Bristol-Myers Squibb Company (BMY) Earnings Call Transcript & Summary

Ladies and gentlemen, thank you for standing by. And welcome to the Bristol-Myers Squibb Hematology Investor Call. [Operator Instructions] I would now like to introduce your host for today's conference call, Mr. Tim Power. You may begin.

Thanks, Kevin. And good morning, everyone. Thanks for joining us again today for the second of our three-part investor series. Today, we are focusing on hematology. And again, today, we'll have a presentation followed by a Q&A session. So if you're not participating by the webcast, you should be able to go ahead and download the materials on bms.com. Joining me this morning for the presentation are Giovanni Caforio, our Chairman and Chief Executive Officer; Samit Hirawat, Chief Medical Officer, Global Drug Development; and Nadim Ahmed, President of Hematology. But also with me for the Q&A session are Chris Boerner, Chief Commercialization Officer; Rupert Vessey, Executive Vice President, Research and Early Development; David Elkins, Chief Financial Officer; as well as some members of our research and clinical teams as well. Before we get started, I'll read our forward-looking statements. During this call, we will make statements about the company's future plans and prospects that constitute forward-looking statements. Actual results may differ materially from those indicated by those forward-looking statements as a result of various important factors including those discussed in the company's SEC filings. These forward-looking statements represent our estimates as of today and should not be relied upon as representing our estimates as of any future date. We specifically disclaim any obligation to update forward-looking statements even if our estimates change. We may also discuss certain non-GAAP financial measures, which are adjusted to exclude certain specified items. Reconciliations of these non-GAAP financial measures to the most comparable GAAP numbers are available on bms.com. With that, I'll turn to Slide 3 and hand over to Giovanni.

Thank you, Tim, and good morning, good afternoon, and thanks to all of you for joining our second investor series today. Let's turn to Slide 4, where you can see the breadth and depth of our pipeline and the potential we have to accelerate the renewal of our portfolio over the next few years. On Monday, we discussed the strength of our research and early development, organization strategy and pipeline, including our plans to deliver greater than 20 assets with proof-of-concept decisions over the next 3 years. We then covered the growth opportunities ahead in immuno-oncology. Of course, the strength of Bristol-Myers Squibb today is the breadth of programs we have across multiple therapeutic areas, including in hematology. Today, we will highlight our industry-leading hematology portfolio, and Samit will discuss our late-stage asset and significant life cycle management opportunities, while Nadim will describe how we can leverage our commercial leadership in hematology to deliver the full value of this pipeline. With that said, let me now turn it over to Samit. Samit?

Well thank you, Giovanni. Good morning, good afternoon, good evening, everyone, and thanks for joining us today. Over the next 20 minutes or so, I will share the status of our hematology portfolio and late-stage development. And let's start with Slide 6. On Monday, I talked about the breadth and depth of our oncology portfolio. And what I'm really excited about in the hematology pipeline is the breadth of our portfolio across mechanisms of action and modalities; the range of diseases we can impact, including B-cell lymphomas, CLL, AML, anemia, as well as a robust portfolio in multiple myeloma with an opportunity to expand the use of these modalities into earlier line settings over the mid and long term. What I want to do today is, first, start out by sharing with you why we are so excited about our multiple myeloma portfolio and how we are building our strategy through 2 novel platforms with BCMA targeting and CELMoDs. I also want to share the breadth of our portfolio beyond multiple myeloma where we have the potential to treat many more patients across a range of serious hematological diseases, as you can see on this slide. Next slide, please. With Slide 7, let's start with multiple myeloma, which has been one of the company's core strengths. Taking a step back, it is really important to remember that there has been significant improvement in outcomes of patients with this disease with evolution of treatments, including the IMiDs, CD38-directed antibodies, proteasome inhibitors and others. But we still haven't cured the disease with a significant unmet need, not just in the late-line therapies, but even in the earlier lines. There are many patients who don't respond well to existing treatments, and all patients ultimately have progression of disease. Turning to Slide 8. I want to start with how we have a very unique opportunity in multiple myeloma with our portfolio because we have 2 platforms with multiple modalities to target BCMA and proteohomeostasis -- protein homeostasis platform where we have CELMoDs in the portfolio, which gives us the potential to launch the next wave of novel medicines as well as a unique opportunity to develop combinations across the platforms. For the BCMA-targeting agents, we've taken an approach that is agnostic to modality, and BCMA has the potential to become the standard-of-care target in multiple myeloma. In addition, I will talk more about the cereblon modulators later in my presentation and how much progress we've made with these as well. We're well positioned, I think, to take these platforms into late lines of therapy and address the unmet need in various populations, but we're also moving these approaches into earlier lines with the potential to combine the 2 in unique ways, as you will hear later on. Let me take a few minutes to walk you through how we are thinking about our opportunities with these approaches as we move to the next slide. As you can see on Slide 9, what I'm so encouraged by when I look at our pipeline is that we have created a very comprehensive way of targeting BCMA. We've effectively set up a portfolio that includes 3 different scientific approaches to targeting this antigen. The first one is about engaging and engineering the patient's own T cell through CARs. In the middle, you can see the next one, which is a different way of engaging the immune system by improving the patient's T cells, recognizing the tumors through our T-cell engager. And the third approach on the right side doesn't actually depend on the immune system at all. It looks at targeting BCMA through linked chemotherapy via the ADC, which is currently in an earlier stage of development, as you heard from Rupert on Monday. Importantly, our portfolio spans all of these approaches, and we have multiple assets that can target BCMA, as you can see at the bottom of this slide. Next slide, please. On Slide 10, as you can see, we've made a lot of progress with ide-cel. You're all aware of the data that were presented for ide-cel at ASCO this year. I'm not going to go into the details. I will tell you, though, what's important about that data from my perspective. In this trial, we've treated a population of patients whose disease has progressed after a median of 6 lines of therapy with the vast majority being refractory to an IMiD, proteasome inhibitor and anti-CD38. What we are seeing here is very deep responses that are durable, translating into significant results in PFS, especially at the highest dose. And the overall safety profile is manageable. Beyond this later line treatment, we are looking to move ide-cel into earlier lines with the potential registration data in the third line plus patient population sometime next year. In short, we are extremely pleased with these results and look forward to bringing the first-in-class treatment to patients as quickly as possible while accelerating our development programs in the earlier lines. Now beyond ide-cel, we have additional next-generation BCMA cell therapies earlier in development and look forward to gaining additional information to inform our development path and understanding these platforms. On Slide 11, as you can see, this doesn't end with the first launch of ide-cel. As I mentioned, we have a robust development program for ide-cel with the potential to quickly expand into earlier lines of therapy. The next data readout will be KarMMa-3 in the third to fifth line setting, as I said earlier. And we also have 2 ongoing studies in earlier line settings with KarMMa-2 in the second line, and importantly, KarMMa-4 in newly diagnosed multiple myeloma patients, where we are studying ide-cel followed by Revlimid maintenance therapy, for example. Slide 12, please. Switching gears to another way of engaging the immune system is with our T-cell engager. What's important here is that T-cell engager is targeting BCMA using the immune system differently than the CAR, where instead of engineering the T cells, we are able to bring the T cells into close proximity of the tumor cells. Again, data we presented at ASH last year and again at EHA recently show that we clearly have an active drug. We are seeing significant response rates, again in the heavily pretreated patient population. As we said at the time of presenting this data, we continue to focus on optimizing the dose, and it's important that we take the time to focus on patient safety and get the dosage optimized appropriately. And once we are through that part of the development, as we said before, our focus will be on accelerating this into registration trials as soon as possible. Slide 13, please. Now I've talked to you a lot about our first platform with BCMA targeting, where we have 2 assets. One is about to launch, and we have a robust life cycle management program. So now let me turn to our second platform with CELMoDs. Monday, you heard Rupert talk about our robust CELMoD library of small molecules that was developed by our scientists internally using foundational patient data sets and molecular disease profiling. And it's taken some time to develop, but now we're seeing clinical data starting with Iberdomide that we presented last year at ASCO. As you can see on the left side of the slide, we have an ongoing multi-cohort trial, looking at Iberdomide plus dexamethasone, as well as in combinations with daratumumab, bortezomib and carfilzomib, which will be important combination options based on the treatment paradigm that is used today to treat these patients. On the right side is data from Cohort B, Iberdomide plus dexamethasone, which is the regimen we've taken into our first Phase II study that could potentially be registrational. Now why is the data important? Well let's remember that almost all these patients have heavily pretreated multiple myeloma and almost all are refractory to IMiDs, and over 50% are quadruple therapy refractory patients, meaning everything, including IMiDs, proteasome inhibitors, CD38, steroids have failed, and patients have had a disease that has progressed through that. So in this type of population, you could typically expect to see a response rate of less than 20% with the IMiDs or CD38 reuse. However, what we're seeing here are encouraging response rate in highly refractory patients, which are durable with this new agent. We should see more data next year. And depending on what that shows, we may have an opportunity to discuss with health authorities in terms of registrational program. And beyond that, as you can see, we already have cohorts in place to look at the potential for Iberdomide in combination with existing agents, and we look forward to seeing how these data evolve and how we quickly can move Iberdomide into the earlier line settings as well with these combinations. Now turning to Slide 14. In parallel, we are advancing another CELMoD, CC-92480. Data were recently presented from the first clinical trial for CC 480 at ASCO a few weeks ago. As you can see, this is also being tested in a heavily pretreated patient population, and 37% of these patients had extramedullary plasmacytomas. In the recommended Phase II dose and schedule, almost 55% of patients achieved a response, with the majority of patients being triple class refractory here. Of course, I'm very pleased with these preliminary clinical data and manageable safety profile in this heavily pretreated patient population. This study is still ongoing, with dose expansion cohorts at a plan recommended Phase II dose starting now, and we'll provide updates at future medical meetings for this as well. So on Slide 15, as I said at the beginning, you can see that we are in a really unique position as a company, not with just one asset to address multiple myeloma or one platform, but the 2 platforms that are the pillars of our strategy in multiple myeloma. In the near term, we are getting ready to launch our first-in-class BCMA CAR T with ide-cel, where as you can see on this slide, we have a lot more coming behind that. Tying it all together, over the next few years, we have the potential to see registrational data for both the CELMoD agents as well. We're hoping that we can get underway and sometime soon with the registrational trial for the T-cell engager as well as soon as we have tied up the loose ends in terms of assessing the safety as well as the proper dosing for T-cell engager. And we also have the potential to expand the use of ide-cel and as well as CELMoDs into earlier lines. When I look at the opportunities we have in multiple myeloma, I truly am excited and encouraged with the potential momentum in the portfolio. On Slide 16, let's switch gears now. When I look at our portfolio, it's not just about the significant number of opportunities we have for our sustained leadership in multiple myeloma, but it is also about the opportunities that we have to benefit more patients with a broader set of diseases in hematology. Let's focus on a few additional assets. Let me start with Reblozyl. Over the last year, Reblozyl was approved for transfusion-dependent beta-thalassemia associated anemia as well as ring sideroblasts positive adipocyte-stimulating agent or ESA refractory MDS in the second line for the anemia associated with that disease. We also presented Phase II data in myelofibrosis-associated anemia at ASH last year and intend to start the Phase III study in that indication this year. Let me turn to our rationale to move Reblozyl into a broader MDS-associated anemia population in the next slide. As you can see on Slide 17, in earlier Phase II trial, we saw the data that demonstrated a 56% response rate in ESA naive patients supporting the initiation of the Phase III COMMANDS study. This Phase III study will enroll about 350 patients with very low or low or intermediate risk MDS in ESA naive subjects who require RBC transfusions. The primary endpoint is 12-week RBC transfusion independence in this patient population. As you can recall, patients who require frequent RBC transfusion can experience complications associated with iron overload. And hopefully, with Reblozyl, we can help prevent those complications. So we look forward to seeing these data. On Slide 18, we can see that beyond MDS, we believe there is a potential for Reblozyl to play a role in chronic anemia resulting from a range of hematological diseases, starting with myelofibrosis. Let me remind you that the Phase II data in myelofibrosis that we presented at ASH of last year, which are shown here, and what is important is that when you combine Reblozyl with a JAK inhibitor, we get strong responses in both nontransfusion-dependent and transfusion-dependent patients. Based on these results, we plan to initiate a registrational trial late, either this year or early in 2021. Moving on to liso-cel on Slide 19. As you're aware, we presented data from our pivotal trial in third-line plus large B-cell lymphoma called Transcend NHL 001 last year at ASH, and that demonstrated that liso-cel has a best-in-class CD19 targeting profile with a high affinity and differentiated safety. We look forward to bringing this product to patients soon because we have a PDUFA date of November 16 this year. Beyond this very refractory setting, we are moving liso-cel into earlier lines in large B-cell lymphoma as well as exploring its applicability in indolent lymphoma as well as chronic lymphocytic leukemia. So let me remind you of the encouraging data that we saw in CLL in the next slide. This is Slide 20, for those who are following off of the webcast. CLL is considered incurable, and patients eventually relapse and become refractory to available therapies. And while targeted therapies and combinations are changing the treatment landscape, patients who progress beyond that have poor outcomes. And effective therapies are, of course, needed, especially for those who have disease progression following the BTK inhibitors and venetoclax treatment. So TRANSCEND CLL was a study that study patients with third line plus CLL whose disease has progressed after both BTK inhibitors and venetoclax, at least in part of the population. As you can see, high response rates, especially complete response rates in patients with ibrutinib and venetoclax has failed are compelling with a manageable safety profile. Now we've not shown it over here, but these patients have a rapid, deep and durable response. We are currently enrolling the Phase II portion of the study and expect to share additional information in due course. Now all that said, let's turn to our broad development program in liso-cel in the next slide. So tying it all together for lifestyle, we have an opportunity to take this best-in-class profile and move it into earlier lines of therapy as well as other disease areas. As you can see here, we have a robust development program for liso-cel, expanding into earlier lines of therapy, including the second line transplant non-eligible population, and the study is called PILOT, where we have the potential to be first, as well as broadening beyond the large B cell lymphoma with CLL, MCL, follicular lymphoma, where data will start to read out in 2021. In addition to these studies, we will be able to learn and think around potential combination strategy in the future as the data evolves from these particular trials. So on Slide 22, let me just wrap up. I wish I had time to get into everything we had in the pipeline. But unfortunately, that's not the case, at least today. As you've seen, our hematology pipeline is not just about multiple myeloma, although we have a diverse and exciting set of assets there targeting BCMA and potent degraders of Aiolos and Ikaros with CELMoDs. We have important opportunities for Reblozyl, liso-cel and CC-486 as well, which we did not discuss today. So we're looking forward to seeing data from our entire hematology portfolio emerging over the next few years. And with that, let me hand over the next part of the presentation to my colleague, Nadim, to give you his perspective. Thank you.

Thanks, Samit, and hello, everyone. So let me start with Slide 24. Our leadership position in hematology is driven by our commercial expertise in the space, which we'll also leverage to expand our presence across the other major hematologic diseases. Our franchise expansion will also be enabled by our global commercial footprint, which covers the length and breadth of hematologists across academic and community settings; and our hematology medical expertise, which is built on deep and extensive relationships with key hematology thought leaders and prescribers. Looking at this slide from left to right. In the near term, the positive momentum of our commercial execution will allow us to maximize our in-line brands. For our launches, our experienced hematology sales force, which has successfully launched multiple products in the hematology space, will drive the uptake of our near-term launches to deliver a range of potentially first-in-class and/or best-in-class medicines to the marketplace. These new launches will deliver important initial indications. However, that's just the beginning of the story. For each of these novel medicines, we have life cycle management plans to deliver additional important follow-on indications. We also have a promising pipeline following closely behind with our next wave of innovation. And finally, our hematology leadership and experience will also allow us to continue to be considered as a partner of choice when it comes to sourcing external innovation through business development. Moving to Slide 25. Our long-term hematology strategy is made up of 3 key pillars, which include driving sustained leadership in multiple myeloma and expanding our presence into other key hematologic diseases. And I'll start out by talking about how we're thinking strategically about the opportunity with cell therapy. Moving to Slide 26. Cell therapy is a very important part of our long-term research, development and commercialization efforts. We believe that this is a really important area of cutting-edge science, which has the potential to significantly transform patient outcomes, both now and in the future. In the near term, we can maximize our opportunity by delivering 2 differentiated CAR T treatments to the marketplace with their initial indications in late-stage disease, followed by additional important indication through life cycle management. In the medium term, we'll continue to make the technology more cost-efficient as well as drive the next-generation of CAR T treatments. For the long term, as you heard from Rupert earlier in the week, we'll continue to ensure that BMS is at the forefront of advancement in the technology and science, both internally and through external partnerships. Moving to Slide 27. Although historically, there have been some headwinds in the adoption of CAR T as a technology, we do believe we're taking a differentiated commercial approach to the marketplace in several ways. Starting with our therapies, we have potential best-in-class medicines for prescribers and their patients. We also have the opportunity to expand the CAR T market through the breadth of our commercial footprint, especially in the community setting, which will allow us to drive referrals to CAR T treatment sites. We've now worked with many sites, including outpatient treatment sites on onboarding, including logistics and training in order to ensure a large number of sites are ready to administer our CAR T treatment immediately following regulatory approval. BMS is unique as a company as we expect to offer our customers 2 CAR T treatments to address unmet need in 2 significant hematologic diseases in the form of lymphoma and multiple myeloma. We have a manufacturing network and the requisite capacity in place, allowing us to fulfill the demand of the marketplace, both commercially and clinically. We also feel very good about access and reimbursement now that CMS has proposed a DRG specifically for CAR T in their draft rule. This is a game changer for CAR T therapy and will allow significantly more patients to access CAR T treatment. Finally, we have a broad and deep development plan, which positions us well to fully realize the long-term potential of CAR T treatment as we move it up earlier in the treatment sequence and also expand into additional diseases. Moving to Slide 28. So as we think about the opportunity for outpatient administration, especially with liso-cel, it's important to point out that the product label does not determine site of care. Physicians will determine the appropriate treatment setting, and so we'll focus our efforts on educating prescribers in the following ways: number one, raising awareness of the clinical profile, including safety data; number two, educating physicians and patients on how the data support outpatient use; and number three, training sites that can deliver treatment in the outpatient setting. Moving to Slide 29. Despite approximately 14,000 patients today with third line plus diffuse large B cell available for CAR T therapy, a relatively small proportion are currently receiving CAR T, and this is despite the fact that patients with multiple relapsed large cell lymphoma have very poor outcomes with the median survival of less than 6 months. We believe we will increase the pool of patients receiving CAR T based on our differentiated approach to the marketplace, as I just described. With liso-cel, we have a potential best-in-class profile, which will allow liso-cel to be delivered to patients locally in the outpatient setting based on both the efficacy and safety profile, including the relatively lower incidence and severity of CRS and neurotoxicity. We now have data presented at both ASH and ASCO, showing the feasibility of liso-cel administration in the outpatient setting. We have also received positive feedback on the clinical profile of liso-cel from investigators conducting the liso-cel clinical trials who also have experience using the other CD19 CAR T treatments in the commercial setting. Our launch priorities for liso-cel are focused on: one, expanding the market by driving referrals and outpatient delivery of liso-cel; two, driving brand share in the treatment sites through a best-in-class profile and providing exceptional customer service. We also have an extensive development program focused on moving liso-cel up earlier in the treatment sequence of liso-cel lymphoma and moving into other B-cell malignancies, including CLL and follicular lymphoma. Moving to Slide 30. Multiple myeloma is a disease area we know very well. Unfortunately, many patients continue to relapse from their disease. A significant number of patients progress to the fourth line plus setting. And in late-stage myeloma, there are still significant unmet needs as current treatments, as you heard from Samit, have delivered low response rates and short progression-free survival of approximately only 4 months in triple class-exposed patients. Ide-cel as a potential first-in-class BCMA CAR T has demonstrated unprecedented efficacy in late-stage multiple myeloma with response rates of greater than 80%, complete response rate of about 40% and progression-free survival of approximately 1 year. The safety profile is also generally manageable with single-digit percentages of serious CRS and neurotoxicity. And following the data presentations for the KarMMa study recently at ASCO and EHA, we've received very positive feedback from physicians who have been impressed by both the depth and durability of responses in highly refractory late-stage patients. Our launch priorities of ide-cel are focused on: one, expanding the market by driving referrals, leveraging our multiple myeloma commercial and medical footprint in the community; and two, using our first-mover advantage to establish ide-cel as the BCMA CAR T of choice. We also have an extensive development program of ide-cel focused on moving ide-cel up earlier in the treatment sequence, including potentially newly diagnosed multiple myeloma. Moving to Slide 31. In multiple myeloma, in addition to our current market brands, we also have a portfolio of novel medicines based on targeting BCMA and developing CELMoD approaches beyond the IMiDs to both strengthen and sustain our leadership of this important therapeutic area. Moving to Slide 32. We initially established our IMiD portfolio as standard of care in multiple myeloma from relapsed/refractory disease through to newly diagnosed multiple myeloma, starting with the entry of Revlimid in late relapse setting and moving up the treatment sequence through the establishment of triplet regimens in the early relapse setting and ultimately developing Revlimid as a standard of care in the form of doublet and then triplet regimens for newly diagnosed disease. At the same time, we were also able to sequence Pomalyst behind Revlimid, starting as a doublet in refractory disease and moving to earlier relapsed disease in the form of Pomalyst-based triplet regimens. So through our dual BCMA and CELMoD campaigns, we now have the opportunity to once again reestablish new standards of care with the BMS novel myeloma pipeline, starting with market entry in refractory disease and then moving up earlier in the treatment sequence, and ultimately, newly diagnosed disease, including novel-novel combinations of BCMA and CELMoDs. We also have the opportunity to sequence these treatments across lines of therapy in the same way we did with Revlimid and Pomalyst. Moving to Slide 33. Our current leadership in the near term will be sustained through our in-line portfolio of Revlimid, Pomalyst and EMPLICITI and the near-term launch of ide-cel. In the midterm, we have the opportunity to move ide-cel earlier in this treatment sequence and launch our BCMA T cell engager as well as our new CELMoDs. And longer term, we have the opportunity to redefine standards of care within and across lines of therapy through novel-novel combination regimens of BCMA and CELMoDs including the appropriate sequencing of treatments. Moving to Slide 34. Samit showed this slide earlier, outlining how we are approaching the clinical development of our novel myeloma pipeline. From a commercial perspective, this slide also shows the unique and competitive nature of the BMS pipeline, which will provide us with the opportunity for sustained leadership in this important therapeutic area. We have multiple modality approaches to targeting BCMA, which is now a very well-validated target in myeloma. We also have multiple CELMoDs, which provide us with the next-generation of small molecules beyond the IMiDs. However, the most exciting and uniquely competitive aspect of our pipeline is the opportunity to develop novel-novel combination regimens, combining BCMA with CELMoDs as the new clinical benchmark for triplet regimens of the future. No other company has this unique combination opportunity in their pipeline. Moving to Slide 35. I'm often asked how multiple BCMA modalities such as CAR T and/or antibodies can coexist in multiple myeloma. And this slide illustrates how the various approaches to BCMA can be applied based on individual patient factors. Each of these modalities will be tailored for different patient segments. So for example, younger patients prefer receiving CAR T as a once-and-done treatment. Older patients who can't travel may prefer to be treated locally in the community and may choose to receive a T cell engager's continuous treatment. And the key point here is that having both treatments will allow physicians to provide tailored treatment for a broader pool of patients, driving greater overall market share for the BMS portfolio within a given line of therapy. Also, across different lines of therapy, we'll have the opportunity to sequence different modalities and combinations. For example, we know BCMA antigen loss is not the main cause of relapse following BCMA therapy. So it may be possible to sequence and treat patients with different BCMA modalities across lines of therapy as their disease relapses. Moving to Slide 36. The CELMoDs represent the next generation of small molecule myeloma agents. Patients with multiple myeloma continue to experience relapse despite the availability of newer treatments. And at the same time, we hear from physicians that there is an important unmet need for patients that fail the current IMiD. And as Samit mentioned, we now have clinical data for both Iberdomide and CC-92480 demonstrating significant clinical activity in patients that have become refractory to Revlimid and/or Pomalyst. We've seen response rates in the range of 30% to 50% in patients with IMiD refractory disease. And so the initial opportunity for these agents is to enter the market for late-stage refractory disease, potentially including the growing pool of post-BCMA patients. We will then move them up earlier in the treatment setting through triplet regimens, and those preliminary combination studies are currently ongoing. We also have the opportunity to sequence the CELMoDs across different lines of therapy, just as we did with Revlimid and Pomalyst. Moving to Slide 37. The third important pillar for the hematology franchise expansion strategy is the area of myeloid diseases, where we have the opportunity to establish potential platform medicines to address a range of myeloid conditions. Moving to Slide 38. We remain very excited about the long-term potential of Reblozyl, including the MDS opportunity. There's a significant proportion of lower-risk MDS patients who are either refractory to ESAs or currently receiving a suboptimal response to ESAs. Reblozyl represents a novel mechanism of action as a first-in-class erythroid maturation agent and has demonstrated a profound impact on anemia across a range of diseases by significantly reducing the burden of blood transfusions. We have also now seen that patients with MDS can experience multiple periods of transfusion independence with Reblozyl. Our launch efforts are focused on educating prescribers on the appropriate initiation of Reblozyl treatment. For example, when patients have failed ESAs or are no longer benefiting from ESA treatment or when patients' transfusion frequency begins to increase. We also have an active life cycle management plan in place with Reblozyl. For example, beyond the initial second line indication, the frontline COMMAND study may significantly increase the addressable MDS patient population. You also heard from Samit that myelofibrosis also represents another opportunity, and we have the Phase III independent study planned in combination with JAK inhibitors. We're currently in the early stages of the MBS launch for Reblozyl and are pleased with the progress so far. Initial feedback from customers has been positive. We were able to quickly pivot to a virtual launch. We're leveraging the novel mechanism of action of Reblozyl and our existing relationships with MBS prescribers through Revlimid, which has allowed us to gain very good virtual access to prescribers. Also with COVID-19, there's currently a shortage in blood supply. So having a treatment that significantly reduces the requirement for blood transfusions has been very helpful to prescribers and their patients. Moving to Slide 39. We're excited about the opportunity with CC-486 as an oral maintenance treatment that has delivered a 10-month overall survival benefit in patients with frontline AML currently in remission, as you can see from this overall survival Kaplan-Meier curve. Moving to Slide 40. AML represents a significant unmet need opportunity, even in the frontline setting, due to the poor prognosis of this disease. Approximately 30,000 patients are diagnosed annually with AML, and most of these patients do go on to receive intensive chemotherapy. Even though the majority of these patients initially respond to chemotherapy, they invariably relapse within 1 to 2 years. Allogeneic transplant can provide patients with longer-term remissions. However, many patients are not eligible due to their age and performance status or they choose not to receive an allogeneic transplant due to the attendant morbidity and mortality. Currently, there are no FDA-approved maintenance treatment in AML. And CC-486 is a first-in-class DNA Methyltransferase Inhibitor, which is the only therapy to demonstrate a significant survival benefit as a maintenance treatment and is also ideally suited for the maintenance setting as an oral therapy. Also note that Vidaza was previously tested in the maintenance setting and was not able to show a survival benefit. The launch priorities for CC-486 are to establish maintenance treatment in AML, just as we did with multiple myeloma, and for CC-486 to become the maintenance treatment of choice for AML patients. Our life cycle management plan for additional indications with CC-486 is currently in development. Moving to Slide 41. In conclusion, we have multiple opportunities to expand our hematology franchise across a range of hematologic diseases. We have a near-term opportunity to deliver a series of potentially either first-in-class and/or best-in-class medicines to address significant unmet patient needs and drive value for BMS. For each of these launch medicines, we have broad and deep life cycle management plans to deliver additional significant indications beyond the initial launches. In the area of cell therapy, we are very well positioned to drive our leadership through our near-term differentiated medicines while ensuring we stay at the forefront of the rapidly changing times. With multiple myeloma, we have plans in place to both strengthen and sustain our leadership through our novel pipeline, targeting BCMA and delivering the next-generation of CELMoDs beyond the IMiD. We also now have important platform medicines to drive our expansion into myeloid disease through Reblozyl and CC-486. And finally, we will leverage our expertise and leadership to ensure we continue to be considered as a partner of choice in sourcing external innovation in the hematology space through business development activities. Thanks for your attention, and I'll now turn the presentation back to Giovanni.

Thank you. Thank you, Samit and Nadim, for describing the breadth and depth of our hematology portfolio. If we could turn to Slide 43, please. I am very encouraged by what we have in hematology, the pipeline and the strength of execution of our teams. We have launched or expect to launch 5 new medicines with potential for additional indications. And as you've heard today, we're also continuing to move the science forward with the potential for new medicines in the future, such as our CELMoDs and future BCMA agents. Overall, we are in a very strong position to sustain a significant leadership position in hematology. So building on what we described on Monday and what we discussed today, there will also be more to discuss tomorrow when we describe the opportunities ahead in immunology and cardiovascular. Now let me move to the Q&A. We have the same members of the management team on the line today to answer your questions as well as additional leaders in the organization. Tim, will you please open the Q&A session?

Great. Thanks, Giovanni.

Our first question comes from Terence Flynn with Goldman Sachs.

Maybe just a 2-part question on CC-93269. I think one of the outstanding questions for bispecifics generally just is durability of response. So maybe Samit, would just be curious kind of how you're think about that question given the data from your ongoing study. And then the second part relates to the next steps. I know you touched on this a little bit. But any additional clarity you can give on when you might be in a position to move into that -- the Phase II study? And would an accelerated approval be possible here if the GSK ADC and your own bb2121 do reach the market? Or would you need to come up with a somewhat different strategy?

Let me start by 269 and certainly on bb21217. Nadim, certainly, feel free to get in there, too. If you recall the presentation, while I did not show the data over here, if you recall the presentation from ASH last year in the swimmers plot that was shown in that slide. When we do see patients responding, and especially, we had an overall response rate of reaching almost about 90%, this is a different bispecific, and I would not bundle all of them in the same category. Certainly, Rupert did show the technology used and the platform that we have on Monday. And what we have seen is that when the patients get into response, the responses are very durable, and they continue to be present. And I think we had follow-up of some of the patients up to cycle 10, and you saw those responses lasting long. So we do believe that there is a differentiation for this asset, and that's why we are taking our time in terms of assessing what the right dose should be, what the right schedule should be and if we should be doing a dose escalation within the patient or should it be a fixed dose. So those are the kinds of things we are focusing on. I'm sure we'll get there very soon. As I said earlier, we're hoping to be able to get to that recommended Phase II dose for expansion, which may serve as a potential registrational trial for this one as well, but that will probably be towards the end of this year. Early next year is what we are thinking is. For bb2121, we have already presented the data per se. And what -- as I said earlier, our time line for submission, we've already declared before the end of July. But let me ask Nadim if he wants to add anything more from that perspective.

Yes. Thanks, Samit. And Terence, thanks for your question. I think I fully agree with what Samit said. And I also go back to -- look, if we think about the temporal nature of this, the near-term opportunity, of course, is ide-cel. And what I tried to describe is also the midterm future where you have modalities that include T cell engagers as well as CAR T treatments. And I think we feel very good having the opportunity to have all of these modalities in our portfolio. And I think, as I described earlier, it gives you the potential for overall greater market share, both within a line of therapy. But again, remember, these patients continue to relapse. So there's, of course, a sequencing opportunity, too, with the BCMA and CELMoDs. And if you look at the market today with both Revlimid and Pomalyst, we actually see the use of both across different lines of therapy. So I think there's a patient opportunity to benefit from multiple modality treatments, and there's also value to BMS that having the multiple modality approach can drive greater market share both within and across lines of therapy.

Our next question comes from Seamus Fernandez with Guggenheim.

I'd like to ask this question because I'm still trying to drill into the size of the market for CC-486. Can you just help us with the number of patients who actually received transplant and then if you think that the transplant patients ultimately could be eligible for CC-486 in the maintenance setting? And then the second question. We've seen a number of other players integrate gamma secretase into the development of their BCMA whether it be ADCs or CAR T therapies. Can you just help us -- you guys have developed gamma secretase in the past for other disease states. Just wondering if you see that as an opportunity to enhance the activity of your overall BCMA portfolio.

Yes. So maybe, Seamus, I'll start with your first question about CC-486. So if you look at the current treatment algorithm, probably about half the patients, a little bit more, that are eligible for intensive chemotherapy, which tends to be about 3/4 of the overall pool of patients that have frontline AML, about half of those under chemotherapy can go on to receive allogeneic transplant. So that's the way I would look at that. Now your question about both those patients that are eligible for transplant or not eligible for transplant. So clearly, those that aren't eligible or choose not to go for transplant, CC-486 offers a different treatment option that has already shown a 10-month survival benefit. I also think now that patients who are on the cusp of whether they're eligible or not for transplant, they now have an additional opportunity that they didn't have before. And I think, previously, physicians had the choice because they didn't have much in the space that showed any benefit to push patients more towards transplant. So I do think there will be a proportion of patients today that are eligible for allogeneic transplant that will favor CC-486. Because, remember, the transplant is allogeneic, not autologous transplant, which has, of course, a higher rate of morbidity and mortality. So I think noneligible clearly are available for CC-486, but a proportion of the current patients going to allogeneic transplant will also be available. So Samit, I think there was a question about the gamma secretase inhibitor.

It's Rupert.

Yes, it's Rupert here. Thanks, Nadim. So yes, clearly, gamma secretase inhibitors, it's well recognized that they can stabilize the expression of BCMA on target cells, and therefore, potentially increase the density of the target. And for some agents targeting BCMA, depending on their characteristics, that may be a way to increase response rate. It's certainly an intriguing hypothesis. It may not be necessary in every instance, and I think it depends on the quality of your BCMA-targeting agents. However, having said that, we do have access to gamma secretase inhibitor agents, and we are engaged in active collaborations, looking at the utility of these agents in combination with some of our BCMA-targeting entities. So I hope that answers your question.

Our next question comes from David Risinger with Morgan Stanley.

I wanted to go up to a little bit higher level with 2 questions please. First, could you please discuss the outlook for hospital reimbursement for cell therapies and implications for adoption? And second, could you just discuss Bristol's manufacturing capabilities and your confidence in your ability to execute on the forthcoming launches?

Thanks, David, and let me pick that up. So as we think about the outlook for hospital reimbursement, we do feel that the new proposed DRG specifically for CAR T, which is currently in the draft rule, assuming that becomes the final rule, I think that's a significant game changer for the marketplace when CAR T is being used in the inpatient setting. So as you may well know, today, the DRG that's used for reimbursement is the transplant DRG, which significantly underreimburses. So I think a couple of things. So the new DRG will take the baseline payment level up to a much higher level, approximately around $250,000 or so on average. Obviously, it varies between sites. Then on top of that, the sites have their own site-specific adjustment based on their geography. And on top of that, you have an outlier payment. So this, I think, for CAR T administered in the inpatient setting, it will make a big difference and will really open up the opportunity to receive CAR T for more patients. In the outpatient setting, of course, which we're thinking about with liso-cel and progressing our plans, that's a very different reimbursement environment, which is ASP-based. So there, we don't see any issues of reimbursement. So we think now the playing field is really being leveled for both inpatient and outpatient administration of CAR T. So that's the reimbursement issue. And in terms of manufacturing capability, I think we feel very good about both our East Coast and West Coast opportunity to supply CAR T both clinically and commercially, both at launch and in the future. We continue to look at our network and expansion opportunity, but we feel very good to be able to supply the marketplace both near term, midterm and long term. Thanks for your question.

Our next question comes from Tim Anderson with Wolfe Research.

I have a question on ide-cel, liso-cel, Reblozyl. Would you agree that all 3 should reach blockbuster status, meaning they surpass $1 billion of sales? And if so, can you give us your opinion on which product gets there first? And lastly, which of those 3 products will ultimately be the biggest? It seems that of the 3, Reblozyl is the most novel and differentiated, but the size of that market may just not be as high as the others. By contrast, the size of the markets with cell-based therapies is larger, but there's much more competition there. So if you could just kind of describe those 3 products in the context of those 3 questions I asked.

Yes. Thank you, Tim. Let me start. First of all, we agree with you that all 3 assets are really important assets. And as you mentioned, there is a real opportunity, as we've said with the first indication, but then there are life cycle management strategies for all of them that provide further opportunities for growth. As you know, we don't actually provide long-term guidance on individual assets. I made some comments on Monday with respect to how we feel about the totality of our late-stage development pipeline. And obviously, the 3 assets that you described are very important components of those -- that group of medicines that generate significant potential I described on Monday. So we're not going to make comments on individual assets. But I think Nadim can add some color with respect to how we think about, again, every one of them and what will drive the short-term opportunity and then the most meaningful life cycle management potential opportunities for all of them. Nadim?

Yes. Thanks, Giovanni. So echoing the same. I'd say with Reblozyl and indeed with all of these -- remember, we're starting in late-stage disease would be initial indications for all of these, and we have a broad and deep development life cycle management plan to open up new indications as we move forward. So for Reblozyl, for example, we're starting off in second-line MDS, but we have an opportunity potentially with ESA naive patients, which significantly opens up that addressable MDS population. You heard from Samit about our plans in myelofibrosis, which is a significant additional opportunity, and we continue to look at other additional life cycle opportunities for Reblozyl. So we're very excited about the long-term potential in Reblozyl. And with both ide-cel and liso-cel, again, we've seen transformative results so far in very, very late-stage patients. And we believe the long-term potential of cell therapy is really earlier in the treatment sequence for both liso-cel and ide-cel. And you saw from Samit today, we have a very broad and deep development plan to prosecute against those opportunities. So I would say, all 3, we're really excited about both the near-term initial indications in terms of launch but also the longer-term opportunity for all of these assets. Thanks for your question, Tim.

Our next question comes from Chris Schott, JPMorgan.

Maybe the first was just on the CELMoD programs. How do -- I'm probably mispronouncing this one. Iberdomide and 480 position relative to each other? I'm just trying to understand like kind of the different profiles there and how you think about the relative attractiveness of each of those assets. And then my second question was on 486 and the development of the frontline maintenance market. Earlier comments are very helpful, but I just want to get my hands around how quickly this can build out. You obviously have very strong data. But do you envision a lot of heavy lifting is going to be needed here just given that you're kind of building out a new maintenance market? Or is this something you envision developing fairly quickly given the overall strength of your data set?

Thanks, Chris.

Thank you, Chris.

Let me start -- oh, sorry. Go ahead, Samit.

Oh, sorry, Nadim. I'll start off with the CELMoDs and then pass it on to you for 486 and additional color on CELMoDs as well. So Chris, thank you for the question because from a CELMoD perspective, so we have the platform of protein homeostasis and cell form. CELMoDs that are coming from there from a degradation perspective certainly are new, and we understand the multiple myeloma landscape as well as the science. So the evolution is going to be important. The early runner was CC-220 or Iberdomide, which has a different profile than a more potent molecule such as CC-480. Both of them, I think, hold a place in the overall development because the profiles that will emerge from the 2 of them, as you saw a 50-ish percent response rate with 480, we had about 34% response rate or so with Iberdomide and that we did present last year. Now when we start to combine these and as the data continues to evolve, we will see which one moves further upfront. As Nadim showed you that other slide of how we developed Revlimid and then pomalidomide and how one was earlier and one was stated to be first line in maintenance and pomalidomide is second line, in a similar way, 220 and 480 could serve that purpose of replacement therapies for the image that we have already placed in that pipeline. And so that's why we are excited about the overall platform and the development of these 2 molecules. And as the data evolves, then the decisions can be made, which one goes earlier versus which one goes later. Nadim?

Sure. So Samit, I think you answered the CELMoD question very well. So maybe, Chris, I'll pick up the CC-486 question. So I think here are the sorts of things that we're thinking about in terms of time to ramp. So one, the maintenance paradigm isn't very well established in AML currently, but I would say, nor was that paradigm established in multiple myeloma. And I think we have a lot of expertise and experience in terms of how to develop maintenance clinical paradigm. So I think we feel our ability to do that is really good. So that's why -- one of our key launch priorities is to establish the maintenance treatment in AML. Secondly, I think today, there are a proportion of patients that are receiving a range of maintenance treatment, probably somewhere in the order of 10% to 20% of patients just because of the poor outcomes currently. So I think displacing those agents and having CC-486 become the treatment of choice based on the strength of our data, we feel very good about. So I think when you combine the opportunity and experience to establish the maintenance treatment paradigm as well as having CC-486 become the treatment of choice in that paradigm based on the data, we feel very good about our opportunity to educate physicians and prescribers on the benefit that CC-486 brings for these patients. So we feel good about it moving forward.

The next question comes from Carter Gould with Barclays.

I guess, first one, probably for Nadim, and I'll let you figure out who the second question go for. I guess, first, Nadim, I know it's early in the MDS launch. But since you sort of opened the door on some of the COVID commentary, I just want to be clear kind of what you're messaging has been. Has COVID really been sort of an opportunity to drive education on our clinicians? Or are you saying uptake is above and beyond kind of what you expected? Just really some color around the push/pulls from COVID. And then as far as lymphoma, clearly, the focus there for you guys is around cell therapy, and we don't really see much else going on from a pipeline perspective. I guess is there implied in there sort of an inherent view around the market and focusing on the higher efficacy options even maybe some cost, maybe at the avoidance of maybe oral options or other options and maybe just lower efficacy but maybe higher convenience?

Sure. Thanks, Carter. So I'll start off with the MDS launch question, and then maybe Samit or Rupert can pick up the lymphoma development question. So I guess my comment was more -- a little bit more of a general statement in the sense that, clearly, right now, there's a blood shortage. And especially in the height of COVID-19, as I might describe it that way, patients were not going to visit as frequently as they were before. So I think in that context, let me be very clear. Reblozyl doesn't solve the problem of transfusions for all indications and all conditions, and that's not what I was trying to say. What I was trying to say is for MDS patients specifically who often are transfusion-dependent, I think having the opportunity for those specific patients to ameliorate their anemia through the use of Reblozyl, we think has been good. That's in addition to the already valuable product profile of Reblozyl. Because remember, the initial indication is for ESA refractory patients, which is an unmet need. So I guess I would describe it as a little bit of a tailwind under the current condition. But the brand promise in terms of addressing anemia still remains as it did before. So that's the way I would probably color it. So maybe Samit on the lymphoma question or Rupert.

Yes. Thanks for the question. Actually, we're really excited about our lymphoma portfolio. So I'm glad you asked us because we've obviously not done a good enough job of portraying that in the earlier presentation. It's obviously tough to cover everything. So just to name a few things. We have a very active CELMoD program in lymphoma. And with the preclinical data we have for the CELMoDs that are in the clinic, the CC-99282 in particular I would point you to is extremely promising as a new entity there. So that's one thing I would really recommend you watch, and it's moving along quite nicely right now. We actually have an Iberdomide combination going with liso-cel in the platform study as well. In addition, we have an antibody drug conjugate program in early development as well with a partnered company that same -- that lymphoma. We have our SIRPa program, which obviously, that CD47 axis can be directed towards lymphoma, particularly in combination with anti-CD20. We have what we think are really best-in-class BET inhibitors as well, which is still being studied in lymphoma, amongst other indications. And we have a lot of combination data for a range of these different entities that suggest that they're much more than the sum of the parts. So I think we're building a really comprehensive lymphoma portfolio actually that in a fairly short space of time could look very exciting. So thanks for the question.

Yes. I would add quickly, Rupert. So thanks for that. So in terms of lymphoma, we do think this is an important area of our expansion strategy, and liso-cel gets us there first. But as you think about the opportunities going earlier in the treatment rates of liso-cel, but the opportunity of CELMoDs in our other pipelines is really exciting. So we do think lymphoma is an important area for us. It's a very significant hematologic disease, and we intend to continue to develop our programs against the opportunity.

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

Just had one basically. When I look at the success of Reblozyl, the long duration of therapy has been a huge value driver, and that's not really the case with either of your CAR T therapies. But it is though with 486 and with luspatercept. So the question is -- and I know your answer will be based on the Phase III data. But what is the potential for either 486 or luspatercept to have chronic dosing or dosing that's meaningfully longer than the Phase III data imply?

Yes. Thanks, Geoff, for the question. So very good question. So I think there's a couple of things. So 486, part of our education -- and if you look at the clinical study, actually, the patients that did -- were able to stay on therapy did benefit the most. So I think part of our education prescribers, especially with AML where patients relapse so quickly, is to make sure that patients do stay on therapy. So certainly, duration will be a driver for the value that CC-486 delivers. With Reblozyl, and I alluded to it earlier and now we've seen in the data, within MDS, the interesting finding that patients can continue to benefit from multiple periods of transfusion independence, I think, is a little bit different paradigm than we're normally used to seeing in some of the other cancer conditions where you treat to progression, then you switch treatment. What we're seeing in Reblozyl is if you stay on, you can actually benefit from multiple periods of transfusion independence as well. So to your question, Geoff, I think duration is a key driver for both of those therapies as we think about the way clinicians will manage these patients. So yes, indeed, that is one of the areas we're looking at, and we think there is an opportunity there. Thanks for your question.

Our next question comes from Andrew Baum at Citi.

A couple of questions, please. Firstly, going back to GSI in myeloma but in relation to safety rather than efficacy. To what extent could co-dosing with a gamma secretase inhibitor be used to enable you to dose lower with the bispecific and the ADC and ameliorating some of the tox? Second question, again, BCMA, the dosing with PD-1. You have obviously Opdivo in the pipeline. I'm aware of the history with IMiD. But it would seem that dosing with the PD-1 would be worthwhile. What's your intentions there? And then finally, I didn't hear you talking about iterating your ide-cel cell therapy. The FDA seems to be opening the door to parent-child INDs and taking forward multiple iterations of cell therapy within one trial. To what extent of this is of interest as opposed to instead combining with other myeloma agents in your portfolio?

So I can answer the first question around the gamma secretase inhibitor. So I think it depends on the agent that you're combining with. I mean, I think in the case of an ADC, where the drug is linked to the BCMA antibody, it causes ocular toxicity as we've seen with the leading molecule. There, if you can get the dose down by increasing the target density then, and I think that's exactly why GSK is doing this is, is to try to get under that threshold of payload that's giving you the toxicity. So I think that is a very reasonable hypothesis. In the case of a T-cell engager, I don't think that's really so clear because you don't need very much antigen on the cell surface to trigger the T-cell response through the T-cell engager. And the toxicity there is a very different sort of toxicity. It's a cytokine release-related toxicity, and it isn't immediately obvious to me that the GSI is going to help with that. It might help increase responses in situations where you have extremely low levels of BCMA expression, but that's yet to be proved. And the T-cell engager-type therapies tend to be more sensitive than ADCs as well. So I think that's really the answer to that. But obviously, it'll have to play out with data.

Yes. And I can continue on where Rupert left with combinations, as you allude to, for example, our PD-1. But the way we are looking at it is BCMA, not only with a PD-1 but actually, there are lots of checkpoint inhibitors that we have in the pipeline. So as we continue to gain an understanding of the biomarker data, evolution of resistance and refractoriness mechanisms to BCMA, we continue to evolve and plan as to what the next iteration should be in our continuous improvement in clinical trials and the combination thereof. So today, while you don't see a trial ongoing with our BCMA platform with the PD-1 inhibitor, but in the future, you will hear more about the combinations within our pipeline. I think your third question was about continuous improvement of the cell therapies in terms of the IND from a manufacturing perspective that you can continue to iterate and improve the product. And there are 2 ways of looking at it that you take, for example, an ide-cel or a liso-cel, and you have certain specs that have been approved by the FDA at the first approval time point. So what it takes is the continuous dialogue with the agencies, not only within the U.S., but also because it's going to be a global product, you have to continue to have that dialogue with global agencies in terms of what changes you're going to make, how many patients' treatment and what data it would take to be able to go back to the agency to get those specs modified in a meaningful way. And so it is certainly true that agencies are open to have that dialogue. But certainly, there's the stringency as well as the quality and compliance aspect that comes along with it. The second way to look at it is how do you, in fact, go to a different way of looking at it of certainly looking at decreasing the manufacturing time by making major improvements in your manufacturing process or the way you collect cells, grow cells as well as transition and infuse cells, meaning instead of the proliferation occurring ex vivo, you do the proliferation in vivo, for example. So those are all aspects that are ongoing. As you know, our IND for the next-generation T cell -- or next T platform is already opened, and it's on ClinicalTrials.gov. So that's another iteration of our platform as we look forward. So we are basically taking a holistic approach of improving the product, not only as a branded product, but as the next cell therapies that are to come. Hopefully, that answers your question, Andrew.

Our next question comes from Steve Scala with Cowen.

Two questions. The issue that caused the Refusal to File letter for ide-cel, did that issue provide insight for the regulatory path for Orva-cel and bb2107 (sic) [ bb21217 ] or was it product-specific? And then secondly, more generally, all 3 drugs underpinning the CVR ran into regulatory headwinds. Are there common threads such as Celgene's regulatory processes? Or were they all one-offs?

Maybe I can start off and certainly then either Giovanni or Rupert, others can chime in. From the Refusal to File perspective, certainly, every time we get a discussion with the agency or hear back from the agency, we learn the nuances. So what we learned, as we said on the call, around the Refusal to File, there were a lot many more questions around the data required in the filing from a CMC perspective. So those are the learnings from there that we will be implementing in our future filings that we provide a more comprehensive view on the protocols utilized from a CMC perspective as well as on the data that we are providing in cell summaries to the -- to a larger format, so to say, in the Module 3. And then, of course, even during the review process, when we get information requests from the agency, we continue to improve on those as well in our subsequent filings so that we don't have repetition of the similar questions for every file. So a good question from you and certainly a learning for us as we continue to evolve. Let me start off and tee off the CVR question. And then certainly, either Giovanni or others can chime in on that. If you recall, the questions around ozanimod were related to certain data that were certainly -- that required a little bit more work to be done in terms of the pharmacology and/or clinical pharmacology, et cetera. So that was one aspect of it. For liso-cel, there are specific questions that were asked that required for us to provide more data that were considered to be large enough that the agency needed to do the scientific review of it and extended the timeline through a major amendment. And the third case for ide-cel, basically, there was a lot more data that was required instead of the summary reports we had included in the file. So there are, I think, different issues. But overall, if you think about it, Celgene has had a huge and long history of filing and getting products approved, whether it be Reblozyl, Inrebic, Revlimid, pomalidomide and so on and so forth, or Otezla in the old days. So it is not that is an issue with the Celgene regulatory process. And by the way, some of these products have been filed when the companies became one as Celgene plus BMS or total BMS. So we all collectively contribute to the learning and contribute to this filing, and so I don't think it is an issue of a singular company having an issue with the regulatory part of it. Hopefully, that answers your question.

Steve, the only thing I would add, and I think Samit has given you his full perspective. I think the only thing I would add is I think when you look at the regulatory processes that we've made as a company, definitely since the closing in November, the approvals of new asset, whether it's Reblozyl in the U.S., Zeposia in both the U.S. and Europe, the positive opinions that Reblozyl has received in the European Union and, of course, the approval of Inrebic and significant progress across the portfolio, we feel really good about where we are from a regulatory perspective. So that applies to products that may be included in the CVR as well as the rest of the portfolio.

Our next question comes from Matt Phipps with William Blair.

And another day full of information. I'm building on Steve's question, but I'm not sure if I'll get an answer. Have you had the Type A meeting yet with the FDA in regards to the Refusal to File? And then another question on BCMA CAR T, what are you looking to see from 21217 or Orva-cel that would make you prioritize development of those assets? Is it just going to come down to more durable responses? Or is there something else you're looking for to improve the profile?

So thank you, Matt. Let me start and just to answer the first part of your question, and then I'll ask Samit to answer the second one. We don't comment on interactions that are ongoing with regulatory authorities. And obviously, we'll provide an update when the resubmission has gone in. Samit?

Thank you, Giovanni. And for the second part, for 21217 as well as for Orva-cel, not that we know what ide-cel has brought, we -- as you heard also from Nadim and myself, about how we are thinking about the overall BCMA-targeting agents from T-cell engagers and evolving data of ADCs from ours and others, we have set criteria for how we are going to look at Orva-cel as well as the 21217 in terms of the evolution of the data both from safety as well as from an efficacy perspective. And those will be drivers for our decision-making of how to improve on the platform and how to bring the next generation of cell therapies into late-stage development and filing perspective. So it is not ready yet for prime time to discuss the data or to say what the next stage of development for Orva-cel and 21217 is. But certainly, data will drive that.

Thank you. Thanks to all of you for your time today. This was another very productive discussion, and I hope you share our enthusiasm about this trend of our opportunities in hematology. As a reminder of what's next, our final session is tomorrow, and it will be focused on our growing immunology portfolio as well as our plans to continue to be a leading company in cardiovascular disease. So we look forward to speaking with all of you again tomorrow, and have a good afternoon, everyone. Thank you.

Ladies and gentlemen, this does conclude today's presentation. You may now disconnect. And have a wonderful day.