Regeneron Pharmaceuticals, Inc. (REGN) Earnings Call Transcript & Summary

Ladies and gentlemen, thank you for standing by, and welcome to the Regeneron Oncology Investor Event, ASCO 2020. [Operator Instructions] And please be advised that today's conference is being recorded. Now it's my pleasure to turn the call to the Vice President of Investor Relations, Mr. Justin Holko.

Thank you, Carmen, and welcome, everyone, to Regeneron's first ever ASCO investor webcast. Joining me today are Dr. George Yancopoulos, Co-Founder, President and Chief Scientific Officer; Marion McCourt, Senior Vice President and Head of Commercial; Dr. David Weinreich, Senior Vice President and Head of Global Clinical Development; Dr. Israel Lowy, Senior Vice President of Translational Sciences and Oncology; and Dr. Andres Sirulnik, Senior Vice President, Translation and Clinical Science Hematology. After our prepared remarks, we will open the call for Q&A. Before handing the call over to George, I would like to remind you that remarks made on today's call include forward-looking statements about Regeneron, including those relating to Regeneron's business and research and development programs, anticipated milestones and regulatory matters. Each forward-looking statement is subject to risks and uncertainties that could cause actual results and events to differ materially from those projected in that statement. A more complete description of these and other material risks can be found in Regeneron's filings with the United States Securities and Exchange Commission. Regeneron does not undertake any obligation to update publicly any forward-looking statements, whether as a result of new information, future events or otherwise. With that, let me turn the call over to Dr. George Yancopoulos.

Okay. Hey there. I'm George. I hope you can all hear me. Let me start by thanking you all for your interest in our efforts and I will lead off the agenda by giving an overview, highlighting our technologies and the rationale behind our prospectively designed combination approaches. And then I will turn it over to Izzy Lowy, who will give an update on Libtayo as well as our bispecific efforts in other solid tumors. Andres, who you just heard, recently joined our efforts, and he will discuss our approaches in the hem onc space. And then to Marion to update you on our commercial advances. So I believe that any story about Regeneron has to start with the science and technologies that we have built over years that empower and allow us to create our homegrown pipeline. From the Regeneron Genetic Center, which is highlighted in the yellow box on the left of the circle on the slide, that leads the world in human sequencing, including of the entire U.K. bio bank, and which has created the largest genetics combined with electronic health record-based big data set in the world. From that to our turnkey approaches that are highlighted on the right side of the circle, such as VelociGene, VelocImmune, TRAPs and so forth that can make the best antibodies and bispecifics in the world. Now including our highly synergistic technology collaborations with partners like Alnylam and Intellia that we believe will help make us leaders in the next generations of genetics therapies. It's really the power of our technologies that have delivered repeated breakthroughs over the years, the most urgent medical needs, such as blockbusters like EYLEA and DUPIXENT. And the world looks to us to exploit these capabilities to deliver when there is an emerging crisis like Ebola or now with the coronavirus epidemic. And I will shortly say a little bit more about that. And it's also these technologies, which we believe are beginning to deliver, an immuno-oncology pipeline that we are hoping will really bring the promise of immune therapies to all the cancer patients still in need of better treatment. Two of the most important foundational technologies for the foreseeable future remain VelociGene and VelocImmune. VelociGene remains arguably the world's most powerful way to generate genetically humanized models for target discovery and validation, in which together with the Regeneron Genetic Center, really gives us a unique combined capability in doing the best of integrated mouse and human genetics. VelocImmune remains arguably the most powerful turnkey solution to make fully human antibody therapeutics to any disease target. And we have created a next-generation VelocImmune mouse that is designed to be a source of our bispecific platform. And [ nare ] I remind you this platform delivers multiple classes of bispecifics from so-called CD3 bispecific to costim bispecifics. All in a highly reproducible and turnkey fashion that allows us to repeatedly produce best-in-class therapeutics, and you'll hear a lot more about these. Using these repeatable and reproducible approaches to deliver these classes of therapeutics, we not only deliver best-in-class agents but we can parallel process while also cutting time lines from years to months. Next slide. Okay. Now I realize that today is supposed to be focused on our cancer pipeline. But I know many of you are also interested in our COVID-19 efforts and the potential impact they may have on the pandemic. And I thought a short digression on this story might be a good way to highlight the very same technological capabilities that I've just been touting that we're using in regards to our cancer pipeline. You all know that the SARS-2 virus has a critical protein on its surface, known as the spike protein. And that the key portion of this spike protein is the so-called receptor-binding domain, or the RBD, that binds to the ACE-2 receptor on human cells, initiating and allowing for lung infection. Of course, we thought that our technologies were perfect for coming up with antibodies as drugs that could block this RBD from binding to the ACE-2 receptor and preventing or even treating COVID-19 infections. One reason we thought this was the impressive track record we had in undertaking a very similar challenge with Ebola, which has its own counterparts to the spike protein, known as the GP protein. If you can go to the next slide. We went in record time, of 9 months, from the start of our effort to make an antibody cocktail against this Ebola GP protein to initiating human trials, and as demonstrated by the World Health Organization in its, now, well-known PALM trial, our Ebola antibody cocktail was highly effective in saving lives. The fact that our approaches were so effective for Ebola, which as you all know is much more universally fatal than COVID-19, motivated us to undertake a similar effort here. And in terms of timing, we broke our Ebola record, in going from initiation of our program to human trials that we will be beginning in about 5 months from initiation, and not just with the single antibody, but a cocktail again. And this is really important. We use our technologies to create the largest collection of highly potent antibodies from both VelocImmune mice and also from convalescent humans, thousands of antibodies and selected picomolar antibodies that are resistant to all-natural occurring viral variance described to date. But we also showed that individual antibodies were not enough. We demonstrated rapid viral escape mutants to all of our single antibodies tested, despite their high potency and binding affinity. And we predicted this beforehand. So our prospectively designed approach was based on the fundamental realization that as previously demonstrated for HIV and other viruses, combination drug therapies could prevent viral drug resistance by requiring simultaneous mutation at multiple genetic position. We reasoned that the same approach might be required to prevent escape to antiviral antibodies. And thus, while others focused on the potential of single antibody treatments, we prospectively pioneered and demonstrated the value of antibody cocktails and how they are necessary to avoid rapid viral escape. Shown on this slide in Blue is the RBD portion, the spike protein and colored in green on the top and yellow and orange to the right are 2 different antibodies that both bind to different portions of the RBD, which both block the interaction with ACE-2. And together, not only highly potently block the ability of the virus to infect human cells, but create enormous resistance against viral escape. So that's what we set out to do, create an antibody combination that could be highly effective and also resistant to escape. That's what our technology has created. And that is what we are now about to begin testing in human trials in COVID-19 patients. Next slide. So I am sure that the relevance and analogy in terms of our approach [Audio Gap] is to cancer does not escape any of you. That our prospective approach in the field of immuno-oncology was to build a set of combination or cocktail approaches that could change the course of cancer treatment. And we are really excited about the progress we are making in becoming a leader in oncology. It all begins with our efforts to have a leading therapeutic in the PD-1 class. And we believe that Libtayo is meeting that challenge. We have rapidly become leaders in the non-melanoma dermato-oncology space, based on our first-in-class data in 2 different skin cancers, that is squamous cell carcinoma of the skin, or cSCC, and basal cell carcinoma of the skin, or BCC. It's remarkable to me that these major opportunities had sort of been missed by the field, especially since the anti-tumor effects that we have demonstrated are as impressive as those seen in any other solid tumor settings for checkpoint inhibitors. And we are very excited that our monotherapy trial in first line non-small cell lung cancer was stopped early by the IDMC for overwhelming efficacy, allowing us to enter into another important cancer setting with Libtayo with data that looks as competitive as any. But most importantly, this is really just the beginning for us. Just as I described before, all of our approaches and efforts start with individual therapies but culminate in combinations that we believe can take therapeutic benefit to entirely different levels. We now have over 10 different therapies in development in multiple cancer types and we have 2 sets of foundational approaches, both of which have now been validated already in the clinics as being foundational. Libtayo provides one of the powerful foundations for one set of combination opportunities, while our CD3 bispecifics act as a foundation for another set of combination opportunities. But moreover, each of these foundational opportunities can be combined with each other as well as with another set of bispecifics, which we term our costim bispecifics. And importantly, just as now Libtayo is emerging as a leader in the immuno-oncology space, in both dermato-oncology and in other settings, we have achieved proof-of-concept with our first 2 CD3 bispecific programs. And I think many believe that our bispec programs there are emerging to establish us as leaders in this setting as well. Next slide. So our entire strategy is built around the notion of creating agents that can compete in particular settings, particularly, for example, with Libtayo. We've shown Libtayo has impressive efficacy in settings now that either we've defined or the world has defined are responsive to PD-1 monotherapy, such as in in dermato-oncology and in lung cancer. We believe this is a very important opportunity and we now have an important drug that really can make us players in this space. Moreover, we believe that we can go beyond these settings where we are seeing and others are seeing PD-1 efficacy. So we're -- of course, we're all looking for more efficacy. We know that even in these responsive settings, more than half the patients do not respond to current I/O treatment. And we're now studying the addition of novel therapeutics to the Libtayo backbone to enhance responsiveness in these already somewhat addressable tumors adding other checkpoints, our CD3 bispecifics, our costims and a variety of vaccine-adjuvant approaches that we're interacting with. Beyond enhancing efficacy in already responsive tumors, we're also looking to extend the benefit of immune therapy to tumor settings with currently very limited response to checkpoint inhibitors. That's where we think not only combinations with Libtayo, but the opportunities that are being presented with our CD3 bispecifics and our costim bispecifics really allow us to explore potential responses outside of the space of where checkpoints have currently shown any activity. So our entire approach is built on this concept of integrating different opportunities to create combinatorial flexibility. Libtayo is a foundation for one set of combinations, CD3 bispec is a foundation for another set of combo opportunities and moreover, the opportunities to mix and match all of these in all sorts of settings where the science points us to the potential benefits. So with that overall introduction, I'll now turn it over to the person who's been leading all of our cancer efforts to this point, Israel Lowy.

Thank you, George. Hi, everyone. This is Israel Lowy. I'm the Senior Vice President of Translational Sciences and Oncology. I had the privilege for about a decade before coming here, of leading many of the foundational first studies of anti-CTLA-4 and anti-PD-1 at a company called Medarex. And after its acquisition by BMS, I came and joined Regeneron to join George and his team to really take combination immunotherapy to the next level. So we're going to start with Libtayo, you can go to the next slide, 15. And as George mentioned, the successful treatment of cancer is going to require creative approaches, the thoughtful and novel combinations. And we view Libtayo as but the first foundational element in assembling a diverse array of foundational technologies that can be brought to bear in cancer as in a very flexible fashion, as George said, and almost a plug-and-play manner. So I'm going to take you through these 3 different things here. If we can go to the next slide. This year at ASCO, we presented longer follow-up on our initial Phase II study that led us to registration in cutaneous squamous cell carcinoma with additional follow-up that remarkably enough, actually we found an increase in the rate of complete responses. Initially, it was about 6%. And then after about 2 years of additional follow-up, responses matured into becoming complete responses in nearly 20% of patients. At 24 months, we still have not reached the median survival in this group of patients for whom prior to this therapy, the mean survival was only a year with difficult treatments. The next slide shows that in addition to being first-in-class in cutaneous squamous cell carcinoma, we have recently announced results from our basal cell carcinoma in the second line, again, a setting where there is no approved therapy and where we achieved impressive response rates, but more importantly, durable responses lasting well over 6 months. And pictures tell -- speak a 1,000 -- better than a 1,000 words, and you can see below how these remarkable changes in lesions and changes in patients that are just life changing. Next slide. We recently shared our excitement about stopping our monotherapy lung cancer study in the population of greater than 50% PD-L1 positive on the basis of an interim analysis conducted by the IDMC. At that time, we announced that the overall hazard ratio was 0.676 on the population of 710. What we're sharing with you here is an additional analysis, a modified intent-to-treat analysis, which we conducted because for the first portion of the study, we were prevented from performing PD-L1 testing according to FDA standards for clinical trials. And the FDA, therefore, asked us to do an additional modified ITT analysis, as shown on this slide, that included only the patients who tested above 50% according to this rigorous standard. And as you can see here, the data look even better. So we are very excited about this. We'll be presenting the data at a meeting coming up. And we can tell you that all the other analyses that go along with this fall into place. Next slide. So we believe that combinations are critical, and we seek to join with -- novel and exciting combinations with partners who develop agents that are outside our wheelhouse. And so what you see here is a list of just some of what are more coming of collaborations with companies that have novel vaccine approaches, oncolytic viral approaches and more to come. So if I can go to the next slide, I'd like to turn it over now to Andres Sirulnik to tell you about the next foundational component in our armamentarium of bispecifics.

Thank you very much, Izzy. I'm Andres Sirulnik. I'm Senior Vice President in Translation and Clinical Science Hematology and as a way of -- a brief introduction on hematology-oncology. Prior to joining industry, actually, I spent several years as a [ doctor at ] Dana-Farber/Brigham and Women's Hospital in Boston, focusing my work in hematologic malignancies. And I spent almost a decade at Novartis in oncology development, focusing my work in developing compounds in both solid tumors and hematologic tumors. And more recently had a role in a biotechnology company, bringing several programs into the clinic in the immuno-oncology space. Having recently joined Regeneron, I really truly look forward to the opportunity to contribute to further advancing existing pipeline and bring transformative new therapies to patients. So if we can move to the next slide, please. Next slide. What makes Regeneron unique is the platform by which we can generate and combine antibodies against many cancer cells. Libtayo is one pillar to our approach, but our portfolio consists of multiple classes of bispecifics in addition to traditional checkpoint inhibitors. And our ability to mix and match tumor targets with other CD3 bispecifics, costims or other technologies highlight Regeneron's breadth of combinatorial potential. Next slide, please. I would like to give you an update of where we are and our progress to date on 1979, our bi-specific on CD3/CD20 as a target. We have been making significant progress in this program. 1979 has shown encouraging responses in lymphoma with responses and rates of greater than 90% in late-stage follicular lymphoma with more than 3/4 of the patients achieving complete responses. And in aggressive diffuse large B-cell lymphoma, we are seeing deep responses of 50% to 70% in patients with and without prior CAR-T therapy. Furthermore, we continue to be particularly encouraged by the durability of those responses. Next slide, please. We continue to advance our program and we now have initiated our potential pivotal Phase II program, both in Hodgkin's lymphoma and in follicular lymphoma. And additionally, we are exploring also with potential for registration other areas in lymphoma. These trials are accruing and advancing. Next slide, please. In terms of our upcoming milestones, what we would expect is that we will continue our work on our Phase I study, where we are combining 1979 with Libtayo. We will also explore combinations with the standard of care and novel internal agents, including the costim bispecific that was mentioned earlier, we will broaden the pivotal development program in diffuse large B-cell lymphoma and follicular lymphoma to include earlier lines of therapy. And specifically also, we are and have started our subcutaneous formulation testing, which is planned to start soon. We are targeting to complete enrollment of our Phase II study in 2021, and we are, potentially, submitting a BLA in 2022. Next slide, please. We are also very excited with the progress that we are making in our 2 BCMAxCD3 bispecific programs. Our first BCMA bispecific is in the early stages of dose escalation. In the first 2 doses we tested, we already saw encouraging responses, including responses that we started in MRD negativity. In addition to this, our second BCMA bispecific is already showing encouraging data. Not only these results make us believe that we will play an active role in the treatment of multiple myeloma, but these results also serve as a validation of our CD3 bispecific platform. A platform where we have multiple additional bispecifics that will enter the clinic over time. Next slide, please. So where do we look forward to in the coming half of the year? We will provide updates on the ongoing Phase I dose escalation by the end of the year. We plan potential registrational studies and [Audio Gap] in relapsed refractory multiple myeloma. We will be initiating combination studies with standard of care regimens and novel agents. And as we discussed earlier with our own costim bispecific and other agents. And we will be initiating registrational trial [ in other lines ] of therapies in multiple myeloma. Next slide, please. I will conclude my remarks by showing you the broad set of monotherapy and combination efforts that are already underway or upcoming. And I am now pleased to turn the presentation back to Izzy. Izzy?

Thank you, Andres. So I'd like to speak now a bit to our efforts of looking at novel combinations of Libtayo and bispecifics in solid tumors as well as expand a bit more on the third category of the bispecifics, the costim bispecifics and why we're so excited about them. We can go to the next slide. So MUC16 is an antigen widely expressed in ovarian cancer. It gives rise to the circulating CA125, often used for following the progress of ovarian cancer. As many of you know, PD-1 as a monotherapy is rather inactive in ovarian cancer. So we developed a MUC16xCD3 bispecific that attaches to the MUC16 on the ovarian cancer cell. And from the outset, Envision's creating a study in which we would combine it with Libtayo. This study is ongoing. The dose escalation of monotherapy is proceeding. We've initiated combinations of MUC16xCD3 with Libtayo, and that dose escalation is on its way. And we recently received an allowance from the FDA to initiate a study with a MUC16xCD28, and which will be actually our second costim bispecific to enter the clinic. And that can be combined with either MUC16xCD3 or with Libtayo. So next slide, please. So why are we so excited about costims? So these -- we call these -- these are all antigen by targeting CD28. And CD28 is the main second signal that T cells require after they recognize an antigen in order to have effective T cell activation. Normally, they receive this via B7 molecules on antigen presenting cells. These molecules are quite plentiful on hematologic malignancies but pretty much absent on solid malignancies. And therefore, what we've done here is create an artificial bridge to use a tumor antigen and link it to CD28 so that we can mimic this opportunity for co-stimulation. Our first one in the clinic is a PSMAxCD28. Again, we envision this as from the beginning, a combination with Libtayo. And in fact, it is dosed with -- in combination with Libtayo from the outset. So this is underway and has enrolled several cohorts and is ongoing in dose escalation. People shied away from targeting CD28 after the TeGenero debacle in 2006, which caused -- where widespread CD28 super agonism caused severe side effects and almost killed some healthy volunteers. But we've created antibodies that are highly specific to activating CD28, only in the context of the tumor and with the tumor antigen. Next slide, please. So this slide here gives you an example of the type of data in the preclinical setting that gave us such excitement about this. What you have on the left, our growth curves of tumors, either targeting with a control, PD-1 alone, or PSMAxCD28, and you can see they do not impede tumor growth, but when we combine PD-1 with the costim PSMA, we do. And by the way, we never -- we always sort of take this for granted, but all of these are done in models where everything is humanized so that we can use the actual clinical molecules in these models, another testament to the power of VelociGene that George and his colleagues have worked tirelessly over the years to develop. We've also shown on the right initial data with the PSMAxCD3 antibody bispecific that also has promising activity and was just recently published in cancer immunology research. Next slide shows additional preclinical data that gives us the basis for our excitement about combining CD3 bispecific with CD28 bispecific. Again, you see here that each one on its own in this model is insufficient to control the tumor, but the combination effectively controls the tumor. And in the bottom right, where you see the glows or where the tumor is, there's no glowing when you use the combination. So what you have here now is a summary of the types of various combinations that are coming into the clinic that we are very excited about. Not only do we have Libtayo as a foundational element within the checkpoint family blockade -- checkpoint family, we have a LAG3 antibody that is exploring a variety of combinations with Libtayo. And we've recently received an allowance from the FDA to explore a GITR targeting antibody, which we think is differentiated from others, which we will be taking into the clinic soon as well. We have a number of these combinations with CD3 bispecifics, costim bispecifics. And ultimately, you could imagine all 3. But as they say in the old commercial, "Wait, there's more." So I'm going to turn it back now to George. To talk through some new things that we're thinking about that add even further combinations.

Well, thank you, Izzy and Andres for reviewing those programs. I hope you guys, on the outside, share our enthusiasm for these stories. It doesn't matter whether we're talking about coronavirus or cancer. All of our efforts are involving these powerful and elegant and expansive combination opportunities that allow us to bring different classes of molecules together to enhance and extend therapeutic efficacy in these variety of different settings. And we're particularly excited that the foundational class members, such as Libtayo for the checkpoint inhibitors, such as the CD3 bispecifics for our entire bispecific platform are demonstrating their capabilities in the early human trial experience and really suggests that the combination opportunities that we have to look forward to could really take cancer therapy to another level. And in terms of that, I'm going to just very quickly, give you 2 short stories. Just to whet your appetites about the sort of things that our technologies allow us to do to layer on even more unique sets of combination opportunities. That allow us to once again enhance any of the previous therapeutic approaches in various settings. This is one that might have application and combination opportunities in lung cancer and a variety of other settings. I'm sure many of you know that the MET tyrosine kinase receptor, which is a receptor for HGF, can as a mutated version or as an amplified version, can promote tumor genesis and cancer activity. Well, thanks once again to our technological capabilities, we were able to make a very novel type of bispecific antibody that does something very different to this pathway that could be explored before. So our bispecific not only binds to MET receptors, blocks their interaction with the native ligand and the HGF and thus blocks that growth signal very effectively. But moreover, it rapidly induces a change in the complex structure information to rapidly result in degradation of the entire MET receptor complex. And this seems to induce a powerful apoptotic signal in the resulting treated tumor cells. Which we think could amplify the potential benefit of targeting this pathway. This agent, this novel bispecific is already in clinical trials as a single agent. And as I said, one could also imagine opportunities of combining this unique reagent or this class of reagent with other sets of opportunities, some of which we've already described to you. So that's one unique class of bispecifics that we're able to make based on our technologies and capabilities. Another very exciting one is summarized on the next slide. We refer to these as peptide-in-groove targets. I'm sure you're all familiar with the fact that T cell activation is driven by peptides that are processed from intracellular proteins, proteins that are normally not accessible to the outside of the surface. But these peptides are processed and presented on the surface of cells on HLA molecules so that they can be recognized by T cells, which are constantly interrogating to look for stealth versus non-stealth. Of course, this is the basis of transplant rejection, but it's also the basis of this emerging new power to use T cells to attack neoepitopes on tumor cells. Well, heretofore, T cell receptors had been the only approach to detect and address these sorts of peptide-in-groove targets. But we've been able to generate a new class of antibody and an antibody that we can generate in bispecific format that can do sort of exactly what T cell receptors are designed to do. But now in a highly selected fashion, once again, generated from a next-generation version of VelocImmune mice. So antibodies that can be made much higher affinity and much more specific for these peptide-in-groove targets than you can normally get from the natural TCRs themselves. But once again, these are very natural created by an in vivo system, peptide-in-groove antibody reagents that can be reassembled into highly potent bispecific antibodies. We believe these create a whole new class of reagents that allow us to attack, potentially, the many tumor-specific proteins that are intracellular and otherwise inaccessible to traditional antibody efforts but will be presented as these peptides and will now be accessible to our PiG put in various formats. And not only as bispecific format, as these bispecifics that you've heard about from Izzy and from Andres that can either directly kill or cause co-stimulation, but they can also put into formats powerfully into genetically engineered T cells to create new classes of empowered T cells that are now directed by these new classes of reagents as opposed to limited by either the traditional chimeric antigen receptors or the utilization of actual native T cell receptors to drive the T cells to recognize tumors. And obviously, we're taking great advantage of the opportunities and the possibilities that are presented to us with this whole new technological capability, not only internally, not only by using our bispecific formats, but in our powerful collaborations with partners that we have such as bluebird who are focused on using engineered T cells to attack cancer. Next slide. So we've tried to summarize a vast number of potential opportunities that we are creating with individual agents, but also in combination to attack cancers of all class. As you might expect, we'll be amplifying our approaches to attack all sorts of solid tumor cancers as well as hematologic cancers, and we're excited about this unprecedented capabilities that we've created of combining all sorts of checkpoint inhibitors, CD3 classes of bispecific, costim classes of bispecific as well as new emerging classes of molecules and bispecifics that we can make, such as the MET x MET that I briefly mentioned, these PiG reagents from the PiG bispecific not to mention the assortment of now collaborations that we've created from companies that we've discussed that allow us to take these reagents and further increase the opportunity to create clinical benefits. So with this overview of our ongoing programs, our pipeline and future classes of reagents, I'd like to turn it over to Marion McCourt, our Senior Vice President of Commercial to describe the commercial advances that we've been making in this space over the last couple of years.

Thank you, George, and hello to everyone. It's a pleasure to talk to you today. We have been able to accomplish a great deal commercially in oncology since launching our first indication for Libtayo. We collaborate, as you know, with Sanofi on Libtayo, and Regeneron is the lead in the United States. Together, we're very proud to have established Libtayo as the standard of care in cSCC. In addition to growing the market since our approval in 2018, we've taken significant patient share from chemotherapy. Further, we've taken share from in-class competitors demonstrating that even when physicians are familiar with specific treatments, they prefer choice, and they're open to trying clinically compelling therapeutic alternatives, according to patient need. We believe this is important as we look ahead to potential future indication approvals for Libtayo. Our commercial team is eagerly preparing for 2 potential new launches for Libtayo, basal cell carcinoma and non-small cell lung cancer. Starting with lung, there are approximately 20,000 first line advanced NSCLC patients with greater or equal to 50% PD-L1 expression diagnosed annually. Only one PD-1 antibody has been commercialized as monotherapy in first line NSCLC. As you heard from Izzy, our Libtayo survival data is strong and competitive. As I mentioned earlier, physicians prefer choice, and if approved, Libtayo would provide additional product choice for oncologists, providers and their patients. We look forward to potential commercial preparation in this important category. Moving to BCC. This is the most common skin cancer in the world with approximately 3,000 cases of advanced BCC in the U.S. alone. Like cSCC, this represents another potential first-in-class approval. There are currently no approved second line therapies and significant unmet provider and patient need exists. If approved, this would demonstrate Libtayo's potential in patients with another difficult-to-treat non-melanoma skin cancer. Before turning the call back to George, for closing and Q&A, let me briefly summarize some of our commercial accomplishments in just the last couple of years. First, we've successfully launched Libtayo and built a new immuno-oncology advanced cSCC market. Second, we've created an experienced, talented and competitive oncology team with our future portfolio in mind. Many of the individuals who have joined Regeneron have worked in oncology for their entire careers. Third, we're very well positioned to apply and extend capabilities for not only new indications, but also our future product portfolio. And with that, I'll turn things back to George.

Thank you, Marion. And with that, we'll talk about upcoming milestones and catalysts. Well, we'll show you that slide. And while we're showing you that slide, we'll open it up to Q&A.

[Operator Instructions] Our first question is from Terence Flynn with Goldman Sachs.

Great. Maybe just 2 for me. I was wondering if you can talk about your confidence level in the safety tolerability profile of 1979, such that you'll be able to move into earlier lines of lymphoma. And I was wondering specifically if you'd comment yet if you're going to conduct a head-to-head trial versus rituxan? And then maybe for Marion, just wondering, do you think you can get the modified intend-to-treat data on the Libtayo -- future potential Libtayo lung label?

Well, in terms of Regeneron 1979 and its safety profile, when Izzy had initiated this program, he devised a whole new approach of how to divide the dose to minimize cytokine release syndrome and other untoward effects, leaving us with a very comforting safety profile to-date. In terms of any details about it, I guess, I'll leave it to Andres who's inherited this program and who's been intensively looking into the safety aspects of it to make some comments.

So in terms of your question, we think that we have a very competitive safety profile. And we also believe that what has been put in place in terms of mitigating CRS, which, as you know, is one of the major concerns. We have addressed that issue very well with the schedule and dosing and premedication that was put in place earlier on in the program. And since then, I think that the safety profile of the drug now has changed dramatically. And I think that the updates that will be presented in due course will show how competitive the program is in that regard. When it comes to what you ask in terms of our plans moving forward in combination and early lines of therapy, we are planning to move forward and expand our program in other lines of therapy and combination therapy, and we will eventually disclose where we are going.

Okay. And in terms of the mITT analysis and the label, I'll turn it over to Marion.

Sorry, my name was mentioned. I actually think Izzy ought to take that and give the latest view from a clinical perspective.

Sure. So as I mentioned, when we were showing the data, the FDA actually asked us to do this analysis to be -- to show that in a rigorously tested PD-L1 population greater than 50%, that our study -- what the study showed. So in fact, you could argue that this is the key data. And we do believe that this will be included in the label, although that's a forward-looking statement. Exactly how it will be included we'll have to turn out with discussion.

And our next question comes from Matthew Harrison with Morgan Stanley.

This is Max Skor on for Matthew Harrison. I just have a quick question. Regarding the Regeneron 1979 trial, when can we expect an update from the DLBCL cohort? Should we be looking towards ASH 2020? Any insight would be great. I appreciate it.

All right. Well, we'll ask Andres to speak on when we hope to have any upcoming presentations.

Yes. We are aiming to provide an update towards the end of the year.

And our next question is from Evan Seigerman with Crédit Suisse.

Congrats on this presentation. Very comprehensive. Just going back to the mITT HR you presented. Can you just elaborate just a little as to what the differences are in the way you measured PD-1 in this particular population versus the overall population? I think we're a little confused there. And is this specific hazard ratio part of your broader strategy to compete? And then I have a follow-up on -- with the LAG3 by Libtayo data?

Yes. So basically, for various reasons we're not going to get into now, we did not have access to the ability to do our PD-L1 testings according to the FDA standards for clinical trial. When we acquired that ability, that resulted in accrual of the majority of the patients in the second half of the trial, and the FDA asked us to do this additional modified ITT analysis, which we showed on the slide to include only those patients who are validated as having PD-L1 greater than 50% according to their standard. We believe that, that represents, in some ways, the most appropriate data set to use when reviewing the study. And it represents the patients who were validated by that study done according to the FDA standards to represent the patient population that is greater than 50%. We certainly are quite buoyed by the efficacy that's seen in that population. What we can say is that us -- when patients who were tested the previous way according to the other standards were retested, a substantial number of them actually had lower PD-L1 level, substantially lower than the 50%, which raised the concerns in the first [ split ]. But as one might expect, if you limited your analysis to those who were truly PD-L1 greater than 50%, you would get there your most convincing and best data.

And Evan, you had a follow-up on like LAG3?

Yes, for sure, Justin. So I noticed that your expansion cohort is enrolling. Any characterization as to what you saw in the dose escalation part of the trial?

Izzy, I'll ask you if you want to make any comments on that.

I think it's still a bit premature for us to talk about the efficacy data, I mean, suffice it to say, we think the place that it's going to really be active is as a combination. And we're exploring a couple of leads there to convince ourselves that we have appropriate activity to proceed further.

And I think what everybody should realize, as I think we have demonstrated with Libtayo, it's not always so easy to make the best checkpoint inhibitors. Not all of them are created the same even against the same target. And not everybody always picks or predict the right settings and the right indications where particular checkpoint inhibitors might have the best efficacy. And I think that as led and demonstrated by Izzy and his team, they can pick some of the best settings and situations and combinations. And our technologies can deliver, in some cases, the best-in-class reagents.

Our next question is from Alethia Young with Cantor.

Just one from me. I just wanted to talk a little bit more about how you plan on positioning with your BCMA program with like so many on the market. Is it, again, the combination approach or is there an inherent differentiation you believe you can achieve on the agent [ loan bank ]?

Was that question about basal cell carcinoma?

No, no. BCMA.

All right, BCMA.

BCMA. Oh, sorry, we didn't hear that. BCMA. Yes. I think the critical thing is, once again, as I've just said, not all agents and reagents even against the same targets are created equally. And I think that the track record of our technologies is that they tend to give reagents that deliver best-in-class or match the best-in-class in efficacy. So that's one thing. There may be a lot of agents out there. They're not all going to be delivering the same amount of efficacy. Secondly is, of course, this opportunity that we have, which I think is unmatched in terms of combining the right type of targeted agents to maximize the efficacy. So we are excited that not only have we now generated, as you heard from Andres, 2 different BCMA bispecifics, using 2 different CD3 arms that are both clinically active but that we can use these essentially as starting points, as hopefully very active starting points, where then we can layer in our additional therapies. So for example, for these combinations, we are very excited about fusing in our CD28 costim agents that will, at least based on what we've seen preclinically, combine very powerfully and hopefully in a safe enough way to enhance efficacy. So we are very excited about having potentially best-in-class initial agents based on the BCMA approach, but also the ability to mix and match them with additional plasma cell costim agents that will enhance that initial activity.

And our next question is from Geoffrey Porges with SVB Leerink.

George, since you opened up the clairvoyance of your CoV-2 antibody. So I just want to clarify a couple of things there. And then I have one question on the oncology side. So previously, you said that you had 2 cocktails in development for CoV-2. And I'm just wondering if that's still the case? And then could you just talk a little bit more about this mutant escape, how fit was that escape variant? And what species did you see that? Should we be concerned about that? And then just last question. There's been some pretty encouraging data about TIGIT at this year's ASCO. You don't have a TIGIT, you have a history of being able to catch up very quickly when promising new targets to identify. Do you have any intentions or interest in developing a TIGIT antibody?

Okay, 15 questions for Geoff. Okay. Try to remember them in order. But yes, we have multiple antibody cocktails that we are considering, one of which we'll be entering into clinical trials within the next week or 2, which is our prime cocktail. We do think that there is enormous reason to be concerned about viral escape. We have shown in our preclinical experimentation that it is trivial to select escape variants with even the most potent single antibodies that have ever been described against any virus. We do not think that this is a surprise. This is the entire history of viral drug therapy, and there is no reason to think that antibodies should represent some new immune class, immune from mutation and viral escape. What we have shown that you could actually -- if you have single antibodies, multiple single antibodies that all bind to a similar region of the spike protein, a single -- a single amino acid change in the spike protein can eliminate the binding of that entire shared class of single antibodies. We think there is enormous danger that if people contaminate the population with single antibody treatments, they may select for these escape mutants and be wiping out whole classes of therapies. When you use a cocktail, it becomes much harder. And the virus, it's much harder to derive resistant viruses. This is just exactly what's been seen with combination drug therapies in the past for HIV and other therapies. So we are very excited about the opportunity with our initial cocktails, and we have our backup cocktails as well as we need them. We think the world should be very concerned about people prematurely going out with single antibody treatments and contaminating the world with escape mutants. We actually already know escapes mutants do not result -- the mutation is not caused by the antibody. It's just selected by the antibody. And we already know that escape mutants to individual single antibodies exist today in the human population. And if we go after these populations with single antibodies, we will tautologically bring out and amplify the representation of these single escape mutants. And eventually, if we do too much of that, we will even make viruses that will then be resistant to cocktails, which I believe, right now, they are not. Okay. So that's the first set of questions that you asked. The second set of questions about TIGIT. As you might expect, we have a plethora of our own TIGIT antibodies. Right now, I have to say that we are not overly convinced or excited about the TIGIT opportunity. The space seems to be overlapping with the PD-L high population, and it's not clear to us that it will actually add to any efficacy over a potent PD-1 blocker on its own. We do think, and we are excited about our GITR antibody, which in some ways, leads to interactions or relationships with the TIGIT space. Our GITR antibody, we believe, is very different from any other GITR antibodies out there. We have shown that ours have the ability to very effectively deplete Tregs, the suppressor cells that are holding back tumor responses while actually sparing the effector cells that you want to go after the tumors. We're very excited about this. We've been able to -- because we have -- the VelociGene technology allows us to create these multiply humanized models that are, we think, more faithful replicas of what's going on in the actual human because so many components we can humanize. We've done a variety of head-to-head comparisons, which make us very excited about the unique ability of our GITR antibody to target intramural Tregs and shift the Treg to T effector ratio, which is something that we've not been able to see with comparators and head-to-head studies in our humanized models. So we are very excited about that program. And as you heard from Izzy, that is already in the clinic.

Great. We still have several callers in the queue. If you could limit your question to one, we'd like to get through as many as possible.

And our next question is from Geoff Meacham with Bank of America.

Just a question on your Libtayo combos with bispecifics. You guys are evaluating a number of less immunogenic tumors or cold tumors. And obviously, this has been an area historically, which hasn't been so fruitful in the I/O field. So the question is, what gives you confidence in these settings? I'm talking about the prostate and ovarian in particular. And do you have a sense for how your combinations may compare in some of the preclinical models to other PD-1 combinations in cold tumors?

Yes. I think that the reason tumors are so-called cold is because they are not generating the assortment of signals that are necessary in order to allow for T cells to be attracted, to be activated, to proliferate and to create a hot -- a so-called hot environment. This is exactly what our costims are designed to do, which is why we want to add these combination of signals. Most reagents to date, as you know, are focused on the so-called signal one. So our costim bispec that you mentioned in prostate cancer or costim bispec that you mentioned in ovarian cancer can hopefully provide this missing signal to and allow for turning hot tumors into cold. We should also mention that our CD3 bispecifics will also offer the opportunity of engaging independently of whether the T cells are there already or not of engaging and bringing T cells by targeting them to recognize and bind to the tumors of interest. Izzy, would you like to add some more to that?

Sure. Thank you, George. First of all, cold is relative. I mean the idea is to really get the sparks going and get the inflammation going. And that's what we seek to do with these approaches that can rely not on specific T cell recognition per se and influx of T cells to have been there before, but to get stuff going where they haven't -- where it hasn't really started. So the CD3 bispecifics basically round up T cells in the neighborhood and say, come on in and let's attack this common antigen. And the costim bispecifics say, "Listen, if you're here, we can boost your signal," whether it's via a CD3 bispecific or if you're augmenting an authentic recognition by a T cell of tumor antigens, but it just doesn't have enough oomph even with PD-1. And so you give it that extra kick. So these have all been supported by our preclinical models, which as we keep saying, we use our clinical candidates in these models. So we're not using surrogates. So the proof will be in the clinical trial, but we think we're excited to bring these forward.

Well, thank you, Izzy. Much better than my preliminary answer. Luckily, that's why he's in charge of the program.

Our next question is from Carter Gould with Barclays.

Congrats on all the progress. I guess, George and team, to what extent should we expect Regeneron to continue to invest and explore in trials in the compete section of your strategy, particularly once you get past the chemo combo in lung? And if that's too vague, I'm trying to understand how you weigh strategic choices pursuing things like Libtayo mono and adjuvant lung and maybe rerunning the playbook of your competitors versus focusing more on combinations? Or can you do both?

Well, I do think that we are very interested in some of the settings where there are enormous numbers of patients who can benefit. Lung represents such an opportunity. We now think that we have compelling data that really creates a competitive profile in lung. We are excited about the cancer settings where we were first-in-class, where we think we have the opportunity to build the opportunity. But we also are also, as you said, the next-generation of technologies are going to allow us to bring the next-generation of potential treatments to patients who really need them. So our focus, as you said, after a lot of these settings in which we're either creating the market or we're very willing to compete, will be in settings where we are now hoping to enhance and extend tumor responsiveness where there isn't enough of a benefit. And that will be a large part of our bonus. We think a large part of our future. So we think that there's enormous opportunity now to be competing with a therapeutic that has such an attractive profile in terms of the Libtayo. But we think there's enormous opportunity to enhance and extend the benefit of Libtayo to other settings, either by combining it with all these other agents that you've heard about or to go into these other settings with these other combinations with or without the Libtayo, it's really, I think, an enormously exciting time for us. And I think for the field and a time that offers a lot of hope to cancer patients, which is why we're in this business in the first place,

Chapter 1.

Chapter 1, Izzy just said.

Our next question is from Yatin Suneja with Guggenheim Partners.

So just a broader question. Can you maybe just talk about the fundamental differences between your approach for CD3 versus CD28 bispecific, specifically in terms of the tumor or the cancer target they might be applicable to? And then what you might be doing just to sort of mitigate the potential CRS or cytokine storm issue that might seem to follow after you stimulate either CD3 or CD28?

Okay. Well, there's a lot sort of in there. Okay, we think that we have a unique platform that allows us to create the best-in-class reagents as we've already been demonstrating over the last years. We can make them that are either targeting or using reagents that create the signal 1 or that create the signal 2. And we have a variety of different versions of these and different versions of signal 3. We believe that we are the leaders in establishing not only these classes, but also in the ability to have a turnkey system that creates them, that allows us to do this plug-and-play approach that Izzy described like few others could possibly even imagine. And along with that, we've been pioneering and developing ways of trying to figure out how to give these, either create them so that they're safe or give them that they're safe. Izzy, would you like to amplify again?

Yes. So there's no tumor that can't be thought of as a target for both the CD3 and/or a CD28 costim. So that's number one. Number two, the extent of cytokine release is probably going to be different for individual agents. And our preclinical data suggests, for example, our costim bispecifics are very mild. And what we've already established, we talked earlier that we know how to manage CRS with our CD20xCD3. And obviously, everything we do when we go into the clinic, we do it cautiously. But we think that the benefit to be gained by combining these is tremendous. And it's really this combination approach that's going to be the key towards really getting effective therapies out there.

And our next question is from John Newman with Canaccord.

Just a quick one. Do you have any plans to explore combining a gamma-secretase inhibitor with any of your bispecifics targeting BCMA?

It's a notch pathway.

Maybe you can tell us why we should consider that because we have not to date.

It's just something that some of the other companies in the CAR-T arena are trying -- some people believe that if you inhibit gamma-secretase, it can prevent free -- high levels of free BCMA circulating, but it hasn't been proven yet. So just curious.

Well, we will keep our eye on that and consider adding it into our collection of potential combinations. Though I have to say, I think we're more excited about our internally-derived combination opportunity.

Our next question is from Ronny Gal with Bernstein.

I'll ask one and a half, the second one is a pretty quick one. First, if you kind of compare the timing of your chemo combo in non-small cell lung cancer to the KEYNOTE-189, it seems you should be in a pretty good position to have your interim analysis pretty soon after you complete enrollment. If you care to give us an -- a IA -- aye or nay there I would appreciate it. And second, George, since you've taken the antibody approach to death, I got a follow-up on Geoff's question and ask you, if we think about the pain approaches, which obviously generate monoclonal antibodies, do you see the mutability of CoV-2 to be a risk of escape there as well? Or is this something that's essentially unique for the single antibody, monoclonal antibody approach?

Well, let me take the coronavirus question first, then I'll turn it to Izzy for the question of the timing for our combination chemo studies in lung cancer. So we do not think that the virus is mutating at a very high rate. It's just that, as with any virus, a selective pressure that does not understand how to avoid selection of rare mutants by allowing for combinations can lead to potential catastrophe even undermining the possibility of future vaccines, meaning that if you select for new spike proteins, that are now resistant to immunodominant epitopes, which some of the first single antibody treatments are designed to attack, then you can actually weaken the benefit that you might see from vaccines because you will now have selected in the population, variants that have now taken over, that are missing these immunodominant epitopes. So I think that there's a lot of danger there. We should point out that the history of viruses has shown how rapidly single amino acid mutants that create whole different classes of resistance can take over populations in just a few months over an entire globe. So anyway, with that, I'll turn it over to Izzy in terms of the timing for the chemo combination.

So we have announced that we are expecting to complete enrollment in the very near future. And we've given guidance that sometime in 2021 is when we expect to see our first analysis that we think may have a chance to be positive. Obviously, if we do one earlier and it's positive, we'll let you know.

Our next question is from Mohit Bansal with Citigroup.

Just wanted to understand your peptide-in-groove approach a little bit better in the sense of how does it compare with the traditional TCR-based therapeutic approaches? And how do you envision your therapeutic in terms of, do you think it will be off-the-shelf or [indiscernible] at this point? And lastly, when could we see something from this program [ entering clinics ]?

[ So it's a great question. But to get into the nitty gritty, as many of you may know, T cell receptors are designed to be low affinity ] agents that recognize in what's called a high avidity state, their counterpart peptide. Antibodies are intended to be high affinity reagents that can essentially monomerically [ bind to and attack their target. So what we've been able to show is that our peptide-in-groove antibody can, on average, be higher affinity and more specific reagent than T cell receptor. And thus, they can be used in soluble approaches, i.e., bispecific approaches for which T cell receptors are not designed by nature to be able to work in. So it's a whole different level, a whole different class ] because antibodies that are recognizing what T cell receptors recognize can be higher affinity and can work as soluble reagents. That said, they may also have advantages in terms of binding affinity and specificity to T cell receptors even when engineered into T cell. I think that the first examples that we may hope to see of these in the clinic may be when they are incorporated into engineered T cell approaches with our collaborators such as a bluebird, for example, and that could be within the next 1 to 2 years.

And our last question is from Kennen MacKay with RBC Capital Markets.

Again, congrats on the progress, especially with Libtayo. On Libtayo, wondering which of the combinations the team was most excited about? If you think with some of these newer targets, the field will be able to surpass the synergistic or additive efficacy bar set by CTLA-4? Thanks and congrats again.

Well, by the way, I should have probably mentioned in my earlier remarks, I hope you all realize that Libtayo is all part of a big and ongoing collaboration with our partners in Sanofi. And I hope you have heard from their own investor conference that they are equally as excited about Libtayo as we are. In terms of which of the sets of combinations we're most excited and interested in terms of extending Libtayo to a previously unresponsive tumor or increasing responses, I think everybody you ask at Regeneron will probably give you a different answer. But since he's running most of these programs, I will turn it over to Dr. Israel Lowy for his thoughts.

Well, we love all our children. And...

[ Equally? ]

[ Yes, they each have their flaws and their pros, but... ]

[ Some of them I like on Wednesday, the ones I like better on Thursday. ]

[ But we wouldn't be pursue -- we're not doing a, throw stuff at the wall and see what's fixed approach. We really take each of these. We vet them very carefully. We think them through. I mean, obviously, the combinatorial universe is impossibly large. So we try to make really good guesses. We look for where there's a need. We look for where we can find an antigen that we can target specifically where we can model it properly and be convinced that what we're taking into the clinic has a shop. And that's the approach we take. And we sort of mentioned this earlier, from the very first days, this is all about combination. That's going to be the future. This is -- people have said, "Oh, you have -- there's a PD-1, it's over." It's not over. It's just beginning. And the future is going to be and coming up with various types of combinations and the more flexibly and facile way you can test intelligent combinations, the more likely I think you'll be towards hitting on some good treatments for previously difficult-to-treat cancers. ]

[ Thank you, Izzy, and thank you to the team. We appreciate everybody dialing in today. We know it's a busy time during ASCO. Hopefully, you found today insightful. As always, the Investor Relations team is around to answer any questions you may have. ]

[ And thank you, ladies and gentlemen, this concludes today's conference. Thank you for participating, and you may now disconnect. ]