Hi, everybody. My name's John Elicker. I lead corporate affairs and investor relations for Bristol. 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. Overall, more broadly, it's a very exciting time for the company. 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. No doubt, we've been on a journey since a little not quite a year ago. Many of you in this room have been on that journey with us. 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. If you look at a lot of the discussion about REVLIMID, we had two IPRs go in our favor, which is unusual. It's about a 50/50 shot. We had another settlement with Alvogen. 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. We're very excited to have an opportunity to compete in lung cancer, given the data that we received from 227 and 9LA. Not everything goes perfectly. We were disappointed, and we disagreed with the fact that we had to divest OTEZLA.
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 two weeks, we've initiated a $7 billion ASR, which was a $2 billion increase that we announced earlier in the year, and on Thursday afternoon, we announced a 10% dividend increase. Things are going really well for the company. 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. 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.
The important point, which you'll hear from Samit in a minute, is that's just the beginning. We have significant amount of data, milestones, and clinical readouts over the next 12- 24 months that we think positions the company very well for the future. With that, we'll get started. A couple housekeeping notes. Both Samit and Nadeem 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. If there are any detailed questions or after the meeting, if you want to catch up with anybody, specifically around the assets, those leaders are here. We're very fortunate to have Giovanni Caforio, our Chairman and CEO here, and Jerry Storch, a longtime Board Member of the company, is here as well.
That's the forward-looking statement, and I will turn it over to Samit. Thank you.
I hope this stage will stay the way it is. It's a little clunky. Well, thank you, John. Thank you for being with us today. I was thinking about today, and I was thinking about this ASH. 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 of 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. From that perspective, why are we excited? 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 CAR T from our perspective from BMS. These data are certainly very exciting, and we look forward to getting the submission and 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 CAR T perspective as well as a T-cell engager.
At the bottom, you see what is happening beyond the CAR-T cell space then with REBLOZYL, which is approved for beta thalassemia, and now looking for MDS, as John shared with you. CC-486 in acute myeloid leukemia, which is certainly going to be absolutely fabulous once we have submitted the data and hopefully will get the approval. 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. From an efficacy perspective, we have to look what population of the patients are we treating. These are patients that are very heavily pre-treated, number one.
Number two, 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 250 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%. Why is that important? In this disease, once you have a response, if you have a complete response, it's very important that that's durable.
What we see over here is that the 12-month mark, 65% of those patients are continuing to stay in complete response. 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. From a safety perspective, 58% of patients never had a cytokine release syndrome experience. Only 2% of the patients had grade 3, 4 cytokine release syndrome. The median time to onset is five days. 70% of the patients do not experience a neurological event. 10% of those patients have a grade 3, 4 event. Median time to onset is nine days. 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'll be important that when we actually do have this product out there for physicians to use, that 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 001. 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 large B-cell lymphoma in both transplant-eligible and transplant-ineligible patients.
Just earlier today, there was data also in CLL in the third-line plus setting. The new studies that are starting will address other indications such as follicular lymphoma and also looking at combinations. 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. 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 six years, and 50%-60% of patients are achieving the complete response. As relapses occur, and especially third or fourth 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 four months or less. 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. 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 CAR T, somebody with T-cell engagers, maybe with ADCs. We are fortunate that we have all these modalities available. In the CAR T-cell space, of course, you've seen some of the data, and I'll talk a little bit more about this with bb2121. There are early phase studies that are ongoing with JCARH125 as well as with 21217, and you've seen some of that data as well.
We are excited to see the T-cell engagers. Of course, the ADCs are early in development. While these data were not presented for ide-cel bb2121, it's important that I highlight a few features that were presented in the press release. Number one, these patients are very heavily pretreated, meaning they were triple refractory to proteasome inhibitor, IMiDs, as well as the CD38 antibodies. 94% of them were refractory to the CD38 antibody. Number two, patients had to have a progression of disease and get into the study within 60 days of progression. This is a very stringent criteria as defined by the guidelines.
Third, 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. 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 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.
There's the CD3 portion, which attracts the T-cells and activates them for the cell kill. These data are early, but they're 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. It is important that new ways of attacking BCMA and attacking myeloma are available because these data are quite interesting, where there are 13 responders, especially there is a dose relationship. You see at the higher dose, more responses are occurring, more complete responses are occurring, and these are MRD negative. Of course, we are 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 rare instance of grade 3 or higher cytokine release syndrome. 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 trials in the short term. Switching gears one more time, looking at REBLOZYL. REBLOZYL is the first 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 a diseases. 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. One of the actual side effects most commonly seen is anemia, and you have to tinker 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. 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. The REBLOZYL is being explored in the first line setting, patients with myelodysplastic syndrome, low grade, who have not yet received ESAs or erythrocyte-stimulating agents. We are hopeful that in the late 2021, early 2022, we have that data, and we can expand that indication as well. As I said, myelofibrosis is the next one that we're going to be looking at.
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, followed by consolidation. If those patients then get into a CR, the only way to potentially cure a disease and take them for a longer term is through transplant, which is allogeneic. Many of these patients are not eligible for that. At the current time, there are no approved therapy for maintenance setting for these patients. Once they are in CR, 60%-70% of these patients will have a recurrence of disease within 24 months. What did we do? CC-486 is an oral 5-azacitidine.
The patients who had achieved a CR or CRI, meaning incomplete recovery of the bone marrow, were randomized to receive CC-486 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. 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. These data are very encouraging.
In talking to many a 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. Our job doesn't stop there. If we look forward, 2020, 2021, these are very busy years for us. There are more data evolving in hematology as well as in immunology and cardiovascular diseases. Many of these trials will start to read out, we have a lot of work to do to take these forward and accelerate our delivery of these promising medicines to the patients. There's a full pipeline in the oncology space as well.
We have a lot of data readouts for OPDIVO and YERVOY in 2020, and we look forward to sharing those data with you also as they emerge. 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 REBLOZYL, as well as with CC-486. Our hope is that we can move these forward very quickly so that patients can receive them to transform their lives. Thank you. I will pass it on to Nadeem 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 Samit said. 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're seeing here with all of our assets. It really continues to position ourselves as the new BMS, as a leader in hematology across all of the major hematologic diseases. 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 first-in-class.
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 Samit, for 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. We just saw the data. Deep and durable responses, end-stage myeloma, heavily pre-treated patients. Every single patient that entered that study was a refractory patient. That's the context for the results we're seeing with ide-cel and across all of these assets. CAR T, since the initial approval of the first CD19 CAR T, has been a challenging marketplace. 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 inpatient 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. Most of the use today is in end-stage disease. 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. We also think liso-cel and the clinical profile associated with it would allow us to disrupt the site of care for these therapies. We have the opportunity for liso-cel to be administered in the outpatient setting.
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. You're going from the inpatient DRG setting to the hospital outpatient prospective payment system or HOPPS, which is very similar to Part B. There, the reimbursement is very different. 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. 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. Wherever CAR T is delivered, we are able to provide first-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. We're actively engaged with those lymphoma treaters already, so that gives us a head start. 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. 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. 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. 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. Some of these indications, we will either be best in class or first in class.
You heard from Samit today about the data that were presented in the third-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. You also saw from Samit, beyond the third-line setting, we have a deep and broad development program to continue to move liso-cel up earlier in the treatment sequence. Switching gears to REBLOZYL. REBLOZYL 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 REBLOZYL, so that's another long-term opportunity. The opportunity I'm most excited about is the near-term opportunity for REBLOZYL 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. 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. Patients who 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.
Patients that are on ESAs in the U.S. today tend to be treated for longer than they should, beyond the derivement of clinical benefit, because again, there aren't that many treatment options. That's why we think REBLOZYL offers a significant clinical opportunity and commercial opportunity in this patient segment. We've had the opportunity to share the profile of REBLOZYL 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 REBLOZYL and continue to receive benefit with continued treatment, is that at an individual patient level, many patients experience multiple episodes of transfusion independence. The primary endpoint for the study was achieving one episode of transfusion independence. As we follow these patients up with continued REBLOZYL treatment, they were able to experience multiple episodes of transfusion independence.
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. They liked that aspect of the profile of REBLOZYL. And of course, the safety profile we feel is very favorable. When you combine the efficacy and the safety, we're receiving very good feedback. That's why I'm so excited about the near-term opportunity that we have with MDS beyond beta thalassemia. As we think about the longer term aspects, commercially, of REBLOZYL, as Samit 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 COMMANDS study, which is actively recruiting, which will move REBLOZYL up into that frontline treatment setting, significantly increasing the addressable patient population.
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, oral presentation for the use of REBLOZYL in myelofibrosis. We have the pivotal study that Samit mentioned, the independent study that will kick off next year. The other very exciting element of this is myelofibrosis is now the third distinct disease in which we've seen a profound impact on anemia of this agent. The life cycle management opportunity with other chronic anemias is being explored by our global drug development group. We're very excited about the opportunity that REBLOZYL presents both today and in the future. Think about this continued treatment opportunity with REBLOZYL.
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. CC-486 kind of popped out of nowhere for us and for you. Let me talk a little bit about CC-486. AML is a terrible disease. Even in the frontline setting, the survival for newly diagnosed patients at five years is about 10%-15%. What you'll often find with upfront intensive chemotherapy, patients do go into complete remission. In fact, two-thirds of them do. 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. 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. The unmet need in AML for a maintenance treatment specifically is very high. With CC-486, 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. 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.
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 physicians who are treating patients with AML. The other thing with CC-486, 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, survival is really important. We've seen a 10-month improvement on 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. Just as important for the maintenance setting, having an oral treatment is really important. CC-486 potentially will be the first drug approved for first-line AML maintenance in the U.S.
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 BMS 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 first-in-class or best-in-class agents. Again, a unique opportunity for us to drive these launches. The indications for each of these assets represent just the beginning of both the clinical opportunity, but also the commercial 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. Behind these assets and the life cycle management of each of these assets, we also have a very rich and early pipeline. For example, CC-93269, 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. From a commercial positioning perspective, the in-line business is going very well, and we're 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. 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.
Okay.
Happy to take your questions. Elizabeth, can we go to Terence?
Thanks. Terence Flynn, Goldman Sachs. Maybe just two for me. Nadeem, 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 IMiD space? Then the follow-up part to that is, again, 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. Let me just say, thanks for the question, Terence. 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 wins." We always have felt that there's room in the market for a BCMA CAR T, a BCMA T-cell engager. Of course, the ADC is much earlier in development. As we think about the patient segments that we can address with our BCMA multimodality approach, there's various opportunities and it's multifactorial. It can depend on the patient characteristics, it can depend on the site of care. Just to give you a very simple example, BCMA CAR T is a one-time infusion. 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. We think that by having this multimodality approach, we'll be able to address every patient segment. That's how we're thinking about it, Terence. What was the first part of your question?
Competitive landscape.
Sure. Sure. Yeah. A couple of things I'd say about that. With ide-cel, and touch wood, we're still a first-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. Again, I will point out that as you start comparing data sets, this is a different patient population in that almost 100% were daratumumab refractory, almost 90% were triple refractory, and every single patient was refractory from their last treatment regimen.
Within 60.
Within, yes, either the standard treatment, either through treatment they were refractory or they relapsed within 60 days. Samit showed you 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 for second line. We have plans for frontline also. 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. The last thing I'll say, since you mentioned IMiD, we have something that nobody else has, and that's the ability to combine BCMA modalities with the new CELMoDs . I think there we can push the efficacy bar even higher.
Great. Can we go, maybe Seamus over there, Tim?
Thanks for the question. I think you guys have covered a lot of the combination discussions, but as we think about liso-cel and CD19, so moving outside of myeloma, the JCAR017.
Ide-cel.
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 JCAR017 is genuinely safer, but at what point do you hit that threshold? 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. To get through the approval process and then to subsequently actually get effective cells into the patients. Those are two 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 JCAR017, when you target a patient with JCAR017 therapy and then actually achieve a successful outcome in terms of actually getting an effective product into the patients?
Do you want to start with bridging therapy?
I'll start off with the bridging therapy part. I think if you think about the real world, how these patients are treated, many of these are aggressive lymphomas. You can have the leukapheresis 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. These are the patients who are, again, third, fourth line patients who do require management of their disease. 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 their PET scan is still positive for most of these patients.
They are able to get the therapy, and then we see 73% overall response and 53% CRs. From a real-world dynamic perspective, having the ability to deliver that bridging chemotherapy is very important. 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 in terms of manufacturing, we're certainly very well aware that we want to continue to decrease the turnaround time. 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 with or given to the patients. Those are very important specifics for this product as compared to what others are doing in terms of supplying it in a cryopreserved bag, et cetera. There was a third question.
Let me address the outpatient one first.
Yeah, exactly.
There's a couple of things, I think. Again, I do think the transition, again, in the academic centers from inpatient to outpatient, I think is greatly underappreciated. Today, a lot of the agents that are administered in these academic centers, whether it's rituximab or something else, is usually done in the hospital outpatient setting. Once you go into the hospital outpatient setting, you're outside of the 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. I think that is a game changer, to be able to move liso-cel, even in those academic centers, into the outpatient setting. As we think about beyond the hospital, because I think that was your specific question.
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? The discussions we've been having are with the big oncology practice groups. What they tell us is they want to be involved in CAR-T. They're not involved in CAR-T currently. You could envisage an environment where I'll use US 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. For example, this wouldn't be where you hit every single clinic in one of those networks.
There may be two or three that have the facilities to do that. What they'll do is they'll refer their patients within their network so they don't have to leave their system. That's why we think there's another tremendous opportunity with the profile of liso-cel in that setting specifically.
Great. Maybe Chris.
Thank you. Chris Schott, JP Morgan. Just building on the outpatient opportunity, can you just help us a little bit as we try to evaluate the ramp of this product? How quickly do you think you can get into that outpatient setting? Is this a multi-year process to really get physicians comfortable, or you think that the example you just cited, this is something that could happen sooner than that?
Sure.
The second question was coming back to the T-cell engager on 269. What are the next steps as we think about development? If I look at this asset, it seems like all else equal, this could be a much easier product from a commercialization standpoint. Are there approaches you can take here to even further accelerate development beyond what we maybe saw with some of the CAR Ts that, just to really push us forward quickly? Just any color you can provide on that would be appreciated.
Do 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. 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. We need to have those discussions. Kristen and her team, they are very well prepared in terms of providing the data that will support the start of that trial. Acceleration is certainly in our mind as well. 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 CELMoDs and others that we will bring along as well. Certainly our intention is to accelerate that.
I'll take your other question, Chris. I think what we want to make sure is we're doing this in a very responsible way. 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? 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." I think we're going to, of course, start with those settings where there's CAR T experience. 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. 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. That's how we're thinking about it.
Maybe I can just add one thing.
Go ahead.
Just as a clarification. What does outpatient setting really mean? At the current time, when patients are receiving CAR T-cell therapy, they're admitted to the hospital and observed for 48 - 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. That's very important that it's not like 1,500 mi away the patient lives, they get the infusion, and they can go home. It is not that intention, at least.
Yeah. 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. I think even with the big oncology networks out in the community, how they've been thinking about it, I gave you the example of this 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 facilities to be able to deal with that. I think for them, the key is the infusion at some else, because there's nothing magic about the infusion. 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. 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 liso-cel in the outpatient setting.
Were never admitted to the hospital, 26% of them, I think.
We go to Geoff. Tim.
Geoff Meacham, Bank of America. Just have a couple for Samit and then one quick one for Nadeem. When you think about your different options for BCMA, obviously moving to first or second line myeloma is a massive opportunity, and I'm not sure how much progress Celgene made in this past year on that front. 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? For Nadeem, for liso-cel, the original pitch was more outpatient. I hate 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. It's kind of harder to make a commercial argument when the clinicals don't necessarily support that.
It's actually more than YESCARTA, but it's still not an overwhelming percentage of that. Can you just address that?
Yeah, let me start that first, Geoff. Thanks for your question, insightful ones as always. I think when TRANSCEND study was started at the beginning, it wasn't set up to be a specific outpatient study, whereas OUTREACH was. 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. 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, Geoff, was 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, et cetera, 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. I think they're the clinicals, Geoff, that will allow us to continue to drive the profile.
I think from the BCMA perspective, first of all, we are in quite an interesting place because of the modalities that are available. BCMA CAR-T, T-cell engagers, ADCs, CELMoDs. Then, of course, the already in-line products, which is the POMALYST, REVLIMID, as well as we think about EMPLICITI. We have all of the agents available. We just have read out the ide-cel study. We're now looking at that, and we are in the process of collating the data so that we can file as soon as possible. We are building the plans, as Nadeem already mentioned. The study is already ongoing in the prior line setting, the third-line setting. This is going to be very important because this is what the FDA is going to ask us to do anyway.
As we think about that, we are also looking at how we can move it to the second line. What would be the right population to move into? One could think about doing it in all-comer population, but then the events are going to come who knows when, because there are the patients with smoldering myeloma or MGUS that could also get into that study. We have to think carefully about that. Those are the kinds of plans that we are thinking about now. Then we have to wait, as was being mentioned earlier, for the T-cell engagers.
It's very early days, so we can't say that we'll go with the t-cell engager 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. Based on that, we can then decide whether we should go with the CAR T-cell in one place, t-cell engagers in the other, or we should even go with the CELMoD in terms of combination therapies, maintenance therapies, and so on. I can't say that we have the plan all worked out today. We have to continue to evolve with the evolving data.
One scenario you could see, Geoff, from a positioning perspective, and we spoke a little bit about earlier T-cell engager versus the CAR T, for example. If the ideal is to have, in a specific patient segment, a one-time treatment, you could 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. Again, the data will emerge, but we think having both puts us in a much better position and that both can coexist together. Yeah.
Matt? Right here, Elizabeth.
Thanks. Matt Phipps, 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? My question then being, do you think that there is ability to treat patients with both, or would treating with one almost preclude the ability to treat with the other? 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. 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.
Maybe Kristen, do you want to comment on the first one about one versus the other, or sequencing of the two?
Is there a microphone?
The data on BCMA expression at time of progression on all of these products is still evolving. 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. If the target is still expressed, then one could envision treating with a different BCMA targeting modality after progression on one.
Thank you.
Andrew?
It's Andrew Baum of 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. Perhaps you could talk to, given, and I appreciate very limited data that's in the public domain, how you see that fitting into the treatment armamentarium, 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 commentary is informed by data in terms of their level of excitement. That'd be the first question. The second question is there was some data presented with one of your CAR T's at this conference with a BCMA gamma secretase inhibitor.
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. Finally, could you talk about whether you're interested in developing a Prodigy-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 two to somebody else. 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. 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. I think with the caveats of comparing real studies, of course, but from a pure efficacy perspective, I think you're still seeing ide-cel as a more potent antibody.
I think with the GSK ADC, investigators trying to get used to the corneal toxicity that they're seeing, which may be okay in a later-line setting, but once you start going early- and newly-diagnosing, that could be a little bit challenging. I think 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 ide-cel and the T-cell engager that seem to be more potent when you compare like patient populations.
Rup, you to-
Hi, it's Rupert Vessey here, research and early development. With regards to your question on the GSI. 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. We do think that this is an approach that's well worth testing, and we'll be looking at incorporating that into future clinical trials with BCMA agents, particularly during the induction phase, where it could be potentially quite useful, I think.
We go to Umar.
I think there was a third question, the closed loop.
Yeah. The Prodigy closed loop. 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. Absolutely, we're active in all aspects of CAR T improvement.
Thanks. Thanks, John. I have three, if I may. Samit, 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. I'd love to hear your take on that, number one. Secondly, on the BCMA bispecific, my question's on durability, especially as it relates to, I think cycle seven 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? 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? How do you see that? Which one is the preferred option?
Yeah. Maybe, Umar, I'll take your last question first. 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. 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. Which one will be the best? Obviously, we need much more data to determine that, Umar. Of course, we firmly believe that our strategy is now being executed where we thought having the ability to bring multiple BCMA offerings for multiple patient segments will play out and will play out well.
Since we are going in the reverse order, maybe Kristen, you want to comment on the PK characteristics? Okay, Mike.
As we move to the-
Oh, just for the mic. Mike?
Mike Burgess from Early Development. As we moved to cycle 6, we went to a Q4W dosing. At that period of time, from the data presented, we only had one patient progress. The exposures tend to increase over the first cycle. Due to target-mediated drug disposition, you have about sevenfold more exposure by the end of cycle 1, and then that persists. The 10-mg dose, we think is still in an active range, even in the Q4W dosing.
For your first question, I think the Q&A session after that presentation probably answered your question well, because there was a lot that could be done with the 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. I'll just leave it at that. Sorry.
On the information related to predictors of CART efficacy and safety, I do think that it's important that people here recognize that in BMS's hands, there's data from more than 1,000 patients treated with different CARTs. 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. We have a team of machine learning scientists absolutely dedicated to teasing out the best and most important features for next generation CART, 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, and we're in a very strong position with respect to that.
Thank you.
Navin, do you have a question?
Hi. Thanks. Navin Jacob, UBS. Two questions, if I may. Very interesting data from your bispecific, obviously. If you could help us understand the exact benefit of the two plus one format binding to BCMA, please. How exactly does that add to the efficacy? 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? Some of the differences between all the different programs, the vein-to-vein time for 2121 versus 21217, versus something like a 125. 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 going to be able to address all of your questions, but let me give it a go. I think things like vein-to-vein times, et cetera, I think we're pretty locked down with both liso-cel, ide-cel because it's near term. 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. We're acutely aware of that. I think from a manufacturing capacity, we're feeling very good about our launch capacity.
Some of you may know, just a year or a couple of years ago, we set up S12 in Summit West as a fully fledged manufacturing capacity to supply ide-cel everywhere. We have a similar sister facility in Seattle for liso-cel. 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. We feel very good about where we are in terms of manufacturing capacity.
Rupert, do you want to comment on the bivalent?
Well, the purpose of the two plus one is obviously you have two 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. There are other features of the molecule that optimize its half-life and so on, which are in the Fc portion. It's an excellent design.
I think we have time for one more question. I think that's Ronnie.
Hi. Thank you for the excellent presentation. I got three, if I may. First one is really easy and practical. liso-cel submission, should we still expect it in 2019? If you could talk a little bit about the basis for expecting accelerated review for this submission. Second, 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 a take. Last, maybe more of a bit of a commercial question. As you're launching with liso-cel, have you thought about the issue of narrowing the price gap between the U.S. prices on oncology drugs and all U.S. prices?
Okay. Maybe we can start with the order of questions.
Sure.
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. We still have a few more days to go in this month. We are on track for that. Second would be NK cells. Maybe, Rupert, you want to take that?
We definitely think that NK cell activation through antibody therapy, multi-specific antibody therapy, is a promising approach that's worthy of exploration. You're probably aware that we have a relationship with Dragonfly Therapeutics, which is a biotechnology company in Cambridge. We've already announced that we've taken the options on two of those molecules, which are moving along towards early development, and we have the option to take several other targets forward as well. That's definitely something that we're actively engaged in and competitive in. Thanks.
On the pricing, Ronnie, you mentioned luspatercept and liso-cel, or did you mean ide-cel and liso-cel, ex-U.S.? Take your pick. Is that. Okay? I think one thing that's 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. Of course, as you go geographically around the world, U.S. versus ex-U.S., you have to deal with the different governments, et cetera, 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 and 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. We will take that same principled approach.
Great. Just want to thank everybody for taking the time. It's a little after 9:00 AM . If you'd like to stick around and have a beverage, some of 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.