Bristol-Myers Squibb Company (BMY)

Investor Update

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Jun 25, 2020

Ladies and gentlemen, thank you for standing by, and welcome to the Bristol Myers Squibb Hematology Investor Call. At this time, all participants are in a listen only mode. After the speakers' presentation, there will be a question and answer session. 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 3 part investor series. Today, we're focusing on hematology. And again, today, we'll have a presentation followed by a Q and 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 Cafforio, our Chairman and Chief Executive Officer Samad Hirawat, Chief Medical Officer, Global Drug Development and Nadine Ahmed, President, Hematology. But also with me for the Q and A session are Chris Berner, 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 will 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. Reconciliation of these non GAAP financial measures to the most comparable GAAP numbers are available on bns.com. And 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 2nd 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 redevelopment 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? 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 CellMOS. 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. By 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 image, CD38 directed antibodies, proteasome inhibitors and others. But we still haven't cured the disease. There's 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 proteomeostasis platform where we have cell mods 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 Celebron 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 are 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 in which is a different way of engaging the immune system by improving the patient's T cells recognizing the tumor through our T cell engager. And the 3rd approach on the right side doesn't actually depend on the immune system at all. It looks at targeting BCMA through linked 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 IDCEL. You're all aware of the data that were presented for IDACEL 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 a vast majority being refractory to an IMID, proteasome inhibitor and anti CD38. What we are seeing here is a 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 3rd line plus patient population sometime next year. In short, we are extremely pleased with these results and look forward to bringing the 1st in class treatment to patients as quickly as possible, while accelerating our developing programs in the earlier line. Lines. Beyond iD Cell, 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 Karma 3 in the 3rd to 5th line setting as I said earlier. And we also have 2 ongoing studies in earlier line settings with Karma 2 in the second line and importantly Karma 4 in newly diagnosed multiple myeloma patients, where we are studying IDACEL followed by Revliment maintenance therapy, for example. Slide 12 please. Switching gears to another way of engaging the immune system is with our T cell engager. Now 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 cell 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. 1 is about to launch and we have a robust lifecycle management program. So now let me turn to our 2nd platform with CellMODs. Monday you heard Rupert talk about our robust cell mod library of small molecules that was developed by our scientists internally using foundational patient datasets and molecular disease profiling. It's taken some time to develop, but now we are seeing clinical data starting with Ibrutamide 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, bertesumab and carfilzumab, 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 a regimen we've taken into our 1st Phase 2 study that could potentially be registrational. Now, why is this data important? Well, let's remember that almost all these patients have heavily pre treated multiple myeloma and almost all are refractory to IMNs 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 IMAGE or CD38 reuse. However, what we are seeing here are encouraging response rate and 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 registration program. And beyond that, as you can see, we already have cohorts in place to look at the potential for iverdomide 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 cell mob CC92480. Data were recently presented from the first clinical trial for CC480 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. At the recommended Phase 2 dose and schedule, almost 55% of patients achieved a response with a 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 planned recommended Phase 2 dose starting now and we will 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 term, we are getting ready to launch our 1st in class BCMA CAR T with iDACEL. But 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 registration data for both the Selmod agents as well. We're hoping that we can get underway sometime soon with the registration 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 CellMODs into earlier lines. When I look at 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 a 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 REBLISIL. Over the last year, REBLISIL was approved for MDS in the second line for the anemia associated with that disease. We also presented Phase 2 data in myelofibrosis associated with anemia at ASH last year and intend to start indication this year. Let me turn to our rationale to move REBLISIL into a broader MDS associated anemia population in the next slide. As we can see on Slide 17, in earlier Phase 2 trial, we saw the data that demonstrated a 56% response rate in ESA naive patients supporting the initiation of the Phase 3 COMMANDS study. This Phase 3 study will enroll about 3 50 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 Revlisil, 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 rablazole to play a role in chronic anemia resulting from a range of hematological diseases starting with myelofibrosis. Let me remind you that the Phase 2 data in myelofibrosis that we presented at ASH of last year, which are shown here, And what is important is that when you combine REBLOCEL with a JAK inhibitor, we get strong responses in both non transfusion dependent and transfusion dependent patients. Based on these results, we plan to initiate a registration 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 3rd line plus large B cell lymphoma called TRANSCEND NHL001, 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 studied patients with 3rd line plus CLL whose disease had 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 had a rapid, deep and durable response. We are currently enrolling the Phase 2 portion of this 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 liso cell, 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 studies 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 strategies 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 over there targeting BCMA and potent degraders of iulose and icarose with cell moms. We have important opportunities for rablozil, niso cel and CC-four eighty six 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 will 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 1st 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 lifecycle 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 lifecycle 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 treatments immediately following regulatory approval. BMS is unique as a company as we expect to offer our customers 2 CAR T treatments to address unmet needs 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 side of care. Physicians will determine the appropriate treatment setting, and so we'll focus our efforts on educating prescribers in the following ways. Number 1, raising awareness of the clinical profile, including safety data number 2, educating physicians and patients on how the data support outpatient use and number 3, training sites that can deliver treatment in the outpatient setting. Moving to Slide 29. Despite approximately 14,000 patients today with 3rd 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 a 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've 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 P treatments in the commercial setting. Our launch priorities for liso cel are focused on: 1, expanding the market by driving referrals and outpatient delivery of liso liso2, 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 live cell 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 Falsign Plus setting. And in late stage myeloma, there are still significant unmet needs as current treatments, as you heard from Sumit, have delivered low response rates and short progression free survival of approximately only 4 months in triple class exposed patients. IVACEL as a potential 1st in class BTMA CAR T has demonstrated unprecedented efficacy in late stage multiple myeloma. With response rates of greater than 80%, complete response rates 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 CALM study recently at ASCO and EHA, we've received very positive feedback from physicians who've 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: 1, expanding the market by driving referrals, leveraging our multiple myeloma commercial and medical footprint in the community and 2, using our 1st mover advantage to establish Idecel as the BCMA CAR T of choice. We also have an extensive development program of Idecil focused on moving iDACEL 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 cell mod approaches beyond the image to both strengthen and sustain our leadership of this important therapeutic area. Moving to Slide 32. We initially established our AIMID portfolio as standard of care in multiple myeloma from relapsedrefractory 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 POMALISSE based triplet regimens. So through our dual BCMA and Cellmod 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 CellMuds. We also have the opportunity to sequence these treatments across lines of therapy in the same way we did with Revlimid and POMALIST. Moving to Slide 33. Our current leadership in the near term will be sustained through our in line portfolio of REVLIMID, POMALYST and IMPLICITI and the near term launch of IDACEL. In the midterm, we have the opportunity to move IdaCel earlier in this treatment sequence and launch our BCMA T cell engager as well as our new cell mods. 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 CellMOD, including the appropriate sequencing of treatments. Moving to Slide 34. Summit 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 cell mods, which provide us with the next generation of small molecules beyond the image. However, the most exciting and uniquely competitive aspect of our pipeline is the opportunity to develop novel novel combination regimens combining BCMA with CellMODs 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 may 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 as continuous treatment. 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 CellMODs 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 image. And as Sumit mentioned, we now have clinical data for both Iberdomide and CC92480, demonstrating significant clinical activity in patients that have become refractory to Revlimid and ORPOMALIST. 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 early in the treatment setting through triplet regimens, and those preliminary combination studies are currently ongoing. We also have the opportunity to sequence the CellMODs across different lines of therapy just as we did with Revlimid and POMALYST. Moving to Slide 37. The 3rd 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 Revlisil, 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. Revlazil represents a novel mechanism of action as a 1st 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 Rebizil. Our launch efforts are focused on educating prescribers on the appropriate initiation of Reblizole treatment. For example, when patients have failed ESAs or are no longer benefiting from ESA treatment or when patient's transfusion frequency begins to increase. We also have an active lifecycle management plan in place with Revlisil. For example, beyond the initial second line indication, the frontline COMMAND study may significantly increase the addressable MDS patient population. You also heard from Summit that myelofibrosis also represents another opportunity and we have the Phase 3 independent study planned in combination with JAK inhibitors. We're currently in the early stages of the MDS launch for REBLISIL 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 mobile mechanism of action of Revlisor and our existing relationships with MDS prescribers through Revlimid, which has allowed us to gain very good virtual access to prescribers. Also with COVID-nineteen, 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-four eighty six 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 allergic transplant due to the attendant morbidity and mortality. Currently, there are no FDA approved maintenance treatments in AML. And CC-four eighty six is a 1st 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 VIDASA was previously tested in the maintenance setting and was not able to show a survival benefit. The launch priorities for CC-four eighty six are to establish maintenance treatment in AML, just as we did with multiple myeloma, and for CC-four eighty six to become the maintenance treatment of choice for AML patients. Our life cycle management plan for additional indications with C646 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 1st 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 lifecycle management plans to deliver additional significant indications beyond the initial launches. In the area of cell therapy, we're 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 for our novel pipeline, targeting BCMA and delivering the next generation of CellMOS beyond the image. We also now have important platform medicines to drive our expansion into myeloid disease through Revlazil and CT-four eighty six. 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 CellModes 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 and 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 and A session? Great. Thanks, Giovanni. Evan, do you mind if we go to the first question, please? Our first question comes from Terence Flynn with Goldman Sachs. Great. Good afternoon. Thanks for taking the questions and hosting the day again today. Maybe just a 2 part question on CC93,269. I think one of the outstanding questions for bispecifics generally just is durability of response. So maybe Sumit would just be curious kind of how you're thinking 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 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 somewhat different strategy? Thank you. Let me start by 269 and certainly on BV217, Nadeem, 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 and the SUMR's plot that we've shown in the 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 along. 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 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 2 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 timeline 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 Idecel. And what I try to describe is also the midterm future where you have modalities that include T cell engagers as well as CAR T treatment. 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, remembering, these patients continue to relapse. So there's, of course, a sequencing opportunity too with the BCMA and CellMODs. And if you look at the market today with both Revlimid and POMLYST, 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. Thanks. Thanks, Terence, for the question. Kevin, could we go to the next one, please? Our next question comes from Seamus Fernandez with Guggenheim. Thanks for the question. So, I'd like to ask you this question because I'm still trying to drill into the size of the market for CC-four eighty six. Can you just help us with the number of patients who actually receive transplant? And then if you think that the transplant patients ultimately could be eligible for CC-four eighty six 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 secretases 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? Thanks. Yes. So maybe Seamus, I'll start with your first question about CC-four eighty six. 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 quarters of the overall pool of CCTL patients that have frontline AML, about half of those that get intensive 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-four eighty six 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 are 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 CP-four eighty six because remember the transplant is allogeneic not autologous transplant which has of course a higher rate of morbidity and mortality. So I think non eligible, clearly available for CD46, but a proportion of the current patients going to allogene transplant will also be available. So, Samit, I think there was a question about the gamma secretase inhibitor. Yes, it's Rupert here. Thanks, Nadine. 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 our 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 agent. 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. Thanks, Rupert. Kevin, can we go to the next one, please? Our next question comes from David Risinger with Morgan Stanley. Thanks very much. 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 and your ability to execute on the forthcoming launches? Thank you very much. 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 under reimburses. 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 a CAR T administered in the inpatient setting, 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 lysosome 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, mid term and long term. Thanks for your question. Terrific. Can we go to the next question please, Kevin? Our next question comes from Tim Anderson with Wolfe Research. Thank you. I have a question on Ide cel, liso cel or blozole. Would you agree that all 3 should reach blockbuster status, meaning they surpass $1,000,000,000 in sales? And if so, can you give us your opinion on which product gets there first? And lastly, which of those three products will ultimately be the biggest? It seems that of the 3, the Lozil 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 three products in the context of those three questions I asked. Yes. Thank you, Tim. Let me start. First of all, we agree with you that all three 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. 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 three 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 Revlazole, and indeed with all of these, remember, we're starting in late stage disease with the initial indications for all of these. And we have a broader deep development lifecycle management plan to open up new indications as we move forward. So for Revlisil, 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 Sumit about our plans in myelofibrosis, which is a significant additional opportunity. And we continue to look at other additional lifecycle opportunities for Revlisil. So we're very excited about the long term potential of Revlisil. And with both Idasil and Lifesil, 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 early in the treatment sequence for both liso cel and iDASOL. And you saw from Summit today, we have a very broad and deep development plan to prosecute against those opportunities. So I would say all three, 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. Thanks, Nadine, and thanks, Tim, for the question. Kevin, can we go to the next question, please? The next question comes from Chris Schott with JPMorgan. Thanks so much for the questions. Maybe the first was just on the SelmaD programs. How do I'm probably mispronouncing this one, abutamide 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 were very helpful, but I was just trying 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 so much. Sure. Thanks, Chris. Thank you, Chris. Let me start sorry, go ahead, Sameet. Sorry, Nadeem, I'll start off with the CellMODs and then pass it on to you for 486 and additional color on CellMODs as well. So Chris, thank you for the question because from a CellMOD perspective, so we have the platform of protein homeostasis and cell form cell mods 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 CC220 or iberdomide, which has a different profile than a more potent molecule such as CC480. Both of them, I think, hold a place in the overall development because the profile that will emerge from the 2 of them, as you saw, 50 ish percent response rate with 480, we had about 34% response rate or so with iverdomide 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 and 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 evolve, then the decisions can be made, which one goes earlier versus which one goes later. Nadine? Sure. So, Samit, I think you answered the somewhat question very well. So maybe, Chris, I'll pick up the CZ486 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 paradigms. 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-four eighty six 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-four eighty six 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-four eighty six brings for these patients. So we feel good about it moving forward. Thanks, Didi. Could we go to the next question, please? The next question comes from Carter Gould with Barclays. Good afternoon. Thanks for hosting. I guess, first one probably for Nadeem and I'll let you figure out who second one should go for. I guess, first, Nadeem, 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 clinicians? Or are you saying uptake is above and beyond kind of what you expected? Just really some color around the push pills 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 those higher efficacy options even at maybe some cost maybe at the avoidance of maybe oral options or other options and maybe just lower efficacy, but maybe higher convenience? Thank you. Sure. Thanks, Scott. So I'll start off with the MDS launch question and then maybe Sumit 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-nineteen 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 give you a very good, Revazole doesn't solve the problem of transfusions for all indications and all conditions. So 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 Rebrazole, we think has been good. That's in addition to the already valuable product profile of REBRISIL 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, Carter. So maybe Sumit 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 cell mod program in lymphoma. And with the preclinical data we have for the cell mods that are in the clinic, the CC99,282 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 ibertamide 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's saying that lymphoma, we have our SIRPalpha program, which obviously that CD47 access 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 are 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, Rupa, 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 of liso cel, but the opportunity of CellMOS and 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. Thanks again, Conor. Thanks, Puneet. Kevin, can we go to the next one? Our next question comes from Geoff Meacham with Bank of America. Hey guys, thanks for the question. Just had one basically. When I look at the success of Revlima, 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 with 48 6 and with luspatercept. So the question is and I know your answer will be based on the Phase 3 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? Thank you. Yes. Thanks, Jeff, 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 or 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 C-four eighty six delivers. With REBLAZO, and I alluded to it earlier, now we're seeing 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 with Revlazil is if you stay on, you can actually benefit from multiple periods of transfusion independence as well. So to your question, Jeff, 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. Can we go to the next one, please? Our next question comes from Andrew Baum with Citi. Thank you. A couple of questions, please. Firstly, going back to GSI in myeloma, but in relation to safety rather than efficacy, to what extent could it 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? 2nd question, again, BCMA, but dosing with PD-one, you have obviously Opdivo in the pipeline. I'm aware of the history with IMiDs, but it would seem that dosing with the PD-one would be worthwhile. What's your intentions there? And then finally, I didn't hear you talking about iterating your IVACEL cell therapy. The FDA seems to be opening the door to parent child INDs and taking forward multiple iterations of the cell therapy within one trial. To what extent is of interest as opposed to instead combining with other myeloma agents in your portfolio? Many thanks. So I can answer the first question around the gamma secretase inhibitors. 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 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 nearly 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 will have to play out with data. Thanks. Yes. And I can continue on where Rupert left with combinations as you allude to, for example, a PD-one. But the way we are looking at it is BCMA not only with a PD-one, 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 refractory 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-one inhibitor, but in the future, you will hear more about the combinations within our pipeline. And then 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 IVASEL 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 a continuous dialogue with the agencies, not only within the U. S, but also because it's going to be 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 is a 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 or 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 NextT platform is already opened and it's on clinicaltrials dot 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. Thanks, Amit. I think we might have time for 2 more questions. Kevin, if we can go to the next one. Our next question comes from Steve Scala with Cowen. Thank you. Two questions. The issue that caused the refuse to file a letter for Idecel, Did that issue provide insight for the regulatory path for Orbicell and bb217 or was it product specific? And then secondly, more generally, all three drugs underpinning the CVR ran into regulatory headwinds. Are there common threads such as Celgene's regulatory processes or were they all one offs? Thank you. Maybe I can start off and certainly, then either Giovanni or Rupert, others can chime in. From the receivable to file perspective, certainly, every time we get a discussion with the agency or hear back from the agency, we learn the nuances. And so what we learned, as we said on the call, around the refusal trial, but 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 sort of summaries 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 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 our clinical pharmacology, etcetera. 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 to a major amendment. In the 3rd case for IdaCel, 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 Revlazil, Indrebic, Revlimid, formalidomide and so on and so forth or VOTEZLA 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 1 as Celgene plus BMS or a 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. Thank you. 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 process that we've made as a company, definitely since the closing in November, the approvals of new asset whether it's REBLAZYL in the U. S, ZYPOZIA in both of the U. S. And Europe, the positive opinions that Rebblozil has received in the European Union and of course, the approval in Rebate and significant progress across the portfolio, we feel really good about where we are from a regulatory perspective. So that applies to products that have may be included in the CVR as well as the rest of the portfolio. Our next question comes from Matt Phipps with William Blair. Hi, thanks for squeezing me in and another day full of information. Building on Steve's question, but not sure if I'll get an answer. Have you had the Type A meeting yet with the FDA in regards to the refuse to file? And then another question on BCMA CAR Ts, what are you looking to see from 21, 20 1.7 or Orvisel 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 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. Sumit? Thank you, Giovanni. And for the second part, for 2,127 as well as for OrbiCell, now that we know what IdeCell has done, we as you heard also from Nadeem and myself about how we are thinking about the overall BCMA targeting agents from T cell engagers and evolving data of the ADCs from ours and others. We have set criteria for how we are going to look at UlvaCel as well as the 2,120 1,700,000 in terms of the evolution of the data, both from safety as well as from an efficacy perspective. And those will be the 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 ORBOSA and IIM-two thousand one hundred and twenty one-two seventeen 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 the strength 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.

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