For joining us. I always have to remember to give that pause. Always thankful to the operators for making this so smooth. early morning on a busy and a little bit interesting week here on Wall Street. We've got Regeneron, one of our favorite companies, joining us. We have Neil Stahl and Jamie from there, and Ryan also joining the three of them. We'll do a modified sort of fireside chat where we'll talk about the company's pipeline and some of the thoughts as to how the company's pursuing current projects and future projects also. One other Regeneron folk was not able to join us, John. Hopefully later on today, sending him our very best thoughts. Ryan, please take it away, and then we'll go to the fireside chat. Thanks, Hartaj. I'll try and keep this brief. Thanks for hosting us here at the Oppenheimer Healthcare Conference. Just wanted to 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 as a result of new information, future events, or otherwise. Okay, Hartaj, back to you. Thank you. Thanks, Ryan. Really appreciate it. You know, Neil and Jamie, maybe just start off very, very broadly. You know, whenever I have kind of heard some of Regeneron's thoughts behind the pipeline, you know, George has spent a lot of time explaining the company's approach. We've also had, you know, one of the heads of IO last year. Maybe we can just start, Neil, with you as to what are the fundamental underpinnings of how Regeneron views its pipeline, both R &D, and then maybe Jamie can give us a perspective from the immunology and allergy side. Sure. First, it's great to be here this morning. I hope everybody's getting used to daylight savings time. I'm not quite used to it yet myself. You know, I've been at Regeneron for 32 years now, it's really amazing that we've had really the same perspective and approach that entire time in that we, couple, you know, deep biological pursuit, that sometimes can last decades on a single problem, along with technology development that is provides us with cutting-edge tools to rapidly get new candidates based on the discoveries that we made. You know, I think one example that Jamie can touch on is Dupixent, where I worked on that for 25 years, just taking the long view before we actually got it turned into a drug. The VelociSuite technologies, which we worked on for two decades at least, those allowed us to do things like make Ebola drug, MERS drug, and a COVID cocktail very rapidly, like in four months, which is really unheard of. We also invested heavily in the Regeneron Genetics Center, which really is the world's largest database of genetics, human genetics linked to anonymous medical records that allows us to discover potential targets in biology that wasn't known before right in human beings. It's a huge, huge tool. Beyond what I think is one of the best, if not the best, antibody technologies in the world, we've also created collaborations to explore some of the new modalities that I think are gonna be critical for the future of biology. That's with CRISPR, who we've partnered with Intellia, and also siRNA with Alnylam. We have a lot of really interesting programs that maybe we'll touch on here in this meeting, certainly in the day. To that point, Jamie, just sort of going over to you know, Dupixent has, you know, for lack of a better word, you know, taken the world by storm, changed the course of the disease in patients atopic dermatitis especially. Just what are your thoughts on next stages for Dupixent? I'm actually kinda asking this question 'cause we'll have to ask about COPD somewhere down the line, but maybe if you can just set the stage for us before we go there. Right. Thank you, and it's great to be here. I can echo a little bit of what Neil said and relate that to Dupixent. You know, I've been at the company for 15 years, also super excited about the work that we're doing at Regeneron and really believe, you know, and see that we're a technology-based company, right? We're constantly thinking of new ways to tackle complex biological questions, right? COPD would be one of those really complicated diseases that we're thinking about. You know, Dupixent, as you know, it started in our Regeneron research laboratories, and we've been working on this for really a long time and constantly trying to understand what are the key drivers of Type 2 inflammation. We believe that IL-4 and IL-13 play a key role. In constantly unpackaging the roles of four and thirteen in different diseases, we've been able to identify areas that we believe we could benefit patients, right? COPD being one of them, obviously asthma, all of the other indications which Dupixent is approved for. It continues to perform well in all of the approved indications, and we have new indications coming down the road in the near future. You know, I think the future's bright for Dupixent, right? I think we're just, you know, at the beginning. Jamie, before going back to Neil, I mean, I just wanna, you know, kinda drill down a little bit there. You know, with Dupixent, you know, the focus on, you know, various types of, you know, inflammatory, you know, mediated conditions. You went from atopic dermatitis to asthma, you know, specific portions within asthma, other indications also. How has the science, you know, translated into these clinical advances? Like, what's been the stepwise process you've taken? Again, I'll ask about, you know, we'll talk about COPD after this. I mean, this is something that I love talking about, right? As a basic science researcher, I think one of the views as the company is to understand the science and use the science to pick indications, right? There are no other deciding factors. It's really what's the biology of the disease, and then once we can understand that, we can apply, you know, medications that we also know the biology of and match the two together, right? We believe that we're making these thoughtful decisions where we understand what are the key drivers of such disease, and in knowing that, then we can take a medication and bring it there. Something like Dupixent, you know, to Neil's point, we've all been working on this for a really, really long time and really trying to understand how this molecule is behaving in patients. In understanding how it behaves mechanistically in patients, we can understand the diseases that we can apply for future indications. Yep. Last question, just on COPD specifically, Jamie. We'll probably come back to this a little bit before the end. You know, I remember a few years ago, it didn't seem like Regeneron or partner Sanofi wasn't as excited about COPD. You know, it's a different sort of a disease from like an asthma, you know, as a lung disorder, more of a smoker's disease, I guess. What's changed in the last two, three years to give, it seems, you know, your partner Sanofi and Regeneron more confidence as you approach the COPD readout? You bring up a good question, right? We all know for COPD, there's been no innovation in this space, right? There are no approved biologics. You know, patients, there's a huge unmet need for these patients, right? As I mentioned, we've been learning more about how Dupixent works in patients, where it can improve specific impacts in airway diseases, right? Improvements to lung function, improvements to exacerbations, applying that knowledge to mechanisms that drive COPD. The two marry, right? We can then, you know, hopefully will see an impact as these trials read out. Yep. That helps a lot, Jamie. You know, Neil, kinda going back to you know, we'll talk about EYLEA maybe a little bit later, you know, but maybe just about oncology, where we've really focused the last few years. You know, and I know if you can maybe just talk a little bit about what we're gonna ask John, you know, which is that how is the company sort of doing its mix and match approach? You know, it's been going on for about two, three years now. It seems every ASH or EHA, the company's getting more thoughtful and smarter about these. Last ASH was definitely, I would imagine, the ASH of bispecifics. I mean, the energy I saw around bispecifics was phenomenal. Just maybe if you can just answer that question, a high-level sense as to how are your combinations working out? How are you thinking about them going forward? Sure. I mean, we have a really good foundational drug, which is Libtayo, which is as good as any PD-1 blocker out there. We call it foundational because, you know, as good as it is, there's still a lot of indications in a lot of patients that are not treated well with it. We firmly believe that adding in some of these other molecules, especially bispecifics, is a way to enhance the activity or increase the indication spread, or increase the number of patients that respond. So far, we've focused on both a CD3 bispecific pathway, as well as now a CD28 bispecific pathway. CD28 is the signal two of T cells that by activating it in the presence of signal one, which is CD3 activation, that you get more activity in many cases. The beauty of the CD28s is, they have seemed to have a really safe profile. There are maybe one or two molecules that do have a bit of activity. You're right that the hardest thing is figuring out what combinations to use. We really are expanding our reach to look at patients and biomarkers and things like that to try to understand, you know, which molecules might be the most effective. The other thing is that I do believe that we have the best mouse models of these diseases in the world, that we've made humanized immune systems and humanized mouse and put in human tumors that I think give us a better readout on which molecules to combine together than perhaps other companies or individuals have been able to access. Yeah. Neil, you know, to that point, I guess, you know, as we see the updates from Regeneron, it seems you're also a very fast follower, for example, in the PD-1 and the LAG-3 dual antibody approach, right? Then you've also got Libtayo combining with bispecifics. Has there been any sort of, you know, I guess, you know, learnings that Regeneron's having that some tumors might be more amenable to two antibodies versus an antibody plus a bispecific? Are there any such thoughts coming to Regeneron when you're thinking of different tumors you're going after, or is it still, you know, You're using the best science to go after, you know, every tumor? I think that we try to pick tumors that we think might have the best bet, but before we do that, we actually have to come up with the best molecule to treat them with. You know, we can compare our LAG-3 antibody to other people's LAG-3 antibodies, and evaluate whether or not we think ours has an advantage. In every single case, our antibodies are either as good or have superior properties to what others have come up with. I think you can see that in our LAG-3 data, where we have some really interesting activity that, although not directly compared to head-to-head, looks really interesting compared to what others have shown. Yeah. No, absolutely. I mean, even the Libtayo, you know, we're doing some work there, especially on chemo combo, and it's really fascinating how much, you know, further Regeneron's been able to push that antibody, even though I think Pembrolizumab is a fantastic, you know, agent also. You know, Jamie, just kind of going back to you know, IL-33 comes up from time to time in COPD. It seems a couple of years ago, you know, Regeneron seemed a little bit less excited. Now it seems it's back in play. Just how to think about IL-33, assuming, you know, Dupixent and COPD works out. Yeah. We've always been excited about IL-33, right? This is another molecule that came from Regeneron Research Laboratories. As you recall, we tested it in asthma, and we also have some really exciting proof of concept data in COPD. In asthma, we also achieved proof of concept, so it's telling us that IL-33 is very active in the airway. With respect to COPD and that phase II study, which brought a lot of excitement to the industry, is looking at our pre-specified subgroup analysis where we found that in patients that were former smokers, there was a 42% reduction in exacerbations. This was really incredible, right? We were really excited about these data. We kicked off two parallel phase III studies, to, you know, see if we can replicate these findings and eventually bring something like this to patients in need. As I mentioned previously, there's really limited options for patients with COPD, so we think this could be really beneficial. I apologize, Jamie, if I indicated that maybe Regeneron's love, quote, unquote, "for IL-33" had waned a little bit. It seems not. Maybe you can just talk to us a little bit about, you know, the, about the COPD population that you're going after in this phase III trial and where that population stands within the overall COPD, you know, sort of patient population. Right. For itepekimab, there's no eosinophil requirement for these patients, right? Regardless of your eosinophil levels, we think that itepekimab could have benefit. Where we see this huge reduction in exacerbation is really limited to the former smokers. That's where we're looking to position this and where we're seeing the clinical benefit for those patients. you know, the other question I have is just on the overall... I know this is more of a commercial question, but I just wanna ask you this because I imagine it's important for you also when you look at the science, you know, biologics are still under-penetrated in various, you know, sort of lung-associated conditions. Asthma probably better than most, when you look at COPD. When you're running these trials, what's the level of comfort physicians have, you know, using biologics to treat, you know, a COPD, for example? I mean, I can start off and then pass it over to Ryan after. From my point of view, I think with respect to COPD, it's gonna come down to what the data say in the end, right? If there's a meaningful reduction in exacerbation together with improvements in lung function, you know, there's reason to believe that physicians will use it. I mean, these patients are really looking for a therapy. I think clinicians are looking for a therapy that can meaningfully impact their disease. Ryan is. Yeah, I'll just add to that. I think heard a variety of opinions on what clinically meaningful is, and I think each KOL sort of has their own view on that. For Regeneron, I think really to Jamie's point, a statistically significant result in this population would be very important. We haven't had one of those in the past. This is a disease that is the third leading cause of death globally, and hasn't had any innovation for decades. I think the low end for us would probably be in the mid to high teens percentage in reduction in exacerbations. Certainly we're gonna aim for higher and hope that because of the enriched population, we're able to achieve that. Yeah. Ryan, when you're talking about the low to mid, this is for the Dupixent COPD trial, right? Yes. Itepekimab. Yep. Yep. Yes. For itepekimab, I think again, there hasn't been any innovation in COPD, so I wouldn't say that my opinion on that is all that different. Yeah. Yeah. Yeah. I also think that there's beginning to be a greater understanding that biologics, antibodies in particular, their specificity is just so high that the off-target toxicity is really low or nonexistent in many cases. I think that gives a lot... Just look at the safety of Dupixent, which is exemplary. I think it gives them a lot of comfort that they have a tool that will actually treat the disease easily. Yeah. No, absolutely, Neil. I mean, it was a little bit of a question I kinda already knew the answer to when I asked Jamie because, you know, rheumatoid arthritis, you already got penetration biologics in the high 40s and 50s, again, you've got six, seven, eight companies marketing there. I imagine Marion's probably licking her chops, you know, assuming Dupixent approval in COPD, a positive phase III trial, approval. I imagine her stock will be very happy. You know, Neil, maybe just coming back to you know, if you can just kinda give us an idea as to where Odronextamab is in terms of a potential filing this year, PSMA, you know, both the CD3 and the CD28, it seems that's where the greatest excitement from Regeneron is right now for those two bispecifics. Yeah. I mean, the PSMA results were really spectacular. In a situation where you don't have any responses, here we are getting 90% decreases in the target biomarkers, which is unbelievable. There was some toxicity accompanying it that we're working on ameliorating, and we have some, I think, strong ideas about how to do that. We're really, really excited by that. I have to say that that data exceeded my own personal ideas of what would actually be achievable, so that was really heartbreakingly good. Our BCMA by CD3 is also a really good molecule that's shown really strong activity. Shows a lot of activity. odronextamab will, I think, file this year, right, Ryan? Yeah. I think our goal for both the BCMA by CD3 bispecific, known as linvoseltumab, as well as the CD20 by CD3 bispecific, Odronextamab, both on track to submit for accelerated approval later this year. Certainly we're excited about both. I think, you know, our whole goal here is to lay the foundation for potentially introducing co-stims to the heme space. Later in the year, we're gonna co-administer a CD22 by CD28 with Odronextamab to hope to leapfrog kind of the levels of efficacy we've seen in that category. With BCMA, we also have a co-stim in the works to work in combination with linvoseltumab. There's some exciting things even beyond just these initial opportunities in the hemo space for Regeneron. No, that. Thanks, Ryan. That's very helpful. I did not realize that, you know, BCMA and PSMA. BCMA would be under the accelerated approval pathway, potentially. Neil, just one last question, which is that, you know, Libtayo seems to be a foundational medicine for Regeneron. Could Odronextamab also be like that? I mean, when we've talked to physicians using bispecifics, they're getting comfortable with the Roche CD20, you know, bispecific. Could Odronextamab sort of be similar in that vein or not really? Libtayo, the PD-1, is sort of the foundational medicine, then you wanna build on that, or just how to think about that? Well, I think that with Odronextamab, there'll be other combinations that we can use, so in that sense that we can add another molecule that might increase the activity, or the number of indications. To that extent, I do think that there is a foundational aspect to it. you know, the beauty of Regeneron's bispecific technology is that it's universal, so we can mix any of the two arms together, which gives us a huge library of different molecules that we can reach into. We have CD28, we have a lot of other co-stimulatory molecules that we really haven't talked about yet as well. I think there is a very broad range of things that we can reach into for the future as well. Yeah, I do think many of them have a chance to become... I think BCMA as well. Yeah. No, I mean, it's the data that you're rolling out is fascinating. Just before going over to Jamie, Neil, can you just mention what are the next sort of level, you know, after BCMA or bispecifics that you get excited about that, you know, a year or two years from now we could be talking about on a call like this? Yeah. You did mention the CD22 by CD28, which I think, you know, is an interesting molecule as well. Just being able to combine different CD28 stimulators together in the same cancer, I mean, we could put in three molecules together, and they all have different cell type specificities potentially, or target binding molecules, but together they could really act to increase the activity of the immune system against the tumors. I think, you know, it's really exciting just to see how these combinations are gonna play out and increase the activity. Yeah. Jamie, I was gonna go to you now. You know Dupixent in atopic dermatitis, asthma, you know, the other indications, which we don't remember as well on the, on Wall Street, or I apologize, but what other areas do you get excited about in allergy and immunology, you know, aside from Dupixent and IL-33? Yeah. I mean, I think as a company, the future is bright, right? We're a research-focused company, just as I was talking before. We're really working hard to understand disease mechanisms, disease drivers, and then apply that knowledge, you know, to actually make our therapeutics, right? How do you make a drug for something when you don't even understand the disease, right? We need to understand the disease and then take things forward. Coming up, you know, we kind of touched upon it already outside of Dupixent. I think the next big thing is itepekimab in COPD, right? We're really looking forward to seeing those data come out because this is an additional population outside of Dupixent, right? That we could see some clinical benefit. We know, for example, the former smokers are 70% of COPD patients. This would really be complementary. It allows for additional potential therapy for patients with COPD. Yeah. Jamie, I mean, you know, if you were to think sort of a little bit what I would call, and maybe Ryan might not want you to do this, but I gotta ask anyway. A little bit outside the box, you know, in the sense for Wall Street folks where, you know, something that you look in the pipeline when you sit down and talk with your team and you're like, "You know, nobody's really paying attention to this, but this, you know, personally excites me a lot." Is there anything, you know, from that perspective? I mean, I could just touch upon, you know, very generally. Obviously, we don't go into the details at this kind of forum, but what excites me is that we're doing precisely that. We're really trying to understand, you know, autoimmune diseases, for example, deeper mechanisms of allergy, so that we can then, you know, just not bring forward another vanilla antibody, but really be creative. Think about combinations. Think about what exactly is doing this. Autoimmune diseases are very complex. They're heterogeneous. You can't just throw something in there and hope for the best. We're trying to, you know, make scientific decisions about where we can see benefit and bring things forward to patients. Yeah. No, it's really fantastic. I mean, I think just the stepwise approach, you know, in ANIs, really something also honestly makes our life easier a little bit as analysts also. Neil, you know, maybe just we can kind of. You know, we're getting to the last three, four minutes here, so kinda like analogous to Final Jeopardy!. You know, John isn't here. I know we've talked a lot about IO. We talked about some of Orion actually I think mentioned some of the other partnerships that I think are interesting. Could you maybe just touch upon what you think about outside of cancer, you know, that you really get excited about, especially in the partnership area 'cause honestly, I don't think we've, you know, as an analyst for our team, I don't think we've spent enough time there. We probably need to this year. Just any thoughts there, Neil? Well, this is one of the most exciting things for the future I think, is these alternative modalities, as I call them, either siRNA or CRISPR. You've undoubtedly seen the data with TTR amyloidosis where, you know, we can get, along with Intellia, who's running the clinical trials, get a much greater than 90%-95% drop in the amyloid circulation levels, which is unprecedented really. This is after a single treatment in these patients. So far, you know, the safety has looked good from that systemic CRISPR approach. We're also very excited about the opportunity to do siRNA both systemically and especially in the nervous system. You may remember that Regeneron was founded as a neurobiology company 35 years ago. Regeneron means regenerate neurons back in the day. Now I think we have an opportunity and the tools in the animal models to actually attack some of the most insidious neurodegenerative, debilitating diseases that face mankind. I'm very excited about doing that. We actually have a trial already in trying to knock down amyloid precursor protein. We have biomarkers that we're looking at to gauge our success in doing that. There's a lot of other really interesting targets in the nervous system that are that we've discovered and others have discovered. Once again, we have the most unbelievably good mouse models that are humanized mice that share the exact features of the neurological diseases with humans in an unprecedented way. I think that gives us a really strong toolbox to try to figure out which pathways we should be blocking and which molecules we should be taking into people since we're using human-specific drugs in these humanized mice. Neil, you know, not to put you on the spot here, and maybe Ryan might jump in, but, you know, the company has really good partnerships. Tell you the truth, you know, as an analyst, I've talked to smaller companies, and quite a few companies have told me they'd like to, you know, Regeneron as their partner of choice now in large cap biotech because of the attention to detail and the collaborative approach Regeneron has. You know, Neil, how do you think as a scientist between wanting to partner and between wanting to internalize? I mean, I don't wanna make this into a capital, this is buy versus, you know, et cetera. Just how do you approach that when you look at a potential, you know, technology, partnering versus maybe internalizing? Yeah. I think, you know, we've always had the same attitude. If we find potential partners that are like-minded, to us, that really like to dive deep into the science and work incredibly collaboratively and have, you know, breakthrough technologies, then, you know, we're really happy to work together with them. Sometimes that just doesn't work out, and we actually take it in and develop it all internally. Yeah. No, that helps a lot. It's actually good to be collaborative. Yeah, a better chance of getting a little bit more money out of Regeneron. Jamie, you know, we'll just maybe end with you. You know, the eye area has been really big for Regeneron, important commercially. Cancer's becoming more important. You know, Dupixent is sort of carrying the load from a growth perspective. How do you think of the pipeline kinda helping Dupixent, you know, not just from geography or ages? I know you talked about IL-33. Which other areas could really add to the Ang2, you know, profile going forward? You know, as you mentioned, we're still invested in Type 2 inflammation and allergy and immunity, right? We're still looking, you know, earlier in the pipeline, what's next after Dupixent, right? Can we bring other things forward in the T2 space? Dupixent has allowed us to understand biology of some of these indications, right? We're learning from our translational studies. We're learning from our clinical studies. Outside of allergy and Type 2 inflammation, we're looking into autoimmune diseases, as I mentioned previously, and relying on some of our tools that we have internally. For example, mouse models, the ability to humanize mice and actually study human disease in a very complicated system that can help. Hopefully, you know, we can translate that into additional therapies to bring forward to help patients. Yeah. I think we're actually on the time or just beyond the time. You know, Jamie, Neil, Ryan, thank you so very much. Again, give John our best regards. Thank you for participating. We really do appreciate it here at Oppenheimer. Thank you, Hartaj. Thank you very much. Thank you. This was great. Everyone, take care. Have a good day. All right, take care. Bye. Bye.