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

Welcome to the Regeneron Pharmaceuticals ASH 2022 Investor Conference Call. My name is Catherine, and I will be your operator for today's call. [Operator Instructions] Please note that this conference is being recorded. I will now turn the call over to Ryan Crowe, Vice President of Investor Relations. You may begin.

Thank you, Catherine. Good morning, good afternoon and good evening to everyone listening around the globe. Welcome to our ASH 2022 Investor Call. Slides for our presentation have been posted to the Investors section of the regeneron.com website. I would like to remind you that today's remarks include forward-looking statements about 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 the 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 on Regeneron's SEC filings. Regeneron does not undertake any obligation to update publicly any forward-looking statements, whether as a result of new information, future events or otherwise. Joining me today are Dr. David Weinreich, Executive Vice President, Global Clinical Development; and Dr. Andres Sirulnik, Senior Vice President, Hematology Clinical Development. After our prepared remarks, we'll open the call for Q&A. With that, I'll turn the call over to David.

Thank you, Ryan, and thanks to everyone joining today's call. Before we focus specifically on the updates from ASH, I would like to first discuss Regeneron's progress towards becoming a global oncology leader over time. We're applying more than 3 decades of scientific innovation to develop therapies that have the potential to advance the standard of care for patients with cancer. Our oncology portfolio is built around 2 foundational approaches: our approved PD-1 inhibitor, Libtayo; and our investigational bispecific antibodies, many of which are being evaluated both as monotherapies and in combination with emerging therapeutic modalities. Together, they provide us with unique combinatorial flexibility to develop potentially synergistic treatments for a wide range of solid organ and blood cancers. With our acquisition of full global rights to Libtayo earlier this year, we are well positioned to continue advancing our oncology pipeline with Libtayo as the foundation. Over the past several years, we have established Libtayo monotherapy as the standard of care in certain skin cancers. Libtayo was also approved in first-line advanced non-small cell lung cancer, both as monotherapy in high PD-L1 expressors and more recently, in combination with chemotherapy, irrespective of PD-L1 expression or histology, a high bar achieved by only one other anti-PD-1 targeting agent. We are excited to continue building our presence in dermato-oncology and lung cancer while advancing other investigational agents and combinations, highlighted by the recent data presented for fianlimab, our LAG3 antibody, in combination with Libtayo in both metastatic melanoma at ESMO and advanced non-small cell lung cancer at ESMO IO. 2022 was a pivotal year for Regeneron's oncology development efforts as we advanced our broad pipeline in diverse indications and settings. Earlier this year, we shared early but encouraging top line data for our PSMAxCD28 costimulatory bispecific in combination with Libtayo for advanced prostate cancer, providing the first evidence for this innovative combination approach. We also presented important data at ESMO, including updated and expanded data for fianlimab plus Libtayo in anti-PD-1 naive metastatic melanoma; first clinical data for Ubamatamab, our MUC16xCD3 bispecific in recurrent ovarian cancer, representing our first CD3 bispecific in a solid tumor; as well as initial clinical data for our novel biparatopic METxMET bispecific in MET-altered lung cancer. We are excited to round out 2022 with data from the potentially pivotal studies of odronextamab and linvoseltamab, which Andres will discuss shortly. The continued advancement of these efforts in oncology is a key focus of Regeneron, and we are well positioned to advance the pipeline in 2023 with additional data readouts and potential regulatory filings. Anti-PD-1 therapy has become a standard of care across multiple tumor types and settings. Despite this progress, there are many cancer patients whose tumors do not respond to PD-1 blockade and many other tumor types that have not responded to anti-PD-1 therapy in clinical trials such as prostate cancer, most breast cancers and ovarian cancer. Our broad oncology toolkit gives us a unique opportunity to mix and match approaches with the goal of broadening and deepening antitumor activity. On this slide, you can see our different categories of investigational medicines in our oncology pipeline today, all of which centers upon Libtayo, including our CD3 bispecifics, our CD28 or costim bispecifics, our tumor-target biparatopic bispecific antibodies and other immune modulating agents. Today, Andres will discuss data presented at ASH for both odronextamab in follicular lymphoma and diffuse large B-cell lymphoma as well as linvoseltamab in multiple myeloma. He will also discuss our first CD28 costimulatory bispecific in hematology, CD22xCD28, in combination with odronextamab in non-Hodgkin's lymphoma, for which initial preclinical data was presented at SITC last month. With that, I will turn the call over to Andres.

Thank you, David, and thank you to everyone joining the call today. Regeneron had a large presence at ASH with over 15 accepted abstracts as we increased our footprint in hematology and hem-onc. My presentation today will focus on data from 2 oral presentations of Phase II data for odronextamab in follicular lymphoma and diffuse large B-cell lymphoma and Phase II data for linvoseltamab in multiple myeloma. I will begin with odronextamab, where we present the data from our Phase II ELM-2 study in FL and DLBCL. Odronextamab is an off-the-shelf CD20xCD3 bispecific effective in patients with both indolent and aggressive lymphomas. We have previously shared data from our Phase I study in FL and DLBCL, which showed encouraging efficacy and a manageable safety profile. This year at ASH, we provided the first interim data from the Phase II ELM-2 study, which were presented in 2 oral presentations. With over 550 patients dosed in the program today, we are preparing to initiate our OLYMPIA Phase III program in early 2023 and plan to submit BLA in both indications in the second half of next year. As I mentioned, we previously shared data from ELM-1. That study is ongoing, and protocols have been updated to include subcutaneous administration arms. Today, we will primarily focus on data from ELM-2 study, specifically in DLBCL and FL. The primary endpoint of the ELM-2 study is overall response as measured by an independent central review. Secondary endpoints include complete response, progression-free survival and safety. In 2021, we revised the step-up dosing regimen for the program, lowering the initial dose to 0.7 milligrams from 1 milligram and adding a 4-milligram dose before moving to the 20-milligram dose and ultimately the final dose for each indication. With a modified regimen, patients are administered the full therapeutic dose on day 21, which is 7 days later than the prior regimen. Over the next few slides, the data will demonstrate that the new regimen had consistent efficacy with the prior regimen have resulted in an improvement in the safety profile for the oral drug, resulting in lower rates of treatment discontinuations, interruptions, dose reductions and dose delays. And this was consistent in both FL and DLBCL arms. Approximately half of the patients in the program are on each regimen across both indications. We also made other protocol changes to help better manage CRS in the step-up dosing cycles. Moving to the data presented at ASH and starting with FL. As of this data cut, 121 patients were available for efficacy. Overall response in these heavily pretreated, highly refractory patients was 82%, with 92% of the responders having a complete response, the highest complete response rate seen in this patient population to date. Based on an assessment at week 12, we observe efficacy with similar for patients regardless of step-up regimen. Here, we see the percentage change in tumor size for each patient. The majority of patients have substantial tumor shrinkage, highlighting the ability of odronextamab to provide significant benefit to these late-line patients. These deep responses also show encouraging durability. Median duration of response was 20.5 months, and complete responses also had a median duration of 20.5 months. The probability of maintaining the response for 18 months was 55%. Median PFS was also at 20.2 months, and the probability of remaining progression-free at 18 months was also 55%. Overall, survival data continues to mature with a median not yet reached. Overall, odronextamab has a manageable safety profile in FL. All patients experienced at least one adverse event, and grade 3 or higher adverse events were reported in 78% of the patients. The majority of adverse events were grade 1 or 2, and the most common adverse events were CRS in 57% of the patients, neutropenia in 40% and pyrexia in 31% of the patients. Treatment discontinuations due to adverse events that were considered related to odro occur infrequently in 7.6% of the patients. Three grade 5 adverse events were considered by the treating physician to be treatment related. All were infections, including one case of pneumonia, one case of PML and one of a systemic mycoses. The changes made to the step-up dosing regimen for odro have led to improvements in the safety profile. As can be seen from the table, the optimized step-up regimen decreased the incidence of grade 2 and grade 3 CRS events. There were no grade 4 or 5 events. CRS was mostly grade 1 and generally occurred during cycle 1 step-up dosing. All CRS results, median time to resolution was 2 days. With a revised regimen, there were no cases of ICANS or tumor lysis syndrome. Overall, in follicular lymphoma, odronextamab show encouraging and durable efficacy with a manageable safety profile that improved with a modified step-up dose regimen. Moving now to DLBCL. As of this data cut, 130 patients were evaluable for efficacy. Overall response in this heavily pretreated, highly refractory patients was 49%, with 63% of responders having a complete response. Based on an assessment at week 12, observed efficacy was consistent for patients regardless of the step-up dose regimen. As a supporting analysis, we evaluated interim efficacy in the Phase I post-CAR-T expansion cohort of the ELM-1 study. Based on the analysis, observed overall response rate was similar for patients regardless of CAR-T experience. Responses were durable, another immediate duration of response nor duration of complete response were reached in the post CAR-T Phase I dose expansion cohort. The deep responses seen in DLBCL patients also show encouraging durability. Duration of response was 10.2 months, and complete responses were particularly durable with a median duration of 17.9 months. The probability of maintaining a response for 18 months was 39%, and the probability of maintaining CR for 18 months was 48%. PFS was also durable with a median duration of 4.4 months. The probability of remaining progression-free at 18 months was 26%. Durability data for responses continues to mature. Odronextamab has a manageable safety profile in DLBCL. 99% of the patients experienced at least 1 adverse event, and grade 3 or higher adverse events were reported in 79% of the patients. The majority of adverse events were of low grade, and the most common events were CRS in 55% of the patients, anemia in 42% and pyrexia in 39% of the patients. Treatment discontinuations due to adverse events that were considered related to odro occur in 7.9% of the patients. There were 5 grade 5 adverse events considered by the treating physician to be related to odronextamab. And again, all were infections and include 3 cases of pneumonia, 1 case of COVID-19 and 1 case of Pseudomonas sepsis. Similar to what was demonstrated in FL, the changes made to the step-up dosing regimen for odro have led to improvements in the safety profile in DLBCL. The majority of CRS events were grade 1 and generally occur during cycle 1 step-up dosing, and all CRS events were solved within a median of 2 days. As can be seen from the table, the optimized step-up regimen decreased the incidence of grade 2 and grade 3 CRS events, and there were no grade 4 or 5 events observed with either regimen. CRS was mostly grade 1 and generally occur with a cycle 1 step-up doses. There was only 1 incidence of ICANS with the optimized step-up regimen and no grade 3 plus ICANS. Beyond the data presented at ASH for odro, we recently shared initial preclinical data at SITC for our first hem-onc costim CD22 by CD28 in combination with odro in DLBCL. In preclinical studies and shown on the right, this molecule showed limited activity, limited T cell activation and nontoxicity as a single agent, but augment T cell activation when combined with odro, similar to what we have seen and demonstrated with other costimulatory antibodies like PSMAxCD28 and EGFRxCD28 in solid tumors. Our first-in-human Phase I combination study will initiate in early 2023. We are rapidly advancing a broad development plan for the odro in lymphoma. With the initiation of our Phase III Olympia program early next year, we will begin testing odro in early lines of therapy for DLBCL and FL, both as monotherapy and in various combinations. We expect the confirmatory Phase III studies to support our planned BLA filing in the second half of 2023. We will also be initiating studies in combination with our CD22xCD28 costim bispecific, as mentioned earlier, and continue to advance studies combining odro with our PD-1 Libtayo. In summary, this initial Phase II data for odronextamab show encouraging and durable efficacy observed in heavily pretreated patients in both FL and DLBCL, including in FL, the highest complete response rate observed in these late-stage patients to date. The safety profile of odronextamab appears manageable, and improved safety was seen with revised step-up dosing, including reduced instances of grade 2 and grade 3 CRS. We are excited about the prospects of odronextamab in these indications and plan to file a BLA in both indications in the second half of 2023, with confirmatory Phase III studies expected to initiate in early 2023. Now moving to linvoseltamab, our BCMAxCD3 antibody in relapsed refractory multiple myeloma. Last year, we presented updated Phase I dose escalation data at ASH, which show that linvoseltamab induced early, deep and durable responses with a manageable safety profile in patients with relapsed/refractory multiple myeloma. This year, we presented updated Phase I/II safety and efficacy data from the dose escalation and dose expansion portion of the study. The Phase II dose escalation part of the study is fully enrolled and pending FDA discussions we intend to file in 2023. Our Phase I/II study began with dose escalation, with doses ranging from 3 milligrams to 800 milligrams. The dose expansion portion is evaluating doses of 50 milligrams and 200 milligrams. Our recommended Phase II dose is 200 milligrams. To date, we have treated over 100 patients in each of the 50-milligram and the 200-milligram expansion cohorts. Importantly, in the 200-milligram arm of the study, patients with a VGPR or better by week 24 can move to dosing every 4 weeks instead of every 2 weeks, offering additional dosing convenience for those patients that typically responds. The primary endpoint of this study is overall response; and secondary endpoints include duration of response, PFS and safety. Early deep and durable responses were observed with linvoseltamab in heavily pretreated relapsed/refractory myeloma patients. These results are in a difficult-to-treat patient population, including 84% for the patients in penta-exposed, 37% with bone marrow plasmacytosis greater than or equal to 50% and in median soluble BCMA of 0.43 milligrams per liter. The latter 2 are representative of high tumor burden. Responses were seen across all those levels with a trend toward higher responses at higher doses. At a recommended dose of 200 milligrams, the ORR was 64% in this heavily pre-treated and highly refractory patients. Over 2/3 of the patients who responded achieved a VGPR or better. Importantly, we have seen a trend for responses to deepen over time. As such, we have expected numbers of patients achieving VGPR or better to increase with further follow-up. Among patients with a CR or a strict CR and available MRD data, 47% of Phase I patients were MRD-negative at 10 to the minus 5 and 60% of Phase II patients were MRD-negative at 10 to the minus 5. Consistent responses were seen in high-risk sub groups, including a similar ORR observed in patients with bone marrow plasmacytosis greater than or equal to 50%, which generally indicates a higher disease burden. Notably, some competitor trials have fewer patients with bone marrow plasmacytosis greater than or equal to 50% and a lower median level of soluble BCMA compared to patients in our trial. Linvoseltamab has demonstrated meaningful response rates in the severe advanced patient population that is associated with poor outcomes and is seen in the area of high unmet medical need. Observed responses in patients occur early deepen with time and have shown promising durability. Median time to response was less than a month for both the 50-milligram and the 200-milligram cohort. And the probability of maintaining a response at 6 months was 85% and 79%, respectively. As of this data cut, the longest responses were over 28 months and ongoing. As we continue to [indiscernible], we hope to continue to see responses deepen over time as has been our experience throughout the study. Importantly, for the protocol amendment, 8 patients who did not respond at the 50-milligram dose were escalated to 200 milligrams. Of these 8 patients, 6 responded to treatment at higher doses, including 4 with the VGPR. Data from these cohorts were not presented at ASH, but will be shared at a later date. Our data suggests a manageable safety profile for linvoseltamab, majority of patients did not develop CRS, with CRS reported in only 44% of patients and importantly, only 37% at a 200-milligram dose. In the 200-milligram cohort, over 2/3 of the CRA cases were grade 1 with just 1 transient grade 3 CRS. Most CRS occurred during step-up dosing with onset on the day of dosing and resolution within 1 day. No correlation between CRS and the full dose was observed. There were 14 grade 5 AEs, none were considered treatment related for the treating physicians. We are rapidly advancing our clinical development program with linvoseltamab. In the first half of 2023, we plan to initiate a confirmatory Phase III study in the first half of 2023 to support this filing, evaluating linvo monotherapy against standard-of-care regimen against LOPD. And we continue to enroll our Phase I umbrella study evaluating linvo in combination with various standard-of-care regimens. Our Phase II study is fully enrolled, and we expect data from this study from the basis of a 2023 BLA submission. We also expect to initiate a study of linvo in combination with a CD28 costimulatory bispecific in late lines of therapy. Altogether, we are rapidly initiating confirmatory studies and advancing studies into early lines of therapy. In summary, linvoseltamab demonstrated compelling Phase II efficacy and manageable safety profile in heavily pretreated multiple myeloma patients. Responses were early, deep and durable with an ORR of 64% at a recommended 200-milligram dose. 60% of Phase II patients with CR or [ strict ] CR were MRD negative at 10 to the minus 5. 6 of 8 patients who dose escalated from 50-milligram to 200-milligram responded to treatment, including 4 VGPR, safety was manageable with only 44% of the patients developing CRS and only 37% in the 200-milligram cohort. Most CRS were grade 1, occurring during dosing step-up and resolved within 1 day. The Phase II study is fully enrolled, and we expect to file for approval in the second half of 2023. And our robust clinical development program is advancing rapidly with a confirmatory Phase III study and starting combination with the costim bispecific, both expected to initiate in the first half of 2023. I'd like to conclude by briefly highlighting our growing hematology pipeline. We have a robust and advancing pipeline across various blood disorders and hematology -- sorry, in hematologic malignancies and benign hematology, including Phase III studies for our C5 antibody in combination with siRNA in PNH and myasthenia gravis. A Phase II data for this combination in PNH was presented at ASH. We are harnessing the power of our technology, along with collaborators to develop potential treatments using antibodies, gene editing and gene knockout technology. An investigational RNA approach is focusing on treating abnormal proteins or blocking disease-causing cellular signaling. We are excited to continue advancing these programs and expand Regeneron's presence in hematology. With that, I will pass it back to David. David?

Thank you, Andres. We are excited about the continuing -- continued positive data for odronextamab and linvoseltamab and the competitive safety and efficacy profile highlighted today. Looking ahead, we expect a continued flow of important data across our immuno-oncology programs, with several proof-of-concept data readouts expected in 2023, including our METxMET ADC antibody, our EGFRxCD28 costim bispecific and data from several MUC16 combinations in ovarian cancer. In conclusion, we are pleased with the progress for odronextamab and linvoseltamab and the encouraging data presented at ASH this year. We are rapidly advancing robust Phase III programs to the clinic to support 2023 filings for odronextamab in follicular lymphoma and diffuse large B-cell lymphoma and linvoseltamab in multiple myeloma. We plan to initiate studies next year, combining both bispecifics with CD28 co-stimulatory bispecifics, applying our differentiated CD28 approach for the first time in hem-onc. And we continue to advance our diversified hematology pipeline, applying our differentiated capabilities to address rare blood cancers. With that, I'll turn the call back to Ryan.

Thank you, David and Andres. We will now open the call for Q&A, where David and Andres can address your questions. [Operator Instructions] And please keep the scope of your question within today's subject matter. Catherine, please go ahead and read the instructions for calling for questions.

[Operator Instructions] Our first question comes from Matthew Harrison with Morgan Stanley.

This is Maxwell Skor on for Matthew Harrison. Yes. Just briefly, can you comment on the competitive profile of your BCMA approach compared to others? And potentially any feedback you've received from the FDA prior to filing in the second half of next year?

Yes. Thank you for your question. We think that we have a very competitive profile in terms of both the safety and the efficacy that is emerging from our study. First, I want to focus on safety. The rates of CRS that we have observed to date with our dose moving forward remains very competitive. As I mentioned to you the selected dose or RP2D to move forward, we have observed a 37% overall of CRS, 2/3 of those being grade 1. And we believe that this is favorable. We also think that linvo has the least amount of hospitalizations recorded based on our current schedule. The efficacy that is emerging, I think, is first -- well, these responses, as I mentioned to you, is early days. We expect the rest of these responses to deepen over time. So we are waiting. But we think that first very competitively vis-a-vis other assets in the same class.

Our next question comes from Chris Schott with JPMorgan.

On your CD22 CD28, how are you thinking about potential toxicity we need to watch as we move, I guess, this platform into hematology? And I guess, how does the early success you've seen with PSMA kind of increase or change your confidence, I guess, in applying CD28 to liquid tumor?

David?

Sure. So thank you for the question. I'll take them in reverse order. The fact that we are now seeing activity of the xCD28 costims from our PSMA experience, I think, validates our approach that this particular costim target is a good one. We can also steal some information from that other trial that the safety during the lead-in period, this is before we add cemiplimab to the patients, looks incredibly clean. The toxicity that we previously reported out was after you introduced the combination. So while we don't know what's going to happen in a hematologic malignancy when we add a CD28, there are reasons to believe that the combination should be well tolerated. And traditionally in immuno-oncology, getting things to work in the solid organ malignancies is a lot harder than working in the hematological ones. So if I happen to be a betting man, I would suggest the likelihood that this is going to work on the basis of all of the preclinical data that we've generated to bring this asset forward, we're quite hopeful.

Our next question comes from Evan Seigerman with BMO.

Congrats on the progress. So I'd love for you to just talk about how you envision both odronextamab and linvoseltamab fitting in a rapidly evolving hem-onc landscape. We saw a lot of bispecific CAR-T data at ASH. I'd love for your perspective there. And then would you consider a subcu formulation for linvoseltamab?

Yes. Yes. So in terms of the -- I'll start with the subcu formulation for both odro and linvoseltamab. We are in -- well, for odro, I can tell you that we have already initiated the -- and as I mentioned during the presentation, the ongoing study is ongoing and exploring subcu formulation. We are initiating at the beginning of next year a subcu formulation study with linvoseltamab. So we will be exploring that as well. Now in terms -- you asked as well on the landscape. It is very competitive. We agree. However, we think that -- I'll start with odronextamab. In follicular lymphoma, we believe that we have set a new benchmark in terms of the level of efficacy that has emerged from our study. Just to remind you, we are observing an overall response rate in follicular lymphoma of 82% with a CR rate of 75%. That's 92% of the patients achieved a complete response when you look at dose responses. And this is, what we think, outstanding and setting a new benchmark for this class. So we think, yes, we are very competitive there. But overall, we see just looking at the field. We look at odronextamab and linvoseltamab as foundational for our -- for Regeneron. As we mentioned, for both compounds, we will be moving forward with combinations with our costimulatory molecules. In the same way, the Libtayo is foundational in our solid tumors. And we think that we have a great opportunity for Regeneron there to differentiate and bring to patients a potential for a chemo-free regimens in the future.

Our next question comes from Tyler Van Buren with Cowen.

For linvoseltamab, you talked about hoping to see responses deepen over time, and the median follow-up of the 200 mg dose is quite short, I believe, at around 3 months. So can you elaborate more on the potential for responses to deepen over time based upon what you saw in the earlier phases of the program? Or in other words, what percent of patients convert from a PR to a CR at later scan intervals? And when do you think the data will be mature?

Yes. So what we have observed previously, particularly as you probably know, we had our patients on the Phase I portion of the study, we also have patients on the initial cohorts and we have presented data from all our cohorts. And we clearly have observed that over time we achieved deeper responses. So even if you look at the -- our prior presentations, our CR rates have increased on not only based on dose, but on the duration. So even after 1 year, we have observed patients deepening the response. So all in all, we expect that over time, as our data matures, we will be seeing a higher number of patients achieving CRs and strict CRs.

Our next question comes from Salveen Richter with Goldman Sachs.

I just wanted to follow up on a prior question on positioning here. Specifically with BCMA, how -- if the thought is to use it post-CAR-Ts and given the GPRC5D data, I guess, how are you thinking about the evolving positioning there?

Thank you for your question. We believe that the level of efficacy that we have observed in late line of therapy affords the opportunity for patients in the future to have what I would call chemo-free regimen. Our goal is to move to early lines of therapy, not only we are exploring in combination with the standard-of-care regimen, but we believe that we have an opportunity to bring to early lines of therapy, monotherapy. And as you will see and I have mentioned that our confirmatory Phase III study will be exploring monotherapy versus standard of care. We are confident, again, that the level of activity we have observed is such that this will be potentially a positive study. That's one aspect. You mentioned post-CAR-T. I'm not sure that there will be a post pre-CAR-T. Remember, these are complementary therapies. Not every patient is amenable to CAR-T, not every patient can be mobilized and CAR-Ts are not available to all patients. There are still issues with manufacturing. We see this as complementary. And remember, bispecifics are off the shelf. The responses that we are observing are getting better, desirability maybe comparable, and we think that these are complementary all in all.

This is David. I'll add one other thing. As is very typical in oncology, you start in late-line therapies, but that's not the end of all this. And the best combinations of the future to treat myeloma patients are unknown. Having multiple different mechanisms of action available to patients provide doctors with flexibility, because toxicity is going to be different across differing agents. For linvoseltamab, the principal toxicity that we're seeing is very low-grade CRS that we think can mostly be managed as an outpatient. You brought up one of the newer CD3s targeting GPR CD5. That safety profile looks different. So providing options to physicians to fit with their patients, I think, is actually a win-win in the grander scheme of things as we look for better combinations that can actually cure this disease. Thanks.

Our next question comes from Brian Abrahams with RBC.

Congrats on all the progress. How are you guys thinking about the optimal tumor-associated antigen combo partner with the costim bispecific to pair with their CD3 bispecific? I guess I'm curious why CD22 for the odronextamab combo. And how you're thinking about it for the linvo combo? Is there a rationale for that to also be BCMA? Or might you consider something like GPRC5D or CD38?

Thanks. I'll answer that question. We have an enormous repertoire of PAA or tumor-associated antigen by either Signal 1 or Signal 2, CD3, CD28 and amongst the Signal 2s, many different signal 2s. And we do a very robust preclinical screening in our Velocimmune mice to help us pick which of these assets and which combination of targets are going to move forward faster than others. But we've essentially got a library of -- if you will, of many of these combinations that we can test preclinically and then decide what to move into the clinic. And in each case, it's a little bit different. For instance, in ovarian cancer targeting MUC, MUC16, we've actually picked the CD3 and the CD28 to target the same thing. So it's a MUC16xCD3 and a MUC16xCD28. In lymphoma, we've picked a different target. So it's a CD22. It doesn't preclude at some point in the future, we would want to do a CD20xCD28, but it allows us to bring different things to bear. By mixing and matching the tumor-associated antigen, you could potentially, if you will, cross-target where maximal activity is occurring and help refine which cells we direct for killing, in the case where one of the antigens is somewhat promiscuous and it has potential for off-target toxicity. Another reason to pick 2 different targets is if one of the targets disappears because of escape mechanisms, you potentially would not lose activity of the entire combination. So it's a fairly complicated calculus as to which ones we pick, but that isn't precluding that other ones won't follow into the clinic.

We have more details on which antigen we have selected for combination with linvoseltamab when we begin dosing early next year, Brian.

Our next question comes from David Risinger from SVB Securities.

I have 2 questions, please. First, bispecifics are increasingly being evaluated with prophylactic anti-infective treatments to reduce the risk of infections. Could you please provide your perspective on that, including how Regeneron may evaluate appropriate duration of anti-infective use? And second, regarding your CD22xCD28, is there any more color you can provide on the development plans, including the Phase I study design and timing?

Yes. In terms of the use of prophylactic antibiotics, we certainly are taking lot of precautions and looking carefully into prophylaxis and have implemented and continue to evolve based on new emerging data, both for linvo and for the CD20 field. So we have implemented prophylaxis across both. And I think this is something that we are learning across the class, both the use of not only antibiotics but also IVIG that will potentially become more prominent in the future. Now you also asked about the CD22xCD20 in combination with odronextamab, we hopefully dosing our first patient in the Phase I study early next year, so first quarter.

Our next question comes from Olivia Brayer with Cantor.

So for the submission next year in DLBCL and FL, is the plan to file both at the same time? Or does it make sense to move forward with one indication first, if it's a bigger priority, especially given the competitive dynamics at play. And then if you could just comment on how you're thinking about the commercial opportunity and market size for follicular, especially initially with those later-line patients?

Sure. We're currently planning on filing both the follicular and the diffuse large B-cell indications simultaneously. Given the timing, I don't think any advantage could be had from trying to file one ahead of the other, and we're certainly capable of doing both at the same time. To answer your second question, we're not specifically commenting on our expectation of market size, but I would just remind you that we're looking at this as a long-term play. It's not just about the size of the relapsed/refractory market in non-Hodgkin's lymphoma, but it's a setup for both earlier lines of therapy, combination therapy and potentially chemo-free regimens in NHL.

Our next question comes from Hartaj Singh with Oppenheimer.

Great to see all the energy at ASH, especially at Regeneron. A quick question, just following up on some of the previous questions on CAR-T versus bispecifics. In some of our calls with KOLs, they have mentioned that sequencing is becoming more and more important for them, especially hematological malignancies, various therapies as they're being developed. Some multiple myeloma patients, for example, are fifth, sixth, seventh, eighth line in various clinical trials. When you look forward to the filing in the second half of 2023 with both these projects, can you just give us a sense for where you see it exactly in that sequence? Will it be pre-CAR-T, post-CAR-T? What line of therapy? Just any sense there would really help us.

Absolutely. So I think that your question was referring to linvoseltamab and odro for both. I'll say that the issue of sequencing hasn't fully been addressed in clinical trials, but I will remind you that with odro, we -- and I mentioned before that the overall response rate and CR rates that we have observed in lymphoma patients, diffuse large B-cell lymphoma are consistent, both in CAR-T naïve and CAR-T experienced patients. And just to remind you, we're seeing an overall response rate of 50% involved with the CR rate of approximately 30% in both. So very consistent, whether they're naive or exposed to CAR-T experience. So that is very encouraging. That's one point I wanted to make. Now talking about sequencing, I think that, again, as I mentioned, not every patient will have access. And we see the advantage or the value on bispecifics being off-the-shelf and accessible to physicians vis-a-vis the experience that is required to deliver CAR-T patients. So I think that, that is eventually going to be an issue of adoption.

Our next question comes from Geoff Meacham with Bank of America.

This is Susan on for Geoff Meacham. Can you comment about the reformulation process for subcu odro, specifically speaking on the regulatory requirements and timing?

All I can tell you at the moment is that we are moving forward and we are exploring already in our Phase I study, odronextamab as a subcutaneous form, and that study is moving along well.

Our last question comes from Michael King with EF Hutton.

Let me add my congratulations on the progress you've been making. A multipart question on DLBCL and odro. In the plenary talk on ELM-1 in the Q&A, the investigator was asked about the step-up dosing and in his comments, his words were that hospitalization was required in a "problem." I'm just wondering about that. And also if you could link that to the grade 5 events and how odro might compare to some of the other CD3, CD20s in terms of grade 5 events.

Absolutely. So the first thing I want to mention is about the grade 5 event. Patients base are inevitably, when dealing with highly refractory patients with advanced disease, especially with a long follow-up, both in DLBCL and in FL. So I think that we need to take that into consideration. Just to remind you that most were -- all these steps were mostly infections complications, which is expected for these patients. So I think that no, I'm not going to compare with other assets. But the question we'll have to be answering in the set of a randomized trial, yes, these are single-arm studies. That is the first point. Then you asked about -- sorry, you asked another question.

About the hospitalization...

Hospitalization?

Yes.

Yes. hospitalization is primarily on the first cycle and during the step-up.

So Mike, it's David. I'll add just a little more color. I think you have to separate out the safety procedures...

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