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

Hello. Thank you for holding, and welcome to the Regeneron Oncology Investor Event ASH 2020. [Operator Instructions] Please be advised that today's conference may be recorded. [Operator Instructions] I would like to turn the call to the Head of Investor Relations, Mr. Justin Holko. Please go ahead.

Welcome, everyone, to Regeneron's Oncology Hematology ASH 2020 webcast. Joining me on the call today are Dr. George Yancopoulos, Co-Founder, President and Chief Scientific Officer; Dr. David Weinreich, Senior Vice President and Head of Commercial and Clinical Development; Dr. Andres Sirulnik, Senior Vice President, Translational and Clinical Sciences Hematology; and Dr. Israel Lowy, Senior Vice President of Translational Sciences and Oncology. 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.

Thanks, Justin. I'm going to be giving a very brief and broad overview and introduction here. You'll hear all the details from my colleagues. I just wanted to remind everybody that what we think really distinguishes Regeneron is that our pipeline is created and developed in-house by our scientists using our own innovative homegrown technologies. It usually starts with our VelocImmune genetically humanized mouse, and then often integrates our collection of highly interrelated VelociSuite technologies, including Veloci-Bi and VelociMab, which altogether span and power everything we do from basic discovery all the way through large scale manufacturing. It is these versatile and flexible homegrown technologies that have allowed us to repeatedly invent and deliver important new medicines across so many disease areas, whether it be blockbusters like EYLEA to fight the most common causes of blindness, such as macular degeneration or diabetic eye disease, or dupilumab as the leading biologic to treat related allergic conditions such as asthma and atopic dermatitis, or Praluent as the first-in-class treatment blocking the PCSK9 genetic target for heart disease. And it is these homegrown technologies that also give us the flexibility and speed that allowed us to deliver the first treatment of any kind to be FDA-approved for Ebola. And I'm sure many of you are aware of our related efforts exploiting these very same technologies to deliver the first antibody cocktail treatment for COVID-19 to receive Emergency Use Authorization. And it's also these technologies that have delivered the pipeline of cancer treatments that you'll be hearing about today, from our checkpoint inhibitors to our multiple classes of bispecifics. And I should note that in addition to our CAR homegrown pipeline products, we have added a selective set of outside collaborators such as Alnylam for when we think the key combination may require one of our antibodies together with an siRNA or a critical vaccine partners, which we think can also be appropriately paired with our antibodies when necessary to enhance activity. So why do we think this is so important? Because by now, I think we all appreciate that the optimal treatment for most cancers will require combinations. We have designed our pipeline to give us the power and flexibility to design and mix and match the right combination of treatments for each cancer. We might start our efforts against a particular cancer with our anti-PD-1 antibody, Libtayo, and then add the selected bispecific that targets that cancer. Or we might start with one bispecific and then add a second class of bispecific. It is this mix and match capability that really distinguishes our approaches, as I think you'll see from the presentations. And so with that introduction, I will turn it over to my colleague, David Weinreich, who is the Head of our Global Clinical Development organization. David?

Thank you, George. Regeneron continues to invest very heavily in our future in cancer and in hematological disorders, as you'll hear later. The core of this is to compete with our checkpoint inhibitor, our anti-PD-1, Libtayo, that is potentially delivering best-in-class data in multiple tumors, including cutaneous squamous cell carcinoma, basal cell carcinoma and more recently, in non-small cell lung cancer, which my colleague, Izzy, will review in a few slides. This is an enormous opportunity, because the PD-1 class is estimated to eventually grow to more than $25 billion and is currently showing more than 25% year-over-year growth. Unfortunately, PD-1 inhibitors by themselves, even in tumors that are responsive, only help about half of the patients. And one strategy that we have, as George has already outlined, is to enhance those responses by combining our bispecifics, either by CD3 bispecifics or our co-stimulatory bispecifics, in combination with PD-1. Even taking the cancers in which checkpoint inhibitors have shown activity, most tumors are not responsive to checkpoint inhibition. And our strategy of using bispecifics, with or without Libtayo, has the opportunity to extend immuno-oncology into otherwise nonresponsive tumor types. We've built a -- over the last 30 years, a number of platforms that has created a toolkit of various different potential therapeutics that we can then mix and match. It started with the VelocImmune antibodies that gave us Libtayo. It's now moved on to Veloci-Bi, which I'll explain in a little detail on the next slide, that are generating multiple different bispecifics, CD3 bispecifics that link a tumor-associated antigen to a killer T cell, a co-stimulatory bispecific to enable a synergistic supportive signal between a tumor-associated antigen and a T cell. And in the future, we'll be talking about even newer classes of bispecifics, like PiGs and VelociNator, but we'll save that for the future. In addition, there are applications for our platform via collaborations with vaccines and CAR-T therapies. Just to briefly go over the science of why we're so interested in this very versatile platform of Veloci-Bi. This technology allows us to rapidly produce antibodies that can target 2 different moieties without the use of any linkers, artificial sequences, without changing our manufacturing processes and that generate PK parameters that are similar to regular antibodies. This is essentially a dial in whatever target we'd like on each of the 2 arms of the antibody. At present, our pipeline is quite full with a number of different xCD3 T cell activators and xCD28 T cell co-stimulators. But the research portfolio has many other targets that we're still working on, including other T cell targets in addition to different tumor types. And today, we're going to spend most of our time talking about the hematology targets of CD20 and BCMA, which my colleague, Andres, will do in a few minutes. When you put this all together, this more completely and has the potential to recapitulate what really happens with a T cell and a tumor when it engages on its own. PD-1 releases the emergency break, causes the T cells, in general, to be more active. The Signal 1 or xCD3 bispecific is the ignition. It's bringing a specific T cell directly up against a particular target cell. And then lastly, our Signal 2, or our xCD28 is like applying a targeted gas pedal that only applies when the T cell and the tumor-associated antigen are brought into proximity with one another. Graphically, this looks like or stylized like this. And it allows us to both, we believe, to increment efficacy, but also to do it in a targeted fashion and not just blatantly open up the immune system in an unspecified fashion. Over the last decade, we've built an enormous portfolio in cancer. And I won't go through everything that's on this list, but it's just the beginning of an even larger research effort as we try and beat this horrible disease. Regeneron has already brought Libtayo across the finish line in cutaneous squamous cell carcinoma, and we showed some phenomenal and best-in-class data at our update in ASCO. And we have a number of pending, potentially pivotal studies ongoing as well as having already read out data that we believe to be registrational, with filings ongoing in non-small cell lung cancer and basal cell carcinoma. The real power to this is the mix and match, and it may be absolutely necessary that based upon individual tumor types, their background responsiveness to immuno-oncology, you may need different combinations of BiSpec, co-stim, PD-1, and although not depicted on this chart, potentially all 3. And having all of them under our roof speeds development and also enables combination therapies without dealing with the typical issues down the road of the expense of oncology drugs. So I think it's important that we review some of the detailed data. So I'll turn this now over to Izzy Lowy, who's our Head of Solid Tumor Oncology, to review some of that data. Izzy?

Thank you, David. So while today, really, the focus of the show is about our burgeoning hematology portfolio, it's a pleasure to just remind you of the steady pulse of progress that we're making with our PD-1 antibody. What we've done in this previous year is demonstrate continued growth in our primary indication, CSCC, where we were the first to achieve approval and where we continue to expand our base in that area. And where we have shown additional follow-up data that shows improvements in CR rates. We've shown neoadjuvant data that is very promising with very high rates of a major pathologic or complete pathologic response. And more recently, we expanded and showed that in basal cell carcinoma, in the setting in which patients have exhausted the responsiveness to hedgehog inhibitors, durable and deep responses that are -- will be reviewed by the FDA with a PDUFA date, the beginning of this coming March. Also, we have demonstrated that in this crucible of the tough place to show efficacy of single-agent checkpoint inhibitors, non-small cell lung cancer, Libtayo demonstrated outstanding results in the patient population greater than 50% of PD-L1 positive. And it is this result, despite high crossover rate, despite including additional patients into the program that were not normally included in other studies, that we feel confident in saying that Libtayo is as good an anti-PD-1 at minimum as anything else out there and that we have succeeded in establishing a robust foundational platform to assist with all of our future combinations. We expect a ruling by the FDA by the end of February, and hope that this will become a new option for providers to offer to their patients. And in the coming year, we expect additional pivotal data emerging, one from our chemo combination study in lung cancer, where we will be doing our first look at data in the first half of 2021. And similarly, our second-line cervical cancer Phase III study, which is fully enrolled and where we also plan to have some looks at data in the first half of the coming year. This represents the potential for 5 different approvals, which we think clearly demonstrate the potency of this antibody. While we were developing this, we stepped in to start looking at ways to combine and extend. So we have numerous combinations underway with agents from in-house, as George outlined, and as David outlined, our bispecifics, either CD3 bispecific engagers or CD28 bispecific engagers. We've demonstrated preclinically exciting opportunities for justification for exploring this. And 2, in particular, that are in the clinic. One is our first co-stim in the clinic PSMAxCD28 in combination with Libtayo. And the second is the MUC16xCD28 co-specific -- bispecific that will be in combination with either Libtayo or our MUC16xCD3. And on this slide, what you can see is an example of the preclinical data that we have developed supporting these efforts. On the left, you see a model in which anti-PD-1, or PSMAxCD28 alone, failed to control tumor growth, whereas the combination augment the potency of syngeneic or normal T cells in the mouse to effectively control the tumor. On the right, you see an example where a MUC16xCD28 is really not effective on its own. A MUC16xCD3 can cause a transient control but loses it over time, whereas the combination provides a deep and durable response in these murine models. So these are examples of how we're taking our foundational PD-1. And now with our new technologies, our co-stim bispecifics, our CD3-engaging biospecifics, are moving them into the clinic. We have moved 3 such co-stims into the clinic this year. PSMAxCD28 in combination with Libtayo is in the midst of dose escalation. And so far, we have shown safe administration. MUC16xCD28 has opened a study, and we hope to be enrolling patients very shortly. And similarly, EGFRxCD28 also will be combined with Libtayo. EGFRxCD28 is an interesting potential co-stim bispecific as many epithelial tumors express the eGFR receptor. And therefore, we can use that eGFR receptor as a means to bridge a tumor cell to T cell and augment the native signal that the T cell has towards the tumor. So we are very excited about this portfolio. But now to turn back to hematology, I'll turn to my colleague, Andres Sirulnik.

Thank you, Izzy. I'll be talking first about our ASH update for odronextamab, our CD20 CD3 bispecific, including the program strategy and outlook. We continue to advance our robust program across non-Hodgkin's lymphoma. At ASH, we presented updated data from our ongoing Phase I study. But importantly, we have already initiated a broad potential pivotal Phase II study that includes 5 disease-specific cohorts. This Phase II study is rapidly enrolling, and we expect to complete enrollment in 2021. Odronextamab, an off-the-shelf agent, has the potential to be a best-in-class therapeutic, effective in both indolent and aggressive lymphoma, including patients who have failed CAR-T therapies. We have already dosed over 350 patients across the entire program. Updated Phase I data remains consistent with prior data points. Odronextamab shows encouraging and durable responses. In follicular lymphoma, responses rates remain above 90%, with durable and complete responses lasting in some patients more than 3.5 years. In diffuse large B-cell lymphoma, response rates of 55% in CAR-T-naive patients and 33% in post CAR-T-naive patients is encouraging. And again, complete responses in these patients are lasting up to 2 years at the time of our presentation. Importantly, odronextamab is demonstrating a good tolerability profile with a manageable CRS observed mainly during the initial step-up dosing. As data matures, odronextamab continues to demonstrate overall a favorable benefit risk profile in patients with follicular lymphoma and diffuse large B-cell lymphoma. In our dose escalation study, the study that we presented at ASH, doses of odronextamab was given in doses of up to 320 milligrams weekly without dose-limiting toxicities or reaching an MTD, and no dose-dependent increase in toxicity was observed. I'd like to highlight here that no patient discontinued odronextamab due to CRS or neurotoxicity. Looking more closely at CRS. The introduction of step-up dosing and premedications have helped considerably in mitigating this risk. The majority of CRS events were mild to moderate in severity. And Grade 3 or greater CRS events occur with initial or intermediate step-up doses. When we focus on follicular lymphoma and diffuse large B-cell lymphoma, the highest rate of CRS observed was Grade 3 with an acceptable frequency, only 1 in 38 patients in follicular lymphoma and 4 out of 78 patients in diffuse large B-cell lymphoma. Turning to efficacy. In patients with relapsed/refractory follicular lymphoma, we observed an overall response rate of 90% and a CR rate of 70%. And as I mentioned earlier, these CRs appear to be durable with a median duration of CR not yet reached. Furthermore, 81% of the CRs were durable and are ongoing up to 41 months. When we look at diffuse large B-cell lymphoma, with no prior CAR-T therapy, we observed an overall response rate of 55% and a CR rate of 55%. And again, these CRs appear to be durable. The median duration of CR has not yet been reached, and over 80% of these CRs were durable and ongoing up to 41 months. Looking now at the post-CAR T diffuse large B-cell lymphoma patients. We observed an overall response rate of 33% and a CR rate of 21%. And similarly to the other 2 populations, we see these CRs to be durable. A median duration of CR has not been reached, and 100% of the CRs are ongoing up to 20 months. So the program is progressing rapidly, with several near-term events in 2021 and a potential BLA submission in 2022. In the first half of next year, we expect to complete accrual in follicular and diffuse large B-cell lymphoma in our ongoing potentially registrational study -- Phase II study. Importantly, we plan to initiate the exploration of subcutaneous odronextamab in the clinic. And with this update, we are also announcing a broad and pivotal development program in both follicular lymphoma and diffuse large B-cell lymphoma, including 3 Phase III trials in early lines of therapy. We also will be exploring chemo-free combinations, including combinations with co-stim bispecific antibodies within our pipeline. In summary, odronextamab, a single agent bispecific, demonstrates efficacy across both aggressive and indolent lymphomas in what we view as a best-in-class therapeutic. Our program is rapidly advancing and our advanced development plan provides a tremendous opportunity to bring this therapy to many patients. Moving now to our BCMAxCD3 bispecific program. We have a robust program for our BCMA bispecifics, and we are very pleased with the data presented at ASH from our ongoing Phase I trial in relapsed/refractory multiple myeloma. Importantly, REGN5458, our first BCMA bispecific in multiple myeloma, has demonstrated competitive efficacy profile in a heavily pretreated vulnerable patient population. And to highlight this, 100% of the patients in this study are refractory to prior anti-CD38-directed therapy and at least 100 -- triple refractory. 60% of the patients had a prior autologous stem cell transplant, and 30% of the patients were 70 years older, all populations that are vulnerable and difficult to treat. We observed these responses across all those levels with manageable tolerability profile, no Grade 3, new toxicity or CRS to date. Last year, we showed 2 dose cohorts with encouraging responses. This year, we are showing compelling data from 6 dose cohorts. And again, we observed early, deep and durable antitumor responses with 95% of the responders achieving meaningful VGPR, very good partial responses, or better. These responses occur early and improve over time. An important update to our program is that we are currently enrolling patients to the potentially Phase II portion of this study. In terms of the safety, we are very pleased to see an acceptable safety and tolerability profile. There was no Grade 3 CRS or greater. Those patients who reported grade 1 or grade 2 CRS mostly experience it within the first week of treatment and was manageable. Important learnings from the odronextamab program has enabled us to dose escalate quickly and manage CRS effectively in this program as well. As mentioned earlier, we are seeing early, deep and durable responses across all those levels, and the data continues to mature. 95% of the responders achieved a VGPR or greater, a clinically meaningful measure of efficacy in multiple myeloma, and 42% of the responders have a CR or stringent CR. When you look at these CRs, 57% of the patients, of the available patients, achieved an MRD-negative status. On the next slide, in terms of the duration of response, I mentioned that those responses occur early, mostly within the first 4 weeks and deepen over time. And 74% of the responders have ongoing -- had an ongoing treatment. Importantly, among responding patients with at least 6 months of follow up or greater, 83% have ongoing responses for up to 13 months. Next. We are encouraged by our progress, and we believe that REGN5458 can play an active role in the treatment of multiple myeloma. We have a robust development strategy, and we continue to expand and expect to enroll our potentially pivotal Phase II portion of the study within 2021, where we will be exploring combination therapy with standard-of-care regimens and novel agents like our co-stim molecules. Similarly to what we mentioned for odronextamab, we plan to explore in 2021 and bring to the clinic a subcutaneous formulation. Also, in terms of our CD3xBCMA BiSpec in this area, REGN5459, which has a lower CD3 arm affinity, continues to enroll, and we plan to present data in 2021. So similar to what Izzy mentioned before, part of our overall strategy and development plan for hematology is to specifically pair CD28 co-stimulatory molecules with our CD3 BiSpecs as a way to extend durability of responses across patient populations and turn no responders to responders. Highlighted here on the right is Regeneron preclinical data demonstrated improved tumor killing of a lymphoma cell and with a combination of odronextamab. And this -- with this co-stimulatory BiSpec, compared to odronextamab alone, this is similar and consistent what was observed and discussed by Izzy in solid tumors. We anticipate that these B-cell bispecific plus odronextamab combination will enter the clinic in 2021 in lymphoma. Additionally, we plan to bring a bispecific directed to T -- to plasma cells in combination with 5458 next year in multiple myeloma. In conclusion, both our CD20xCD3 and our BCMAxCD3 programs each have shown promising single-agent activity. We are progressing these programs in potential pivotal trials, exploring these agents in early lines of therapy and combinations with SOC and other novel agents. While our CD3 bispecifics are rapidly progressing, we want to share some of our ongoing efforts within our classical hematology pipeline. Our insights in biology, available tool kits and the ability to mix and match technology, puts us in a unique position to solve challenging problems across a spectrum of diseases. We have ongoing programs in the areas of complement and coagulation disorders, transplantation and immunology and extending to other areas, such as hereditary amyloidosis. Many programs are in early stages in clinical development. Over time, we will be discussing the specifics of these programs as they progress. However, today, we want to give you a taste of what we expect from Regeneron over the next few years in hematology, a space in which we believe we have the experience and toolkit to successfully advance our projects. Starting with efforts in complement. We are exploring C5-mediated diseases in both monotherapy and in combination with our C5 antibody, pozelimab. We will shortly begin dosing in accessible interior study in combination with Alnylam C5 RNAi inhibitor, cemdisiran. The goal of the combination approach is to achieve convenient self-administration with a subcutaneous formulation and potential to bolster a complete and durable blockade of the complement activation in patients suffering from PNH and other complement-mediated disorders. In terms of transplantation and immunomodulation, we have initiated a Phase I first-in-human study with our IL-2 receptor gamma antibody in patients with aplastic anemia. We plan development in multiple indications that require transient suppression of T cell responses as an alternative to toxic T cell depletion agents such as ATG. With BCMA or our bispecifics in BCMA, in addition to our development plan for multiple myeloma, we are exploring REGN5458 and 5459, our second BCMAxCD3 bispecific, in various disorders caused by abnormal antibody production by plasma cells. I would also like to highlight some recent progress with our collaborators and with Intellia. Intellia is leading a program in hereditary amyloidosis. A patient was first dosed in November of 2020, the first ever CRISPR genome-editing treatment delivered intravenously. This is a single-course therapy that potentially halts and reverses the progression of hereditary amyloidosis. The phase study is ongoing in this patient population, at the moment, focused on patients that experience polyneuropathy, but with plans to evaluate this treatment in a broader patient population that extends to patients with cardiomyopathy. Lastly, we our population efforts are anchored by our recent expanded collaboration with Intellia in which we are co-developing potential hemophilia A and B treatments using jointly owned targeted trans-gene insertion capabilities. Potential single-course gene insertion therapy for hemophilia with these technologies will become an option. We are also advancing an antibody targeting Factor XI, which is currently in IND-enabled studies for thrombotic disorders. In summary, our CD3 class of bispecifics are progressing well and further along in clinical development. Beyond the CD3 class, we have an emerging pipeline across hematology in various stages of our clinical development. Hematology, both in oncology and classical disorders, is an area that Regeneron will continue to invest over the next several years. And as we mentioned before, odronextamab, continues and will progress along in the treatment of patients with lymphoma with a growth program and an accelerated path to approval. 5458, our BCMAxCD3 bispecific, continues to show responses in patients with earlier pretreated multi myeloma, now in a potentially pivotal Phase II expansion. And I would like to turn this now over to George. Thank you.

Thank you, Andres. Thank Izzy and David as well. Well, as you see on the slide, there's a lot of upcoming milestones. This is just some of them on the slide, the key ones. And I guess with that, we'll turn it back over to Justin and open it up for questions.

Thank you, Carmen. We may now queue the audience for questions. We do have several callers in the queue, so please limit your question to one.

[Operator Instructions] Our first question is from Evan Seigerman with Credit Suisse.

Really, congrats on the data at the meeting and this nice overview of kind of what's to come. So one on 1979. So we saw several updates across the spectrum of CD20xCD3 bispecifics. And while you guys really encouraged with the data we saw in follicular lymphoma, I think the Genmab asset might have had a higher ORR and DLBCL. So my question for you is, how do I think about how this competitive landscape in CD20xCD3 bispecifics evolves in DLBCL and kind of other non-Hodgkin's lymphoma?

Well, I think the way to look at all of these is that our goal, and I think what the data is suggesting, with small numbers, from recent presentations, things will bounce around. But I think in the totality of the data, we're pretty confident that we're creating very competitive with competitive best-in-class type of data for each one of our reagents individually, whether it's our PD-1, or whether it's our CD20xCD3, or whether it's our BCMAxCD3, but the real differentiator here is this incredible mix and match portfolio that we've outlined for you. That we're not stopping with, for example, 1979 and a CD20xCD3, we are immediately initiating combination studies with that, not only with our PD-1, but also with a CD28 co-stim. Not to mention, we also have additional CD3 bispecifics coming down the pipe for that class of cancer as well. So it's really the ability to keep moving, pushing the edge, moving the standard forward by mixing and matching the right collection of reagents and agents together to achieve the best results for the patients in terms of increasing the number of people who respond, the depth and duration of their response and so forth. So I think that that's the way to look at it. I think the way the patients are going to win is if we don't look and we don't settle with any 1 particular agent here, it's -- the power and the potential of mixing and matching the right combinations to achieve the greatest potential benefit to the patient, and that's when the patient will win.

Our next question is from Yaron Werber with Cowen.

Great. Maybe, George, for you. I mean we're beginning to see new targets in myeloma, right? We're seeing both targets from Roche, targets from J&J. What was your impression on the data? Is that something that -- those targets, are they relevant to you as well? And then secondly, on the BCMAxCD3, are you thinking about autoimmunity? Is that sort of -- can you dose this chronically at the right dose to get sort of anti-immunity, autoimmunity activity?

Yes, I think those are great questions. Yes. And, like, exactly, as I summarized for the CD20xCD3, we're exactly in the same position with BCMA. Andres already told you that we are going to be pairing it with a CD28 co-stim, a different mechanism of action, where we saw greater -- at least in preclinical models, greater opportunity for added benefit by mixing a CD3 with a CD28 bispecific. That said, as you might imagine, we have also been working on additional CD3 bispecifics for plasma cell abnormalities like we're doing for the CD20s as well. So there will also be an unfolding of a continued pipeline there where we're going to continue to mix and match the best potential agents all together to achieve the maximum benefit of the patients. And that includes not only for patients with these advanced plasma cell cancers. But also, as you indicated, for pre malignancies or even non-malignancies, situations of autoimmunity. So we have Andres and the team have a whole plan for that, which we don't have time to get into today.

Our next question is from Cory Kasimov with JPMorgan.

Curious about the development pathway for your subcu formulation entering the clinic in the first half of '21. I mean you have it for both programs, but most focused on 1979. How fast can you go with this? And will you start the 1979 confirmatory program with the IV or wait for a subcu?

Well, I think we're not going to be waiting in terms of the pivotal program, but to give you some more insights into the subcu plan without too many details, I'll turn it over to Andres.

Yes. Thank you, George. I would want to point out that we will be advancing this very rapidly, entering the clinic early in 2021. In terms of how we are going to bridge or incorporate the subcu into our development plan, we have not yet disclosed externally how we will go about it. I think we have a very robust plan and a clear path in our minds on how we're going to take this forward.

Our next question is from Geoffrey Porges with SVB Leerink.

You touched on the CD28 co-stim portfolio. And I think you've highlighted MUC16, PSMA and eGFR, all in combination with Libtayo. My question is when might we see the first data from any of the CD28 combination? And George, will you be started comparing the combination with Libtayo alone so we can immediately make some inferences about the incremental contribution of the bispecific?

I'll turn it over to Izzy for that.

So thank you. The -- all 3 are just beginning. And the PSMAxCD28 has dosed a few cohorts, the others are literally just starting. So I think it's going to take a little time for us to understand the activity and really be in a position to present data. So it's unlikely that it would be this coming year. But who knows. If we see some great data, we'll certainly let you know. The idea behind combining this with Libtayo is that the -- in general, what we found is that the co-stim bispecifics since they engage signal tube on T cells to sort of press on the accelerator, without the ignition turned on, you're not going to get much going. So you need -- or without releasing the emergency break, you're not going to get much going. So we believe that these are quintessential combination agents. They have -- they rather, we believe they will have little activity on their own, but they will unleash the full power of some of these other agents. So they're all being tested from the beginning in combination with Libtayo.

Izzy, I understand, but could you just tell us whether you're going to have any Libtayo monotherapy patients being enrolled in parallel so we can see the incremental activity of the co-stim?

In our initial studies, we first -- we are going to go into indications where Libtayo monotherapy is known to not be that active. So we will be looking for strong signals in settings where we will clearly know from the outset that there is a synergistic improvement in efficacy. And of course, down the road, if you have to do some kind of pivotal study, you'll need to fully demonstrate contribution of components. But right now, we're pretty confident we're looking in the right tumors where if we see a signal, it's due to the combination.

So obviously, in prostate cancer, the PD-1s do not have that much activity. And what we're hoping to see is a profound combination activity here, which would clearly distinguish from any potential monotherapy actions.

Next question is from Terence Flynn with Goldman Sachs.

Congrats on the progress. I was just wondering if you can share any more details on the design of the 1979 Phase III program? I'm assuming the first line trial would include head-to-head comparison versus rituxan. Maybe what endpoint or endpoints are you evaluating? And any details on powering?

Thanks for your question. We -- as you highlighted, we do plan to explore and we'll be initiating pivotal studies in early lines of therapy in combination with chemotherapy. We have not disclosed nor discussed yet externally what's our comparators, endpoints and so forth will be. Of course, as you know, will be very different. But what we will be looking for in patients with follicular lymphoma, vis-a-vis patients with diffuse large B-cell lymphoma, what the endpoints might be. But we have not yet fully disclosed those studies and the plan.

Our next question is from Carter Gould with Barclays.

I wanted to come back to sort of tease us in the slides around resuscitating the combination of your CD20 with Libtayo. Just your level of confidence that you'll be able to navigate the FDA on that front? And would that be a potentially -- I mean are you thinking about that potentially being a pivotal study out of the gates? Or would there have to be sort of substantial I guess Phase II dosing and scheduling work to be done?

Andres?

Yes. Thank you. So in terms of your question about how we are going to move this forward, we are confident that we will be able to based on what we have learned from our early experience. So we think that we have a good path forward on how to dose and how to sequence the treatment. So saying that, I think that at the moment, we'll be focusing not on initial pivotal study but confirm the safety schedule and dose of the combination. Once we have that, we'll move forward very rapidly.

Our next question is from Kennen MacKay with RBC Capital Markets.

Congrats on the conference and progress. I was just hoping you could shed a little bit more light and color around the 5 treatment emerging death that occurred with odronextamab in the presentation. Obviously, not CRS, some were TLS, but we just want to understand that a little bit more?

Andres?

So in terms of the 5 treatment death that the -- treatment-related that you discussed. I will say that, 1 -- I can go on each of the patients, but we have those events occurring early in terms of the dose escalation. 4 out of the 5 events occur in the early cohorts, 1 event occur in the later cohorts. However, the patient never received the full dose. And in terms of what led to this patient's death, we have 1 patient with a gastric perforation on a gastric tumor that perforated, a known risk when you have a lymphoma involving the stomach. The other events that occur was 1 patient with tumor lysis syndrome in a patient with multi-cell lymphoma. Again, a disease where these patients have higher tumor burden and a more accelerated and rapidly dividing cells. So it is not unusual to see the potential for TLS in these patients, and speaks to the efficacy of the drug, actually, in this patient population. We have 1 patient with a cardiac arrest, which although was considered related, it's very difficult to confirm and that, of course, makes sense that it's an unrelated event. And then we have 2 patients with infection in heavily pretreated patients. So 1 was a pneumonia and the other 1 was a PCP pneumonia, a Pneumocystis; carinii pneumonia. So all in all, when you look at those deaths, they are not unusual in the patient population that we are treating and include in our study.

To summarize, I think the important thing is only 1 of the 5 occurred at the target doses that we're dosing patients now. And that was the only 1 in which there was a direct probably relationship. The patient did indeed die from tumor lysis syndrome, and that was indeed probably related to the drug that was given. But the other deaths occurred not at the target doses that we're moving forward.

Our next question comes from Robyn Karnauskas with Truist.

So it strikes me -- if it's okay, I'll ask a big picture question. It strikes me that your program has the most shots on goal as far as breadth of different types of molecules as well as different affinities and different drugs. But I'm just -- we're all trying to compare which drug is going to win out or which one's going to be out, or which one's going take more share? Can you talk a little bit about how you're thinking about which drugs to move forward to find that 1 treatment for patients? And if someone else you see has a better drug than you, how quickly could you get a similar drug or similar profile developed with similar affinity into the clinic to be competitive with that program?

Well, Robyn, as you said, I mean we're all about and we've historically been about these shots on goal and about, in almost every case, trying to create a competitive best-in-class reagent in this field. And I think as we all know, it's really going to be this ability to mix and match that's going to win at. So right now, I think, and it's probably going to be true going forward that the leading agents in each individual class are probably going to be performing quite similar. There's probably not going to be a clear winner in each class. But when the patient wins is when the efforts appropriately combine the right classes of agents to maximize the benefit for patients. And as you said, that is what we think is our big picture competitive advantage. I mean we have the ability to create the widest, and I think we are delivering to the clinic the widest and most comprehensive portfolio of mix and match reagents, each 1 likely on their own to be near, if not best-in-class in activity. And as you said, because of our technologies, if for some reason, it can always happen, in 1 particular class for 1 particular setting, maybe our first reagent might have some sort of limitation, we have backups upon backups, like you just heard. Andres, not for -- more so for the non-oncological indications of the BCMA class such as we've touched upon about, for example, in autoimmunity and so forth where we might want to decrease side effects where we think efficacy is not going to be the issue, we have the ability to even be comparing like we're doing different reagents of the same class. In that case, we're going to be maybe decreasing the affinity, as you heard, to decrease the chance for side effects, where we think getting the maximum efficacy like you might need in cancer might not be as important for some of these autoimmune indications. So we're doing exactly what you're saying is what we're doing, is we have the ability and flexibility. We have backups upon backups for any individual agent in any class, but we also have the ability to mix and match as might make sense to maximize the benefit for the patients. And that's what we think it's going to take to really, really make differences for patients here, to mix and match intelligently the right sets of agents from different classes, and that's what we've been building towards doing now for the better part of the decade.

Our next question is from Mohit Bansal with Citi Group.

Congrats on all the progress. Staying on the combination approach with the bispecifics, especially in follicular lymphoma as well as multiple myeloma, so these drugs appear really potent. And if you consider the safety issues, they are manageable but not trivial considering the elderly patient population you are going after. So keeping that in mind, do you really need a combo strategy, especially in earlier lines of patients where T cells could be healthy and these cells could be even more potent there?

Yes. Well, we agree with your last point, for sure, that the activities are likely to increase as one goes back to earlier lines of therapy. And it may be quite possible that in some of these earlier lines of therapy, combinations, for example, with toxic chemotherapies may not be required so that these agents may have very competitive abilities without chemotherapy to have monotherapy activity in that -- in these dose setting. But we also know, of course, that cancer is cancer. And that we will invariably, in different settings, need combinations. The dream and the beauty behind our combination approaches is that they're intending to maximize efficacy without exacerbating potential toxicity. And you'll see as our programs unfold. Once we think we have maybe dealt with tumor load, which, as you've already seen, I think we were sort of leaders in doing these divided dosing approaches and so forth that are minimizing toxicity. Once we deal with that, we think that the addition of combinations to increase efficacy, because they're also targeted, can do so without any increase or with very little danger or toxicity increases. So that's why we're very excited about doing it. Once we have, for example, 1 agent on board and we've dealt with the bulk of the tumor, we may be able to add our combinations and hopefully, completely oblate or obliterate the ability of the tumors to regrow. So we think, as you said, monotherapy here with these agents has prompts. But there will always be the need for the right combinations and the right setting to completely ablate the chances of the tumors coming back or to extend activity or deepen responses in the patients who we already know in these late-stage settings won't be doing well enough on monotherapy on their own. And we think that it's a very exciting position to be in, where we have these opportunities, not only to be moving forward with these agents as monotherapies, but in these very precisely targeted combinations for the right settings. Andres wants to add a point here.

Just very briefly to the topic of toxicities and tolerability. I want to remind everybody, without minimizing what this is for the patient, that most of the adverse events, particularly CRS, occur in the first 1 to 2 weeks of therapy. We have patients ongoing for 3.5 years tolerating the drugs well. So if the rates of CRS that we are observing are manageable, they're mostly Grade 1 and 2. And this is consistent across the class when you look at CD3 engagers bispecifics within our portfolio. And what we are learning is that it is manageable, reversible -- readily reversible, mostly Grade 1, 2 and in the first 2 weeks, if not, 3 weeks of treatment and once that the patients reach the dose, the target dose for the most part, the adverse events that are accumulated are mostly related to their disease and the usual course of treatment.

And these points are really important because it's not as if we're necessarily going to immediately deluge the patients with both targeted treatment simultaneously and increase the short-term risk. One would, for example, deal with the short-term risk with one of the single agents and then layer on the enhancing agent after that. So we're hoping -- we're hoping that we can, in that way, get greatly enhanced activity without causing any more danger for the patient.

Our next question is from Ronny Gal with Bernstein.

So just a quick clarification. You kind of mentioned the CD3, CD20 safety profile. And I was kind of wondering, as you go to the pivotal program, what is, like, the required hospital stay that you're targeting? Is it like 1 night for the first dose, so 1 night for day 1 and 8? Or do you think you'll need more of a hospital stay than that to stay on the safe side? And then the question I have for you, George, is a bit broader. And it is about the profile of BCMA CAR-T versus bispecific. We are seeing really good results on the CAR-Ts. And as we can kind of see the bispecific going up to a similar level of ORR, it seems that the CRS and NTs are coming up to meet the same kind of bar. In your mind, what will allow the bispecifics to take over that market from the CAR-Ts?

Why don't we have Andres answer the first part of the question?

Yes. In terms of your question on hospitalization, I want to highlight that we are in the -- for at least in the data that we presented is on the Phase I study. But I want to mention that the hospitalization, we're talking about 1 night on weeks 1, week 2, and eventually on week 3 and beyond, potentially, not having a hospitalization at all. So -- and that's one of the points. And one of the, I would say, objectives that we have by introducing subcutaneous formulation, we hope that we can further minimize the need for hospitalization. Nonetheless, I think that in the initial first dose, probably the most prudent approach is observation.

And in terms of the second part of your question, we don't really see this as a competitive scenario with the CAR-Ts. And I think that what we all envision here is that assuming that the profile of these bispecific continues to evolve and build on what these initial profiles are saying, you would imagine, though, right now, they have activity after CAR-T, that eventually, these would be placed before CAR-T in the treatment paradigm because of the off-the-shelf nature of these things, the ease with which they would be used, the length of time that's required, you don't have to do the conditioning and so forth and subject the patients to this toxic chemotherapy to condition them and so forth. So if these bispecifics continue to evolve as they look like, I think that most people would imagine that these would move up in the treatment paradigm. And CAR-Ts would be more of for the patients who are not going to be responding well to these. And then I think eventually, if there still remains any sort of activity gap once we take these to and really explore them, that the additional co-therapies that we'll be adding, such as a co-stim or other combinations, will then now increase the activity and so forth and maybe make that not of an issue as well. But if they do have somewhat less activity than a CAR-T, I think all the other advantages for most patients would probably bring them up in the treatment paradigm. David, did you want to add anything?

No.

And our last question is from Yatin Suneja with Guggenheim Partners.

With regard to the 2 BCMAxCD3 bispecific, what type of profile differentiation do you expect in terms of both activity and sort of tolerability profile? And then how are you thinking about the subcu for the BCMA, given that some of the competing products are subcu?

Well, as you heard from Andres, we will be aggressively exploring subcu formulations. And as I alluded to before, I think that we're imagining that in certain non-oncologic indications, there might be advantages to something that might be, indeed, that are tolerated. And that's why we're exploring the second BCMA at this point in those settings. And so -- and we have a variety of other bispecifics there that we can be exploring as well. But that is the major goal as I was getting at before.

And I would like to turn the call back to Justin for his final remarks.

Thank you, Carmen, and thank you for everybody for dialing in today. We know it's a busy time of year with the ASH conference, and we know that you have many competing priorities. So we appreciate your attention and your interest in Regeneron. As always, the Investor Relations team is available to answer any further questions. Thank you, and good night.

Ladies and gentlemen, thank you for your participation in today's conference. You may now disconnect. Good day.