking and delivering these CRISPR enzymes to other tissues outside the liver is a huge area that we are working on very, very actively, and we have multiple different targets outside the liver. On the editing space, in addition to targeting these enzymes outside the liver, CRISPR-Cas9 outside the liver, you also have availability now of newer generations of those enzymes. There are more and more types of enzymes that are available that allow you, when you utilize them properly, to make different types of edits. You don't go and you make a blunt cut into your DNA, but you can make more precise modifications. With our partner, Intellia, we are making actually very directed CRISPR-AAV-mediated gene insertions, and we have programs like that. We have shown some of the data, the preclinical data, for hemophilia inserting Factor IX. We also have some data that we've published for enzyme replacement therapies by expressing these enzymes from the liver. When it comes to gene therapies delivering AAVs, okay, we've partnered with Decibel to deliver AAV for a genetic deficiency, otoferlin. We picked that because it's a very defined genetic lesion, and we have very strong preclinical data that expression or restoration of expression of otoferlin restores the hearing function in all these preclinical models. We are very excited about that. Our partner, Decibel, very recently announced that we are in the clinic, so hopefully we're gonna start recruiting patients and announce some data soon. We can take all of this into the next level by unlocking again the delivery, right? You can see that all of these modalities have progressed very, very fast. What we are lacking in many, many places is how to deliver them properly to the right tissues specifically. That's exactly where we believe that antibodies can actually play a major role. We have published some preclinical data in both mice and non-human primates that you can conjugate antibodies to AAVs, for example. You can strip them of their natural tropism, so they don't go to the liver and where they normally go to. You all know that liver is a huge scene for all these AAV therapies that results in lost vector, but also sometimes some toxicities being seen. Then you can add an antibody on the surface of these viruses, and you can let the antibody take the virus to your favorite tissue. That is a technology that works extremely efficiently in both mice and non-human primates. There's a conference going on in Los Angeles this week, the American Society of Gene & Cell Therapy, and a lot of the data that, you know, we are presenting there during this week. We are very excited about this technology. You can imagine that you can encode your favorite enzymes, your favorite transgenes into your AAVs and target them with antibodies to your favorite tissue, so that you can unlock the use of these enzymes and use of these genetic medicines to these patients. It's super interesting. How far away is that? I know you've had some proof of concept data in animals and non-human primate models. How far away from the clinic is this antibody-directed gene therapy, would you say? Yeah, we are finalizing now a lot of the preclinical data sets to validate, you know, the precise target that we are talking about, and we are trying to prioritize the first clinical applications where we can use them. We are in the process of doing a lot of the scale-up that is required to develop all these processes so that you can produce all these vectors in the right quantities and at the right scale. Then both internally and with potential partners, we are thinking about how to best position in the clinic. We are not too far away from that. Is this something you imagine or envision developing or utilizing sort of your own vectors and payloads for delivery of or using, I guess, making external collaborations, for to try to improve the specificity and biodistribution of others' gene therapies? Both. Okay. I mean, traditionally in the genetic medicine space, I think as Aris mentioned, there are a lot of like homegrown efforts, both from the target discovery side, from the RGC and other efforts within Regeneron. A lot of effort on the technology development side that are homegrown efforts to take some of these programs and put them in the clinic. We also, especially in genetics medicines, we really enjoy these very productive collaborations with like-minded companies. They have been extremely fruitful for us, so we hope that we're gonna be continuing collaborating with those companies and potential others in the years to come. Great. I know we've only got a couple of minutes left, but I wanted to ask about your COVID efforts. You obviously had a very successful antibody that really helped mitigate some of the morbidities at the height of the pandemic. We're all here now unmasked. Obviously, we've come a long way since then, but there's always the threat of a mutation and an outbreak kinda lurking around the corner. Can you talk about the process by which you were able to find a conserved epitope for COVID, what you've observed pre-clinically? It looked like from some of the recently published patent filings, you see good binding kinetics and kinetics and consistent neutralization potency across a lot of different tested COVID variants. I'm curious, the next steps for your lead compound there, or lead antibody there, 14287, once it enters the clinic mid this year and how I guess how you discovered it and what you think the challenges might be now, from this point forward, where we are in the pandemic to develop a COVID antibody and sort of generate the same sorts of returns that you got in the past? Right. The process here is very similar to what, I think, Aris was describing for genetic diseases, where you rely on a huge dataset of sequences to try and understand patterns, right? It's the same thing that you are trying to do when you are studying virus evolution. What we've learned is that over the last, you know, more than two years now of available sequences of the virus, you can see that there are certain regions of the virus that are changing very frequently for the virus to evolve, spread faster, you know, amongst the population, but also as a result of immune pressure. All of us, when we are vaccinated and when we are infected, the majority of the antibodies that we are developing are against this region of the virus that is called the receptor binding domain. They are very potent neutralizing antibodies. They block the virus very well. Also the problem is that this is the region of the virus that is changing very frequently. The clinical development of these antibodies is very challenging because you are basically chasing an ever-evolving target. It's very difficult. What we were able to do is we were able to identify sequences that over the multiple years of the evolution of the virus did not change very much or didn't change at all. Then we were able to isolate antibodies against those sequences. Out of those antibodies, we only chose the ones that are very potent, as potent as the antibodies that are targeting the receptor binding domain. We chose one, the one that you mentioned, as the one that is gonna be our clinical candidate. The antibody has been scaled up. We've already discussed all these things with the regulatory agencies. We are gonna be in the clinic in the next few months, and we are hoping that by the end of the year, we are gonna start collecting data as these antibodies being tested in patients. Got it. I feel like we can talk for another hour or two on all the things that are going on. This has been a fantastic overview and deep dive. Aris, Christos, thank you guys so much for being here. Thank you. Thank you.