Status Update

Dec 9, 2019

Slides

Hi, everybody. My name is John Elicker. I lead Corporate Affairs and Investor Relations for Bristol. A lot of familiar faces in the room, but also a lot of new faces. It's a very exciting time for us to come together for the first time at a very important medical meeting. And overall, more broadly, it's a very exciting time for the company. And as we reflect back over the course of the year, you don't get to an exciting time like this without being on a journey. And no doubt, we've been on a journey since a little not quite a year ago. And many of you in this room have been on that journey with us. But when we look back and think about the last 11.5 months or so, pretty much everything has gone at or ahead of our expectations. If you look at the business performance of both Bristol Myers Squibb and Celgene over the course of 2019, very strong, good strong underlying fundamentals, which positions the company very well for the future. Fifty-fifty shot. And we had another settlement with Alvogen. Fifty-fifty shot. And we had another settlement with Allogene. And then on the regulatory and clinical side, both fedratinib and luspatercept were approved. And luspatercept has a PDUFA date for MDS in early April. Ozanimod has a PDUFA date in late March. And we're very excited to have an opportunity to compete in lung cancer given the data that we received from 227 and 9LA. Now not everything goes perfectly. We were disappointed, and we disagreed with the fact that we had to divest O Tesla. But when we look back and look at the value received and the speed with which we were able to execute that transaction, we think we ended up at a really good place there, which brings us to then the closing of the deal. And in the last 2 weeks, we've initiated a $7,000,000,000 ASR, which was a $2,000,000,000 increase from that we announced earlier in the year. And on Thursday afternoon, we announced a 10% dividend increase. So things are going really well for the company. But ASH this year, I think, is really a demonstration of the fundamental reason why these two companies were put together, and it's the opportunity in the pipeline. And at this meeting, we've been able to present and will present over the next couple of days data from multiple assets across multiple hematologic malignancies. But the important point, which you'll hear from Summit in a minute, is that's just the beginning. We have significant amount of data, milestones and clinical readouts over the next 12 to 24 months that we think positions the company very well for the future. So with that, we'll get started. A couple housekeeping notes. Both Summit and Nadim will have comments on the data and the commercial opportunity from the data that's been presented here at ASH or disclosed over the last couple of days. We have leaders from the asset teams here. So if you're if there are any detailed questions or after the meeting, if you want to catch up with anybody specifically around the assets that those leaders are here. And we're very fortunate to have Giovanni Caforio, our CEO or Chairman and CEO here, a long time Board member of the company is here as well. So that's the forward looking statement, and I will turn it over to Sumit. Thank you. I hope this stage will stay the way it is, a little clunky. Well, thank you, John, and thank you for being with us today. I was thinking about today and I was thinking about this ASH. And over the last 20 years that I've been in the pharmaceutical drug development side, this has been one of the most exciting times. This 61st American Society for Hematology meeting, the data that is being presented over here is certainly going to change the practice of medicine in hematology. And I'm so glad that we are part of it. We're going to be contributing in a big way as we look forward. And from that perspective, why are we excited? And this slide tells you the story. If you look at the left side of the slide, it tells you that we are here with certainly game changing and potentially differentiated data for the first CD19 card from our perspective from BMS. These data are certainly very exciting and we look forward to getting the submission then potentially getting it to the patients as soon as possible. Secondly, we continue to make progress. We already have the strength and the knowledge and the understanding of multiple myeloma. And as we look at the BCMA as a target that is being validated, we continue to make progress and we have shared data during ASH at ASH of the progress that is being made with BCMA directed therapy, both from a CARDS perspective as well as a T cell engager. And at the bottom, you see what is happening beyond the CARDS cell space then with Revlozil, which is approved for beta thalassemia and now looking for MDS, as John shared with you, but then CC-four eighty six in acute myeloid leukemia, which is certainly going to be absolutely fabulous once we have submitted the data and hopefully we'll get the approval. Now liso cel, I do want to spend a little bit of time here just to make sure that we understand what is the differentiating feature. From a patient perspective, from a treater perspective, from a physician perspective, three things are always going to be important: the efficacy, the safety and the burden on the patient. So from an efficacy perspective, we have to look what population of the patients are we treating. These are patients that are very heavily pretreated, number 1. Number 2, the variety of diffuse large B cell lymphoma or large B cell lymphoma patients that have been enrolled in this study, the largest of its kind with more than 2 50 patients enrolled. We've got patients with aggressive lymphoma. We've got patients with transformed follicular lymphoma, mediastinal lymphoma, CNS involvement as well as Grade 3b follicular lymphoma. These are patients who also received 59% of them bridging chemotherapy, which means the disease is even more aggressive and needs to be controlled. These are really poor outcome patients that were enrolled in this study, who, if they were not treated, would have a dismal outcome. Liso cel obviously showed remarkable activity in terms of an overall response rate and complete responses of 53%. So why is that important? Well, in this disease, once you have a response, if you have a complete response, it's very important that that's durable. And what we see over here is that the 12 month mark, 65% of those patients are continuing to stay in complete response. And that also translates then into an overall survival with continued follow-up. We will obviously update these data, but it is very heartening to see that 86% of patients with CR are surviving at the 12 month mark. Now obviously, the second point, as I said, is very important, which is safety. So from a safety perspective, 58% of patients never had a cytokine release syndrome experience. Only 2% of the patients had Grade 3, IV cytokine release syndrome. The median time to onset is 5 days. 70% of the patients do not experience a neurological event. 10% of those patients have a Grade IIIIV event, median times to onset is 9 days. So what does that mean? I think it's very important for these patients because that means there is a possibility that these patients do not need to be staying in the hospital after infusion, but could be managed while staying outside in the vicinity of the hospital. It will be important that when we actually do have this product out there for physicians to use the hospitals and the infrastructure of the hospitals is well set so that they can also manage these patients from an outpatient perspective. We don't stop with the first study TRANSCEND-one. There's a slew of studies that are ongoing. Some of these data have been presented here at the meeting. And next year, we'll be starting to see the data in the second line setting for diffuse Lard B cell lymphoma in both transplant eligible and transplant ineligible patients. And then just earlier today, there was data also in CLL in the 3rd line plus setting. And then the new studies that are starting will address other indications such as follicular lymphoma and also looking at combination. Now changing gears towards multiple myeloma. Multiple myeloma is a disease that has not yet been cured. It remains a disease with high unmet medical need. And why is that? When patients are treated with a new diagnosis of multiple myeloma, certainly the combination regimens that have been developed and certainly Celgene has played a big role in that, the progression free survival is about 6 years and 50% to 60% of patients are achieving the complete response. But as relapses occur and especially 3rd or 4th relapse, the likelihood of these patients achieving a complete response with the currently available therapies is less than 5%. The progression free survival is only 4 months or less. So we do need new therapies. We do need to make sure new ways of attacking this disease are available so that we can make an impact in this outcome. And in that regard, we are very fortunate. We are at a place where there are multiple other players in the field trying to target the disease with different modalities, including somebody with cards, somebody with T cell engagers, maybe with ADCs. We are fortunate that we have all these modalities available. So in the card cell space, of course, you've seen some of the data, and I'll talk a little bit more about this with bb2121. And then there are early phase studies that are ongoing with JCAR125 as well as with 2,127 and you've seen some of that data as well. We are excited to see the T cell engagers and then of course the ADCs are early, early, early in development. Now while these data were not presented for IDACEL bb2121, it's important that I highlight a few features that were presented in the press release. Number 1, these patients are very heavily pretreated, meaning they were triple refractory to proteasome inhibitor, image as well as the CD38 antibodies. 94% of them were refractory to the CD38 antibody. Number 2, patients had to have a progression of disease and get into the study within 60 days of progression. So this is a very, very stringent criteria as defined by the guidelines. 3rd, when these patients are treated with bb2121, responses occur early, they are deep, they are durable and as you can see that at the target doses, we see high response rate and high complete response rates with a median progression free survival of 11.3 months at this time. Continued follow-up will be there, and we'll present updated data at a later date. From a safety perspective, the experience of a cytokine release syndrome as well as the neurological toxicity remains very low and quite manageable. We'll continue to follow these patients as we go forward. The other data that were presented actually at ASH a couple of days or yesterday morning was a T cell engager, which has the unique feature of being a bivalent avidity for the BCMA antigen expressed on the myeloma cells. And then there's a CD3 portion, which attracts the T cells and activates them for the cell kill. So these data are early, but they are very promising. Overall, 29 patients, 30 patients have been treated, and we do see that these are very heavily pretreated with at least five lines of prior therapy. 77% of these patients are refractory to daratumumab, 67% of these patients are triple refractory. But it is important that new ways of attacking BCMA and attacking myeloma are available because these data are quite interesting with their 13 responders, especially there is a dose relationship. So you see at the higher dose, more responses are occurring, more complete responses are occurring and these are MRD negative. Of course, we're in the Phase I right now, so safety and observation of the safety and outcomes is very important. The most common side effects over here are cytopenias, which are quite reversible. We do see very, very rare instance of Grade 3 or higher cytokine release syndrome, now we do have one patient over here that had a Grade 5 CRS. And we have to, therefore, continue to manage and optimize this dose, optimize the schedule for future development of this therapy. We are encouraged with this data, and we are paying a lot more attention to accelerate the development of this molecule and take it into the registration trial in the short term. Switching gears one more time, looking at Revlozel. Revlozel is the 1st in class erythrocyte maturation agent already approved for beta thalassemia, and now we are looking forward to the PDUFA date for MDS indication as well. This therapy allows us opportunities for further growth in terms of looking at using this for management of anemia in many diseases. And when we talk about that, data are being presented looking at the combination of this agent with ruxolitinib in patients with myelofibrosis. At the current time, what happens with patients with myelofibrosis is presentation of this huge spleen. And therefore, these patients are treated with JAK inhibitors, which takes care of this symptom. But one of the actual side effects most commonly seen is anemia, and you have to twinker with the dose to get them to a certain dose level, and it takes a while before the anemia can even come back to normal or by the low levels of normal. What we see in this trial, very early data, small trial, but we are encouraged with these data because both non transfusion dependent and transfusion dependent patients who have myelofibrosis associated anemia benefit with the combination and now we are planning the Phase III study to start in the next year after we have talked to the authorities. At the current time, we are looking forward to expanding the indications that we are looking at. So the rAVLISEL is being explored in the first line setting patients with myelodysplastic syndrome low grade who have not yet received ESAs or exercise stimulating agents. And so we are hopeful that in the late 2021, early 2022, we have that data and we can expand that indication as well. And then as I said, myelofibrosis is the next one that we're going to be looking at. And the last indication that I want to touch upon is acute myeloid leukemia. Acute myeloid leukemia is a disease of the elderly, And the way once a patient is diagnosed, they're treated is intensive chemotherapy, induction, induction followed by consolidation. And if those patients then get into a CR, the only way to potentially cure disease and take them for a longer term is through transplant, which is allogeneic. But many of these patients are not eligible for that. And at the current time, there are no approved therapy for maintenance setting for these patients. And once they are in CR, 60% to 70% of these patients will have a recurrence of disease within 24 months. So what did we do? CC-four eighty six is an oral 5 azacitidine. So the patients who had achieved a CR or CRI, meaning incomplete recovery of the bone marrow, were randomized to receive CC486 or placebo for 14 days in a 28 day cycle. Primary endpoint was overall survival, secondary endpoint of relapse free survival and others listed over here. As can be seen over here, there is a remarkable improvement in overall survival, 67% improvement compared to placebo arm. It is very important to understand that these patients are elderly and convenience of dosing as an outpatient through the oral route is maintained. And that's why these data become very important because these patients can now take this medication and live longer. We have to continue to evolve on this data and how to utilize this medication for further addition of indications, but these data are very encouraging. In talking to many physicians who treat AML, they believe this is a game changer as we look forward. The second important thing is the side effect profile is quite tolerable. Only 5% of the patients actually discontinued the drug because of adverse event. Now our job doesn't stop there. If we look forward, 'nineteen, 'twenty 2020, 'twenty one, these are very busy years for us. There are more data evolving in hematology as well as in hematology and cardiovascular diseases. Many of these trials will start to read out. And so we have a lot of work to do to take these forward and We have a lot of data readouts for Opdivo and Yervoy in 2020. And We have a lot of data readouts for Opdivo in Yervoy in 2020, and we look forward to sharing those data with you also as they emerge. And in conclusion, I have to say this is one of the best ASH meetings that I've been a part of. I hope that we can continue that trend in the future with liso cel, with BCMA directed therapies, with Adlusal as well as with CC486. Our hope is that we can move these forward very, very quickly that patients can receive them to transform their lives. Thank you. So I will pass it on to Nadim to give you a commercial perspective. Thank you. Good evening, everyone. It's good to see many friends and colleagues from the past here, and it's a pleasure to be here at a very exciting time at ASH, as Sumit said. So a couple of things I'd like to say at the outset is this is a very exciting ASH, the breadth and depth of data that we've seen here with all of our assets. And it really continues to position ourselves as the new BMS, as a leader in hematology across all of the major hematologic diseases. So that's one thing. Secondly, I think we're very uniquely positioned to really drive these near term launches because we have years of deep and extensive relationships with hematology prescribers. We have a commercial footprint in both the community setting across all the major academic centers. And we have a set of assets that are either best in class or 1st in class. And the thing is the launches of all of these assets, their first indications, it's just the beginning of the life cycle of these molecules. You heard from Sumit, but every single asset that I'm showing on this slide, we have a deep, thorough and broad development program. I'll give you the example of Ide cel. So we just saw the data. Deep and durable responses, end stage myeloma, heavily pretreated patients. Every single patient that entered that study was a refractory patient. So that's the context for the results we're seeing with Ide cel and across all of these assets. Now CAR T, since the initial approval of the first CD19 CAR T, has been a challenging marketplace, and we're going to talk a little bit about that. In terms of the safety profile so far has meant most of these agents have been had to given in the patient hospital setting. The market access or reimbursement environment has been challenging. These are not small molecules or even biologics. So the manufacturing is complicated, as are the logistics. And most of the use today is in end stage disease, so last line of therapy. Now with liso cel, we really do think we have a best in class profile for this asset, competitive efficacy but a truly differentiated safety profile that we think will allow us to reset the expectations for CAR T in the lymphoma setting. The profile for liso cel will allow us to expand and deepen our prescriber base. And we also think liso cel and the clinical profile associated with it will allow us to disrupt the site of care for these therapies. So we have the opportunity for liso cel to be administered in the outpatient setting. Now one thing that's underappreciated about CAR Ts, even in the academic center, if you're able to move the CAR T from the inpatient setting to the outpatient setting, that tremendously opens up the reimbursement opportunity because now you're going from the inpatient DRG setting to the hospital outpatient prospective payment system or HOPs, which is very similar to Part B. So there, the reimbursement is very different. And then if we extend the use of liso cel out into the community setting in these major clinics that are sophisticated that do Phase I studies, we have the opportunity again to expand that prescriber base. So we're very excited about liso cel, and we think it will disrupt the way people are receiving CAR T in the marketplace today. We also have a leading hematology organization as the new BMS. We have our representatives across the U. S. In the academic centers, as I mentioned earlier, as well as the outpatient community setting. So wherever CAR T is delivered, we are able to provide 1st class support for our customers. Specifically with liso cel, our engagement with lymphoma prescribers is deep, especially since the launch of the Revlimid R2 regimen earlier this year. So we're actively engaged with those lymphoma treaters already. So that gives us a head start. And over the past year or so, we've had the opportunity to speak with people in these CAR T treatment sites as part of our onboarding to understand what some of the challenges have been. So that will allow us to take those key learnings as we launch liso cel. The second point I will make on that topic is that we will be the only company that will be offering multiple CAR Ts within such a short space of time. So that will allow us to have one platform where lymphoma treaters and multiple myeloma treaters will be able to pick the CAR T that they want to use, which will allow us to deliver a best in class service offering in addition to best in class assets. So we're very excited about the opportunity of liso cel. The other thing I'd like to point out, this best in class profile takes us beyond third line plus diffuse large B cell lymphoma, which will be the initial indication. It allows us to expand within lymphoma or large cell lymphoma into second line transplant eligible and transplant ineligible patients. And some of these indications, we will either be best in class or first in class. You heard from Summit today about the data that were presented in the 3rd line plus setting for CLL. We're seeing complete response rates of around 50%, which we haven't seen with other treatments in CLL. We also have the opportunity to address late stage follicular lymphoma. And you also saw from SUMMIT, beyond the 3rd line setting, we have a deep and broad development program to continue to move liso cel up earlier in the treatment sequence. Switching, yes, to REBLAZYL. So REBLAZYL was launched just a few weeks ago in beta thalassemia, a very important indication from a patient perspective. These are patients who suffer from chronic lifelong infusions. We also saw the data for myelofibrosis with Reblazil, So that's another long term opportunity. But the opportunity I'm most excited about is the near term opportunity for REBLAZYL in MDS. Patients with low risk or intermediate MDS invariably end up becoming dependent on blood transfusions. And all the attendant complications, for example, iron overload, which will lead to serious end organ damage. So if you have a treatment that can significantly reduce the number of transfusions or make patients completely independent from transfusions, you're really solving for a significant unmet need in myelodysplastic syndrome, which is only partially addressed by ESAs today. ESAs are not approved by the FDA for the treatment of MDS even though they're widely used. And patients who receive MDA receive ESAs with MDS often have very transient responses. The other thing with ESAs, because there aren't many other treatments in this setting, often, patients, even though they have high EPO levels, they will still receive ESAs. And patients that are on ESAs in the U. S. Today tend to be treated for longer than they should beyond the deriving of clinical benefit because, again, there aren't that many treatment options. That's why we think Revlisil offers a significant clinical opportunity and commercial opportunity in this patient segment. And we've had the opportunity to share the profile of REBLAZYL with a significant number of clinicians. And the feedback we continue to hear based on the MEDALIST study results that showed patients can become transfusion independent with Revlisil and continue to receive benefit with continued treatment is that at an individual patient level, many patients experienced multiple episodes of transfusion independence. The primary endpoint for the study was achieving one episode of transfusion independence. But as we follow these patients up with continued Revlisor treatment, they were able to experience multiple episodes of transfusion independence. So clinicians are very excited about that. Also, we saw sustained increases in hemoglobin levels. And it's hemoglobin levels that clinicians will use to adjust whether they need to increase the number of red blood cell transfusions. So they like that aspect of the profile of REBELIZIL. And of course, the safety profile, we feel is very favorable. So when you combine the efficacy and the safety, we're receiving very, very good feedback. That's why I'm so excited about the near term opportunity that we have with MDS beyond beta thalassemia. And as we think about the longer term aspects commercially of REBLISIL, as Sumit covered. Beyond second line MDS, which I just explained to you, we also have the opportunity to take on ESAs head to head in the COMMAND study, which is actively recruiting, which will move Revlisil up into that frontline treatment setting, significantly increasing the addressable patient population. So this will allow us to have an opportunity for a treatment that starts in the ESA refractory patient population but quickly moves up into that frontline treatment setting. We're also very excited about the Phase II data that was presented here at ASH for oral presentation for the use of REBLAZYL in myelofibrosis. And we have the pivotal study that Sumit mentioned, the independent study, that will kick off next year. The other very exciting element of this is myelofibrosis is now the 3rd distinct disease in which we've seen a profound impact on anemia of this agent. So the life cycle management opportunity with other chronic anemias is being explored by our global drug development group. So we're very excited about the opportunity that REVISO presents both today and in the future. And think about this continued treatment opportunity with REBLAZIL. We have the opportunity to make patients free from transfusions with continued treatment, both a clinical opportunity and a commercial opportunity at the same time. So CC-four eighty six kind of popped out of nowhere for us and for you. So let me talk a little bit about CC-four eighty six. AML is a terrible disease. Even in the frontline setting, the survival for newly diagnosed patients at 5 years is about 10% to 15%. So what you'll often find with upfront intensive chemotherapy, patients do go into complete remission. In fact, twothree of them do. But that remission is very transient, and you see a very high relapse rate, especially in the patients who can't go on to receive transplant. Remember, AML and MDS, they're both diseases of the elderly. So many patients can't receive transplant. And the transplant I'm talking about here in AML is not autologous stem cell transplant. It's allogeneic transplant with the attendant complications you have with a significant morbidity rate, a significant mortality rate. So the unmet need in AML for a maintenance treatment specifically is very, very high. And so with CC-four eighty six, we have the opportunity with this novel agent to really establish a new clinical paradigm for these frontline patients, and that is to establish maintenance therapy. And if you remember, we did this once in multiple myeloma already. We established the maintenance treatment paradigm in multiple myeloma. We know how to do this. Our representatives are already engaged with AML treaters through IDHIFA. So just like liso cel, where we're already engaged with lymphoma treaters, with AML, we're in the field already, and this will be another welcome and smooth transition to be able to offer this treatment to patients to physicians who are treating patients with AML. Now the other thing with CC-four eighty six, it has all the ideal attributes of a maintenance treatment. Remember, the standard of care in this setting is observation because there is no maintenance treatment established. So survival is really important. So we've seen a 10 month improvement in our overall survival in AML patients as well as an improvement in relapse free survival with a drug that has a manageable safety and tolerability profile. But just as important, for the maintenance setting, having an oral treatment is really important. So CC-four eighty six potentially will be the 1st drug approved for first line AML maintenance in the U. S. So I'm going to conclude and close out by saying just a couple of things. The data at ASH, I think, continue to position the new VMS as a significant leader in the area of hematology across all the major hematologic diseases, whether it's myeloma, lymphoma, CLL, MDS, AML. With our unique footprint in the market and our existing relationships with hematology prescribers that we've built over years, we feel very excited about the near term launches. I also mentioned that these near term launches and all of these assets represent a portfolio of 1st in class or best in class agents. So again, a unique opportunity for us to drive these launches. And the indications for each of these assets opportunity. Through life cycle management, which Samit spoke about very eloquently, we have a deep and broad development program for every single one of these assets to again maximize the clinical opportunity as well as the commercial opportunity. And behind these assets and the life cycle management of each of these assets, we also have a very rich and early pipeline. For example, CC93,269, the BCMA T cell engager that you all heard about and saw about at ASH, we're really excited about that portfolio aspect of everything that we're doing as well. So from a commercial positioning perspective, the In Line business is going very, very well, and we are very excited about the near term launches. John earlier on spoke about the integration. It's been seamless. The launch team hasn't skipped a beat with any of these assets. So we're very excited about the opportunity and look forward to hearing your questions. Thanks so much for your attention. Why don't you hit that slide one more time? Which one? Hit that slide one more time. So happy to take your questions. Elizabeth, can we go to Terrence? Thanks. Terence Flynn, Goldman Sachs. Maybe just 2 for me. Nadim, obviously, a lot of competition in the BCMA space. We've seen additional competitor data. As you think about building a moat around your franchise, what can you guys do there? And what gives you confidence that you can own this market like you did in the image space? And then the kind of follow-up part to that is, can a CAR T and a T cell engager coexist in a market in your view? Thanks. Sure. I wasn't expecting that last question. So let me just say so thanks for the question, Thera. A couple of things. Our strategy for the BCMA space has always been a multimodality strategy. It's never been, let's just pick the one that market for a BCMA CAR T, a BCMA T cell engager. Of course, the ADC is much earlier in development. So as we think about the patient segments that we can address with our BCMA multimodality approach, there's various opportunities and it's factorio. So it can depend on the patient characteristics. It can depend on the site of care. So just to give you a very simple example, BCMA CAR T is a onetime infusion. So you can envisage where the patients feel like they need to have a treatment free period, you have a BCMA CAR T. In the community, a physician may want to keep close contact with the patient. Patient may not want to travel to a center where they have to go to travel to get the CAR T. They will have the opportunity of a T cell engager more locally for them. There's also physician considerations. There's comorbidities. So we think that by having this multimodality approach, we'll be able to address every patient segment. So that's how we're thinking about it there. And then what was the first part of your question? Competitive. Sure. Yes. So a couple of things I'd say about that. So with IdaCel and Touchwood, we're still a 1st in class CAR T from a BCMA perspective. We feel very good about the data that were disclosed and released, especially at the highest target dose where we're seeing deep and durable responses. And again, I will point out that as you start comparing data sets, this is a different patient population in that the almost 100% were daratumumab refractory, almost 90% were triple refractory and every single patient was refractory from their last treatment regimen. Within 60? Within so yes, either the standard treatment, either through treatment, they were refractory or they relapse within 60 days. So Sumit showed you kind of the development program for liso cel. In a similar way, we have a development program for ide cel, which starts at end stage multiple myeloma patients, but we have a third line study ongoing. We have plans second line. We have plans for frontline also. So I think if we continue to maintain our differentiated clinical profile, aggressively move the treatment early in the treatment sequence, We're going to make sure we maintain our leadership position there. And the last thing I'd say since you mentioned the IMiDs, we have something that nobody else has, and that's the ability to combine BCMA modalities with the new cell mods. So I think there we can push the efficacy bar even higher. Great. Can we go maybe Seamus over there, Tim? Thanks for the question. So I think you guys have covered a lot of the combination discussions. But as we think about liso cel and CD17, so moving outside of myeloma or sorry, the JCAR17 and the CD19 opportunity. Can you just help us understand the opportunity that you see to get into the basically outside of the into the standard clinics, outside of the main, outside of the hospital setting. I think that's a real safety dynamic that we're trying to understand. It does appear that physicians believe that JCAR-seventeen is genuinely safer, but at what point do you hit that threshold? And one of the questions that we get from investors is a concern around the frequency or the duration that it takes for patients to actually get therapy. So to get through the approval process and then to subsequently actually get effective cells into the patients. So those are 2 main questions that we're getting today. Is it a 10% failure rate? Is it a 30% failure rate? What's the sort of hit rate that you're getting when you start JCAR7 when you target a patient with JCAR17 therapy and then actually achieve a successful outcome in terms of actually getting an effective product into the patients? You want to start with the bridging therapy part. And I think if you think about the real world, how these patients are treated, many of these are aggressive lymphomas. So you can have the leukopheresis done and it does take a little while before cells are returned back to the patient because they have to go through the manufacturing process. And these are the patients who are again 3rd, 4th line patients who do require management of their disease. So in the real world, you do have the ability to give these patients a bridging chemotherapy to control the disease. If you look at the trial itself, these are patients who are not getting cured with that bridging chemotherapy because a PET scan is still positive for most of these patients. But then they are able to get the therapy and then we see what the data we see 73% overall response and 53% CRs. So from the real world dynamic perspective, having the ability to deliver that bridging chemotherapy is very important. And over here, you saw the data that it has become a necessity for others to try to do that same thing, where in the clinical trial bridging therapy was not allowed, but now the data is being generated for exactly that reason, because that is the reality. That's number 1. I think the in terms of manufacturing, we're certainly very well aware that we want to continue to decrease the turnaround time. And that's in the process. We continue to work towards that. But certainly, there are certain aspects of manufacturing that we cannot touch because cells do have to proliferate, cells do have to be checked for quality control and then we return the cells. We also have a unique way of delivering these cells, the ratio of the CD8 and the CD4 product that we have to then give it to them and then they're infused or given to the patients. So those are very important specifics for this product as compared to what others are doing in terms of supplying it in a cryopreserved bag, etcetera. So the third question which Let me address the outpatient one. Yes, exactly. So there's a couple of things, I think. So again, I do think the transition again in the academic centers from inpatient to outpatient think is greatly underappreciated. So today, a lot of the agents that are administered in these academic centers, if it whether it's rituximab or something else, is usually done in the hospital outpatient setting. And once you go into the hospital outpatient setting, you're outside of DRG reimbursement. You're much more in the environment that's pretty analogous to the Part B environment that you see out in the community setting. So I think that is a game changer to be able to move liso cel, even in those academic centers, into the outpatient setting. And then as we think about beyond the hospital because I think that was your specific question, look, this is not a treatment that's going to be used in a single partner business owned out in rural. I hope no one's from Kentucky here, Kentucky, for example, right? He's the discussions we have been having are with the big oncology practice groups. And what they tell us is they want to be involved in CAR T. They're not involved in CAR T currently. So you can envisage an environment where I'll use U. S. Oncology as an example, right? They have multidisciplinary specific clinics. Some of them do Phase I studies. Some of them do transplants. Some of them have the sophistication. What they want to do is offer it within their network, and then they want to make it available to all patients in their network. So for example, this wouldn't be where you hit every single clinic in one of those networks. There may be 2 or 3 that have the facility to do that. And then what they'll do is they'll refer their patients within their network so they don't have to leave their system. And that's why we think there's another tremendous opportunity with the profile of liso cel in that setting specifically. Okay. And maybe Chris. Thank you. Chris Schott, JPMorgan. Just building on the outpatient Is this a multiyear process to really get physicians comfortable? Or you think that the example you just cited this is something that could happen sooner than that? The second question was then coming back to the T cell engager on 269. What are the next steps as we think about development? Because if I look at this asset, it seems like all else equal, this could be a much easier product from a commercialization standpoint. So are there approaches you can take here to even further accelerate development beyond what we maybe saw with some of the CAR Ts just to really push us forward quickly? And any color you can provide on that would be appreciated. You want to start with the development question? Sure. I can start with the second question first, the 269 question. Look, we are very encouraged with the data and certainly want to move as fast as we can. We are in the process of basically quantifying the dose and ensuring that we have good coverage in terms of management of the safety. And we are pretty pleased with what the safety is. Safety profile is quite good, but certainly we don't want to overstep our boundaries. We are in the process of writing a protocol that will be more directed towards registration. And so we need to have those discussions. But Kristen and her team, they are very well prepared in terms of providing the data that will support the start of that trial. So acceleration is certainly in our mind as well. But we haven't stopped there. We are also thinking what would be the next step in terms of the combinations, because as Nadeem mentioned, the pipeline is quite rich from various modalities from the cell mods and others that we will bring along as well. So certainly, our intention is to exploit that. So I'll take your other question, Chris. So I think what we want to make sure is we're doing this in a very responsible way. And from a commercial perspective, it's going to be much easier to go to a treatment site that is currently administering CAR T, is used to giving that therapy and get them to transition from inpatient to outpatient versus going immediately to the clinic setting where there's been no experience, right? So we want to make sure that first experience is the best experience. We already know and have been told by the treatment centers that are offering, for example, multiple CAR Ts commercially today but are involved in our clinical trials, the experience they've had with liso cel, the hands on experience when they see that safety profile, they're telling us when your drug gets approved, we really want to use it. So I think we're going to, of course, start with those settings where there's CAR T experience. So the clinic or the multitude of clinics, that's not going to be a switch that happens overnight because we want to do it in a responsible way. So I think if we tackle the treatment centers that are currently administering CAR T and we switch them to liso cel, that will be the first go to place. And then we also have the opportunity then to extend beyond that. So that's kind of how we're thinking it. Maybe I can just add one thing, just as a clarification. What does outpatient setting really mean? So at the current time, when patients are receiving card cell therapy, they are admitted to the hospital and observed for 48 to 72 hours, because that's probably the time when the CRS can happen. What outpatient setting really means is that they can get the infusion and then be away from the hospital, but within the vicinity, so that if fever develops, if hypotension develops, if the symptoms of cytokine release syndrome happen, that they can easily be transported to the hospital and be admitted. So that's very important that they it's not like 1500 miles away the patient lives. They get the infusion and they can go home. It is not that intention at least. Yes. Which is why, by the way, I used the example of the single practice, right? That's not the place you want to do it. But I think even with the big oncology networks out community, how they've been thinking about it, I gave you the example of this like hub and spoke model where the patients in that system get referred in. These are the centers that are either proximally located to a hospital or have the infusion at Summit House because there's nothing magic about the infusion. But if you can give the infusion in the outpatient setting purely from a reimbursement perspective, You're now in a different environment, but you want to make sure you do it in a safe way so that you have the facility available as such. If you run into complications, you can go there. But I will remind everyone, we do have the outreach study that was presented here at ASH where a significant number of patients were able to receive in the outpatient setting. And were never admitted to the hospital, 26% of them, I think. We'd go to Jeff. Tim. Jeff Meacham, Bank of America. Just have a couple for Summit and then one quick one for Nadeem. So when you think about your different options for BCMA, obviously, moving to 1st or second line myeloma is a massive opportunity. And I'm not sure how much progress Celgene made in the state in this past year on that front. So where are you in moving upstream? And is there a modality that you think ultimately is more viable early in the myeloma treatment paradigm, say CAR T versus bispecific? And then for Nadim, for liso cel, the original pitch was more outpatient to dwell on this, but it was outpatient versus Yescarta. But there weren't many patients actually in the study that were treated on the outpatient basis. So it's kind of harder to make a commercial argument when the clinicals don't necessarily support It's actually more than Yescarta, but it's still not an overwhelming percentage of that. So can you just address that? Yes. Let me start that first, Jeff. So thanks for your question, insightful ones as always. So I think when TRANSCEND study was started at the beginning, it wasn't set up to be a specific outpatient study, whereas outreach was. And so I think the way the study was set up because whenever you do initial clinical trials, you want to make sure you don't run into safety issues, that everything's manageable in a tight way. So I think with the emergence of studies like OUTREACH, as we do more work in that setting, that was the reason actually we did the OUTReach study, Jeff, or specifically to your point. We wanted to generate the data that showed you could go into that outpatient setting. That wasn't what TRANSCEND was specifically set up to do. TRANSCEND was specifically set up to get us a registration in an environment where patients could be safely managed, etcetera, which is why we then initiate the OUTreach study, which is why now we're having these big groups coming to us, and some of them are involved in those studies. So I think they're the clinicals, Jeff, that will allow us to continue to drive the profile. And So BCMA CARs, T cell engagers, ADCs, So BCMA cards, T cell engagers, ADCs, cell mods. And then of course, the already in line products, which is the thymolist, Revlimid as well as we think about Emplicity. So we have all of the agents available. We just have read out the ide cel study. We are now looking at that and we are in the process of collating the data so that we can file as soon as possible. Now we are building the plans, as Nadeem already mentioned, The study is already ongoing in the prior line setting, the 3rd line setting. So this is going to be very, very important because this is what the FDA is going to ask us to do anyway. And as we think about that, we are also looking at how we can move it to the 2nd line. What would be the right population to move into? Because one could think about doing it in all comer population, but then the events are going to come who knows when because they are the patients with smoldering myeloma or MGUS that could also get into that study. So we have to think carefully about that. So those are the kinds of plans that we are thinking about now. And then we have to wait to as was being mentioned earlier, for the T cell engagers, it's very early days. So we can't say that we will go with the T cell engagers there or not, because we have to see the evolving profile and the data, what the response rates are, which are the patients who respond, what the durability is, what the safety profile is. And based on that, we can then decide whether we should go with the card cell in one place, T cell engages in the other or we should even go with the cell mod in terms of combination therapies, maintenance therapies positioning perspective, we spoke a little bit about earlier T cell engager versus the CAR T, for example. So if the idea was to have a, in a specific patient segment, a onetime treatment, you can envisage if you did a study where you were able to displace transplant, just like we're doing with liso cel in the transplant eligible patient populations. That could be a very attractive opportunity for that segment of patients. Another segment of patients, the elderly upfront patients, you may want to go with an antibody. So again, the data will emerge, but we think having both puts us in a much better position and that both can coexist together. Yes. Matt? Right here, Elizabeth. Matt Thibault of William Blair. Two questions. One, have you had any chance yet to look at patients who relapsed on 296 or Ide cel and really looking at BCMA expression? And my question then being, do you think that there is ability treat patients with both or would treating with 1 almost preclude the ability to treat with the other? And then secondly, as you move these up into earlier lines of therapy, how confident are you that the outcomes are going to get better? That's generally how we think about it, but initial pilot data, very small number of patients, CR rate looks similar to the TRANSCEND data. Again, it's a very small number, but just curious. So maybe, Kristen, you do want to comment on the first one about 1 versus the other or sequencing of the 2? The data on BCN expression at time of progression on all of these products is still evolving. But if you look at the data that's already available publicly, it appears that BCMA antigen loss is likely to represent a minority of the mechanisms of relapse with these therapies. Of course, with the T cell engagers, it's much earlier days. It's way too early to say anything about mechanisms of progression, mainly because almost none of the patients have progressed who have responded. So if the target is still expressed, then one could envision treating with a different BCMA targeting modality after progression on 1. It's Andrew Baum at Citi. There are alternative approaches, which obviously have a lead time compared to yours of the new modalities. I'm thinking about Glaxo's ADC. So perhaps you could talk to, given I appreciate very limited data that's in the public domain, how you see that fitting into the treatment momentarium given our lead time and given the potential for combinations, they're running an open label combination trial with PD L1. And therefore, one has to assume their is informed by data in terms of their level of excitement. So that will be the first question. The second question is there was some data presented with one of your CAR Ts at this conference with a BCA, a gamma secretase inhibitor. So perhaps you could talk about how that fits in as a complementary asset in order to obviating some of the resistance mechanisms, be it the soluble BCMA depot? And then finally, could you talk about whether you're interested in developing a Progyny like system for transfection, a closed loop system, to further broaden your CAR T access? Maybe I'll address the first one, and then I'll happily give the other 2 to somebody else. So I think one of the things as we speak about all these agents in the BCMA space, this is where patient populations are really important so that you can compare results across studies, one which you shouldn't do. But when you do, you should do it in a way that the patient populations are consistent. So when you look at the GSK ADC data today and you look specifically in that daratumumab refractory patient population, you're seeing a halving of the response rates, and you're seeing a halving in the duration of progression free survival. So I think from a purely with the caveats of comparing all studies, of course. But from a pure efficacy perspective, I think you're still seeing Ivocell as a more potent antibody. And also, I think with the GSK ADC, investigators trying to get used to the corneal toxicity they're seeing, which may be okay in a later line setting. But once you start getting early and newly diagnosed them, that could be a little bit challenging. So I think at least from a the convenience obviously is better with an ADC. But if you look at like for like patient populations, you still see the results from both IDACEL and the T cell engager that seem to be more potent when you compare like patient population. It's Rupa Bessi here, Research and Early Development. With regards to your question on the GSI, so yes, we've been collaborating with the Hutch on the GSI. It obviously stabilizes cell surface BCMA expression. So potentially has utility for myeloma target cells that have low levels of BCMA expression. As Kristen said, so far, lack of BCMA or loss of BCMA hasn't been a significant reason for failure of BCMA based therapies. However, we do think that this is an approach that's well worth testing, and we'll be looking at incorporating that into clinical trials with BCMA agents, particularly during the induction phase where it could be potentially quite useful, I think. We got a Umer. I think there was a third question, the closed loop. Yes. Yes, the Prodigy closed loop. So we're constantly looking at ways of improving our manufacturing and approaches to delivering CAR T cells to our patients. We have a number of different approaches already in the clinic and a very innovative group in Seattle that came to us from Juno, and they're looking at multiple ways of improving our CAR T therapy. I think there's an enormous distance to run-in terms of not only manufacturing improvements but also improvements in other ways of making CAR Ts more efficacious, for example, with regards to their effects on the tumor microenvironment and so on. So absolutely, we're active in all aspects of CAR T improvement. Thanks, Jan. I have 3, if I may. Sameet, first, a central premise for Juno had been the consistency between CD4 and CD8 ratio. Your former company showed an analysis yesterday suggesting it did not correlate with efficacy at all. I'm assuming that wasn't your slide, but I'd love to hear your take on that, number 1. And secondly, on the BCMA bispecific, my question is on durability, especially as it relates to, I think, cycle 7 onwards where the dosing shifts from twice a month to once a month. Can you speak to the PK parameters, which could help us understand what the durability looks like and relapses look like? And finally, Nadeem, it seems like you guys are in a unique position with presence in BCMA both on the bispecific side, but also on the CAR T side. In the long run, do you see bispecific being your best asset in that category? Or do you see a role for both? Like how do you see that? Which one is the preferred option? Yes. So maybe, Umer, I'll take your last question first. So I think I come back to the principle of our original strategy was to make sure that we had multiple offerings for physicians and patients, and we still think that's the case. So we think there are different segments and different characteristics of patients where, for a certain given patient, a T cell engager may be better, and for another given patient, a BCMA CAR T may be better on a whole host of multifactorial reasons that we discussed earlier. So which one will be the best? Obviously, we need much more data to kind of determine that, OMA. But of course, we firmly believe that our strategy is now being executed where we thought having the ability to bring for multiple patient segments will play out and will play out well. And since we are going the reverse order, maybe Kristin, you want to comment on the PGA characteristics? Yes. Okay. Or Mike. As we move to the Just for the Mike. Mike Burgess from Early Development. As we move to cycle 6, we went to a Q4 week dosing. And at that period of time, from the data presented, we only had one patient progress. The exposures tend to increase over the 1st cycle. So due to target mediated drug disposition, you have about 7 fold more exposure by the end of cycle 1, and then that persists. So the 10 milligram dose, I think, we think is still in an active range even in the Q4 week dosing. And for your first question, I think the Q and A session after that presentation probably answered your question, Lal, because there was a lot that could be done in that presentation and we did not get to see the totality of that data. With 66 patients, it's hard to draw very concrete conclusions that were drawn over there. So I'll just leave it in that. On the information related to predictors of CAR T efficacy and safety. I do think that it's important that people here recognize that in BMS' hands, there's data from 1,000, more than 1,000 patients treated with different CAR Ts. And there are a huge number of parameters that have been evaluated, both in terms of the manufacturing, the translational data and the patient response data, whether it be in terms of safety or efficacy. And we have a team of machine learning scientists absolutely dedicated to teasing out the best and most important features for next generation CAR T, and we're already moving those things into early development. I don't think you should underestimate the value of that information as these therapies move forward. We're in a very strong position with respect to that. Navin, do you have a question? Thanks. Naveen Jacob, UBS. Two questions, if I may. Very interesting data from your bispecific, obviously. What is the if you could help us understand the exact benefit of the 2 plus 1 format binding to BCMA, please. How exactly does that add to the efficacy? And then second, just a lot going on with your CAR T programs. Just from a practical standpoint, what exactly is your manufacturing capacity? Where does that stand right now as you continue to expand all the clinical programs that you have undergoing as well as planned? Any color there? And also some of the differences between all the different programs of vein to vein time for 2021, 2021 versus 2021, 2021 versus something like a 125? And also differences in COGS rates or manufacturing failure rates? Any kind of color around all the different programs would be helpful. Sure. Maybe I'll start with I don't know if I'm prepared to address all of your questions, but let me give it a go. So I think things like vein to vein times, etcetera, I think we're pretty locked down with both liso cel, ide cel because it's near term. But I think the next generation of compounds, that's an evolving and moving thing as we develop both the follow on compounds and our next T generation. What I would say, it's all moving in the right direction for the next generation in terms of turnaround time, COGS, all of those things. So we're acutely aware of that. And then I think from a manufacturing capacity, we're feeling very good about our launch capacity. We have some of you may know just a year or a couple of years ago, we set up S12 12 in Summit West as a fully fledged manufacturing capacity to supply IDACEL everywhere. We have a similar sister facility in Seattle in for liso cel. And then for the long term, we're looking to continue to expand our opportunity for capacity in the long term, both in the U. S. And outside of the U. S. So we feel very good about where we are in terms of manufacturing capacity. And Rupert, do you want to comment on the bivalent? Well, I mean the purpose of the 2 +1 is obviously you have 2 binding sites for the BCMA target. So that increases the avidity for the target and focuses the antibody on the targets that you actually want to destroy through T cell activation. That's what the CD3 component is for. It seems to be a very good format for these bispecific antibodies. And then there are other features of the molecule that optimize its half life and so on, which are in the FC portion. So it's an excellent design. I think we have time for one more question. I think that's Ryan. Hi, thank you for the excellent presentation. I've got 3, if I may. First one is really using practical. LIFO self submission, should we still expect it in 2019? And if you could talk a little bit about the basis we're expecting accelerated review for this submission? 2nd, if you can comment about NK Cells as a bispecific platform, there's been quite a bit of that here at ASH and we'll be interested in taking your tick. And last, maybe more of a bit of a commercial question. As you're launching luspatercept and liso cel, have you thought about the issue of narrowing the price gap between the U. S. Prices for oncology drugs and all U. S. Prices? Maybe we can start with the order of the questions. So as we had communicated right at the beginning of the year for liso cel submission, We are on track for submitting liso cel by the end of this year. And we still have a few more days to go in this month, so we are on track for that. 2nd will be NK cells. Maybe Rupert, do you want to take that? I mean, we definitely think that NK cell activation through antibody therapy, multispecific antibody therapy is a promising approach that's worthy of exploration. You're probably aware that we have a relationship with Dragonfly, which is a biotechnology company in Cambridge. We've already announced that we've taken the options on 2 of those molecules, which are moving along towards early development, and we have the option to take several other targets forward as well. So that's definitely something that we are actively engaged in and competitive in. Thanks. On the pricing, Ronny, you mentioned luspatercept and liso cel? Or did you mean liso cel and liso cel ex UF? Or take your is that okay? So I think one thing that's very, very important is to make sure that we set the price that delivers the value proposition for each of our assets. And that's always a principled approach we take. Then of course, as you go geographically around the world, U. S. Versus ex U. S, you have to deal with the different governments, etcetera, right? Again, we'll take the same principled approach of this is what we think the value is being delivered to society with our assets, and then we'll have those discussions, negotiations. Obviously, it's much earlier today ex U. S. Because we've got to get the approvals and we have to go through the reimbursement process. But we will take that same principled approach. Great. So I just want to thank everybody for taking the time. It's a little after 9 If you'd like to stick around and have a beverage, some of these the people that you might want to follow-up with will be here as well. Have a good rest of the meeting. Thank you. Thank you. Thank you.