Well, good morning, everybody. You're very welcome to the Bristol Myers Squibb investor event. I'm Tim Power from Investor Relations here at Bristol, and I just wanna say it's great to see people in person for the first time in a long time. Welcome to you who are here. Welcome to everybody who's joining us online as well. Let me just move forward, and this is our legal slide. Let me take a minute and just explain what we're gonna do this morning. You're gonna hear some presentations today from our Board Chair and Chief Executive, Giovanni Caforio. You'll hear from Rupert Vessey, who runs research and early development here at BMS, and from Samit Hirawat, who runs late-stage development. We'll take a 10-minute break. Strictly 10-minute break.
Welcome back, and you'll hear from Christopher Boerner, our Chief Commercialization Officer, and then from our CFO, David Elkins, and then Giovanni will close the meeting to give us plenty of time for Q&A at the end. We plan to finish the meeting around noon so we can go get lunch together outside. I just wanna say again, really excited to be here in person with so many of you, and we've a lot to cover. With that, let me hand over to Giovanni to start the meeting.
Thank you, Tim. Good morning, everyone, and welcome. It's really a pleasure to see so many of you live in the meeting room again after almost two years since the last R&D days we had. I also would like to welcome those of you that are attending through the webcast. Let me just say that during the last two years, a lot has happened, and we've made extraordinary progress at Bristol Myers Squibb, advancing our pipeline and advancing our company. We look forward to sharing with you the progress we've made with our pipeline and also sharing our enthusiasm for the future. You've seen this slide before.
It describes our strategy to combine the innovation of a biotech company with the scale, the capabilities, the resources of a larger pharma player, and the strategy remains very relevant for us. Over the last two years, we've made progress across all of these four fronts. In terms of the breadth and depth of the pipeline, obviously you will hear a lot about that today, strengthening our external collaborations. Given our financial strength and flexibility, we've been able to continue to invest in our business, invest in our internal pipeline, and continue to bring external innovation to the company through business development. What I am most proud of is that we have some of the best talent in the industry that work at Bristol-Myers Squibb with a real passion, delivering on all of our opportunities.
Many of our members of the R&D organization and commercial team are here today. They look forward to participating in the Q&A and meeting with all of you during the lunch break. It is important to remember the journey that BMS has been on during this long period of time. In fact, in the early 2000s, we led the industry to a new model. We decided to focus 100% on innovation and transformative medicines that address areas of high unmet medical need, and this was a very successful transformation. At the beginning of the last decade, we continued to sharpen our focus. We focused on specialty care medicines, and that resulted in the launch of important medicines like Orencia. We pioneered in IO through Yervoy and our flagship medicine, Opdivo.
Obviously, we were successful renewing our leadership in cardiovascular medicine through the launch and commercialization of Eliquis, which became the important product it is today. The strength of our commercial organization and our ability to execute in the marketplace really enabled these medicines to be successful, and they enabled the company to be successful in renewing our portfolio during and through multiple cycles of loss of exclusivity. Over the last two years, we've made progress continuing to broaden and deepen our opportunities, diversify the company through the acquisition of Celgene and MyoKardia, and in many ways, we've started a new chapter. We have strengthened, we have deepened our innovation engine. We're very proud of that. Our pipeline has grown. We've built a stronger and more diversified company that is well-positioned to renew its portfolio once again.
Our commercial strength will be critical again going forward as we do just that. When we look at the R&D organization today, we've actually doubled the size of our pipeline. We are investing in creating leading scientific platforms. When you look at protein homeostasis, we have five CELMoDs in the clinic today. Looking at cell therapy, we're really proud to have been able to launch two treatments in the last 12 months alone. We have strengthened our collaborations with biotech and with academia, and that will be critical for us to sustain a higher volume of innovative medicines through the development cycle into the marketplace in the future. You'll hear more about our R&D efforts from Rupert and Samit today.
I know that while the focus on the investment community tends to be on late-stage opportunities, I think it is important to reflect on the strength of our innovation engine because that will be critical to ensure the long-term and sustainable growth of the company. Turning to this slide now, you can see the strong company we are today. We have leading-in-line medicines across all four therapeutic areas, and that provides a strong foundation for the future. We are launching nine innovative medicines in a short period of time, which is an unprecedented opportunity. We like the profiles of these products, and we believe strongly in their potential opportunity. Over the last two years, the midstage pipeline has also continued to advance. We have a number of high-potential assets that are emerging, and we will cover some of them today with a focus on milvexian and iberdomide.
We will also discuss our growing portfolio of early assets. Finally, thanks to our performance, we have tremendous financial strength and flexibility, and we will be able to invest in innovation as well as the commercialization of new medicines. Now, as we've created a leading company, a new company with a broader impact on innovation and science, we're also focusing on the broader responsibilities we have in the community as a global player, spanning from our new commitments to the environment, to our decision to lead in the areas of health equity, diversity, and inclusion. We've made progress with the diversity of our workforce and our suppliers.
I'm particularly proud of the efforts where we are leading the industry in increasing the diversity in clinical trials to ensure that the BMS clinical trials patients will look as diverse as the population of patients that will need the drug. Finally, we continue to hold ourselves to very high standards in terms of corporate governance. Now, let me turn to a question that I know is of critical importance for investors. You've told us that you are focused on how we offset the impact of patent expiries for some of our key brands, including and beginning with the loss of exclusivity of Revlimid that we acquired with Celgene. Well, let me be very clear that I am confident that we can address LOE headwinds.
I'm gonna walk you through more detail on this in the next few slides, but let me just take a moment to reflect on the multiple drivers of growth we have as a company. First of all, I have great potential in the new product portfolio that we will describe today. Second, our pipeline is advancing, and our financial strength gives us the opportunity to complement our internal assets with disciplined business development. I'm confident of this because I see the strength of execution in the company, demonstrated by our ability to deliver on virtually all key milestones in the last two years. Now, let's talk about the period when we lose exclusivity for Revlimid first. This is a slide that you've seen before, and I showed it at the beginning of the year. I'm providing some additional and important information.
It describes how we at BMS expect to deliver during this time frame. Let me point out a few things. First, we do expect a significant headwind from the loss of exclusivity of Revlimid, coupled with Abraxane, Sprycel, and later on, Pomalyst. As we've consistently said from the beginning, we see this as somewhat greater than reflected in external analysis. We're confident in the growth of Eliquis and Opdivo during this period, particularly as Opdivo has returned to growth and the positive flow of news from the clinical program continue. We are confident in the significant potential of our new product portfolio, which we believe can generate $10 billion-$13 billion in sales by 2025. Overall, we remain fully committed to growth in this period.
We've also heard your concerns that a lot of our current revenue is concentrated in a small number of large medicines that are facing patent expiration. Well, in fact, when you look at the acquisition of Celgene and MyoKardia, diversifying our business was a key driver of those decisions. On this slide, you can see how we have made great progress with diversifying our business. In fact, by 2025, our growing and diverse portfolio of new products will constitute about a quarter of the business. Obviously, it is expected to continue to grow much faster than the total company. Importantly, our exposure to top LOE brands is expected to come down from 70% last year to only about 50% by 2025.
That will continue to be a smaller part of our total business going forward and before they lose exclusivity. Let me also say this is obviously a risk-adjusted view, which does not give us full credit for the optionality that exists in our pipeline. In summary, when you look at 2025 and our business in 2025, we will have a very young portfolio growing rapidly to enable us to successfully manage the loss of exclusivity of Eliquis and Opdivo towards the end of the decade. Central to our strategy is the potential of the new product portfolio. I will not spend a lot of time on this because Chris, during his presentation, will go in detail into every one of our key brands.
We view this portfolio as having significant potential. In excess of $25 billion of revenue potential in 2029 if our expansion opportunities continue to pan out over time. These are all first-in-class, best-in-class assets, four of which have revenue potential of at least $4 billion, and two more having at least $3 billion in revenue potential by 2029. Let me say that given what we hear from physicians, our perspective about their strength has actually grown significantly since we last got together. Beyond the products that we're launching today, our pipeline has continued to advance and provides additional important levers for our future growth. This quarter, at two important conferences, we are presenting and discussing important data on two of the key assets in particular. Milvexian, you've seen some first data release from yesterday, and iberdomide.
We can discuss, and we will discuss them today. Overall, we feel that the midstage pipeline is progressing on all fronts. More broadly, what you can see here is that our pipeline is focused on addressing diseases with large and expanding commercial potential. As I mentioned, we are really excited about the potential of our pipeline. I'm looking forward to Rupert and Samit updating you on our great progress. Our pipeline is strong, is deep and broad, and we have the resources and the expertise to develop it. Beyond our internal opportunities, I want to be very clear, we continue to view business development as a priority. David will describe our strategy for business development in more detail, but let me give you a few important points.
First, we believe we have a real opportunity to deploy capital to further strengthen the long-term value of the company, and we are focused on executing deals that can accomplish that. Our focus today is to continue to execute science-based early deals that strengthen our research portfolio, and focus our M&A effort on both small and mid-size acquisitions like MyoKardia, that strengthen our R&D engine and further provide opportunities for long-term growth of our portfolio. Now, given our progress with addressing the Revlimid LOE through the period between now and 2025, obviously and naturally, the focus has shifted to the second half of the decade. Here, let me be very clear, and let me start by saying that our view is very different from what is reflected in consensus. We see 2029 sales higher than 2025 sales.
The drivers for portfolio renewal during this period are similar to the 2020 to 2025 period, but the opportunities are just much broader. They include realizing the full potential of the new product portfolio, including their significant expansion into new opportunities. There is an important role for the mid stage pipeline, starting with milvexian and iberdomide. The pipeline is rich, and there is a pipeline within most assets. We mention here multiple paths to growth because we realize not all of the opportunities may materialize, but we have significant optionality in our pipeline, and we are committed to growth under multiple scenarios. Today, we wanna share our belief and our excitement in our ability to execute again the renewal of our portfolio, like we've done as a company consistently in the past.
Let me tell you that we are focused on the most important milestones in order to accomplish this. There are multiple, but I've listed here five key milestones that we need to deliver over the next 18-24 months. Successfully launching mavacamten next year. For deucravacitinib, establish its differentiated mechanism of action and position it as the oral of choice in psoriasis. Enable the potential of Zeposia ulcerative colitis by executing our plan to broaden access. Realizing the full potential of Reblozyl, which requires us to achieve a positive result for the first-line COMMANDS trial. We need to establish a leading cell therapy business built around our best-in-class CD19 agent, Breyanzi. My management team and I will be very focused on ensuring that we do what's required to accomplish on these milestones. There is still...
Well, before I close, let me say that I know there is still a lot of discussion in Washington about healthcare reform, and I know this is top of mind for you. Let me just give you my perspective. There is still a lot of uncertainty, and obviously, as you know, key elements of legislation are unclear. We see some promising elements, specifically regarding the redesign of the Part D benefit and patient affordability. This is something the industry has advocated for a long period of time, and obviously, we're very supportive. We're seeing some concerning proposals, though, regarding government price setting. This is not the right way to support innovation. Having said that, let me say our portfolio is broad and diversified. That includes reimbursement mechanism and geography, and we are continuing to invest in innovation and confident about our future.
Now let me give you a quick overview of what you will hear about today. You will hear from Rupert about the fact that we have strengthened our innovation engine internally and externally, and about some emerging early-stage assets that are starting to deliver really exciting data. Samit will walk you through some of the exciting progress we're making with our late-stage pipeline, including with milvexian and our hematology pipeline. Chris will tell you why we have strong conviction in the potential of our new product portfolio. David will provide you with some more details around our financials and our path to growth during the LOE period. I hope that when we finish today, you'll share my enthusiasm for the future opportunities that we see for our company.
Now with that, let me turn it over to Rupert to talk to you about our R&D engine and the level of excitement that we have for our early pipeline. Thank you. Rupert?
Thank you, Giovanni. Great. It's good to be here. Thanks for the introduction, Giovanni, and I'm gonna talk to you about our innovation engine and also some of the key emerging programs in early development. Just to start, I'd like to review with you some of the key components of our R&D strategic foundation. We can't do anything without great talent, and I'm delighted to say that we have been very successful over the last couple of years in adding terrific talent right across our organization, and in particular to our leadership team. Many of those folks are here today and will be available after we finish the presentations. Portfolio execution. Giovanni mentioned this. It's obviously critical. I think we've demonstrated over the last couple of years great portfolio execution.
You're gonna hear more of that from Samit and some of the key things that we have in front of us that we will keep our eye on. I'm gonna talk to you a little bit more about our innovative R&D platforms just to show you what is behind the next wave of products, and I'm also going to show you how we've been assiduously building up our external partnership network to complement what we focus on with our internal resources. I'll also say a word or two about the emergence of digital innovation, artificial intelligence, and machine learning as it's applied to research and development at BMS. This is just to remind you of how our R&D organization is set up.
My organization, Research and Early Development, is responsible for identifying the next wave of innovation, selecting drug targets, identifying the right platforms, bringing forward the best-in-class and first-in-class molecules, de-risking them, and then demonstrating that they have some evidence of clinical activity that drives large-scale investment in late phase development. Samit Hirawat leads Global Drug Development, where the assets are fully developed right through life cycle management to create the medicines for our patients. Over the last couple of years, we've seen dramatic evolution of our portfolio. First, you can see here the diversification of therapeutic areas. Look at the expansion of hematology assets. Look at the growth in immunology and cardiovascular with the recent acquisition of MyoKardia, and also the beginning of a new area in neuroscience. Our early and mid-stage pipeline has doubled in size. We can manage this size.
We've got the organization and the skill sets, but it gives us tremendous optionality for generating the next round of innovative medicines. We've also broadened our modality approaches so that we can tackle the most important biological questions for the diseases that we're interested in. Company has always been great at small molecule drug discovery and had a very strong biotherapeutics organization. We've added to the small molecules through peptide therapeutics, and very importantly, our protein homeostasis platform, which I will describe in more detail. Our biologic capabilities have expanded to embrace more complexity, and we've added cell therapy. Furthermore, through our extended network of outside collaborations, we're also tapping into new areas and new modalities beyond those that are already up and running in our company. Just to talk about a few of these in a little more detail.
BMS has been a great medicinal chemistry organization, and you're gonna hear about a couple of molecules today from Samit that exemplify that. Deucravacitinib, a first-in-class TYK2 inhibitor, a very highly genetically validated drug target with a completely novel mode of action, allosteric binding to TYK2, totally different from active site inhibitors that target other members of the JAK family. You're gonna hear about milvexian, another really important genetic validated target, Factor XIa, and another first-in-class molecule with strong data from the BMS small molecule organization. In terms of biotherapeutics, we've moved well beyond monoclonal antibodies.
You can see here a range of different types of approaches of complex biotherapeutics that allow us to engage the immune system for anticancer activity, bring together two targets in bispecifics, and beyond that, site-specific antibody drug conjugates to bring in new payloads and open up the therapeutic index for this class of agents. Protein homeostasis, I'll go into more detail on the next slide, but this is a key plank of our drug discovery capability, allowing us to go after a wide range of previously inaccessible drug targets that need to be degraded rather than inhibited for therapeutic benefit. Of course, cell therapy, where we have already two approved products, and as you'll hear in subsequent slides, a wide range of approaches to take us to the next generation of this extremely promising and effective modality.
Protein homeostasis, what is this all about? This is built off our understanding, our unraveling of the mechanism of action of the original IMiD drugs, Revlimid and pomalidomide. What was discovered was that these agents could bind to an E3 ligase called Cereblon. The molecules act as what we call a molecular glue, so they can attract in specific protein substrates and then have them tagged for destruction and then subsequent therapeutic benefit. The understanding of this mechanism of action has thrown open a whole new field of drug discovery, and you can see that not only through our pipeline, but through the investments that are being made by others in biotechnology companies. This is an exploding area of great importance. We now have five CELMoDs in clinical development, which is far more than any other pharmaceutical company.
We are the leaders in this field, and we're targeting a range of different substrates and different diseases. In discovery, we have many more to follow, particularly in the field of solid tumor. We've also been able to take this know-how and design other Cereblon-targeting drugs, heterobifunctional molecules or ligand-directed degraders, where we can grab other proteins in the cell and bring them together with Cereblon without the necessity for the molecular glue structural features. That opens up the undruggable universe even further. We have a lead compound in the clinic degrading the androgen receptor. We continue to invest in this space, looking for other stars in the galaxy of protein homeostasis, other E3 ligases that are tissue specific and also intrinsic degraders, and we've been building our team internally and adding additional collaborations externally.
This is a really important area for people to pay attention to. In terms of cell therapies, we are investing in a wide range of next-generation technologies through a set of selected partners, some of which you can see listed on this slide. I'll just take you through a few of the approaches here. We know now that cell therapy works very well in certain hematologic malignancies, but there's still room to improve. Can we deepen the responses? Can we get longer duration of response? One approach we're going to take to this is by creating dual targeting CAR cells. You will see at ASH a presentation by our colleagues at MSKCC of a trial that we supported to generate proof of concept for GPRC5D as a new cell therapy target in myeloma.
The data are very promising in a small dataset, and this of course leads us to a pathway where we could combine BCMA and GPRC5D into a single cell therapy and further improve responses in myeloma patients who need these therapies. Beyond hematologic malignancies, we're of course intently focused on getting cell therapy into solid tumors. There are some challenges with targeting solid tumors. One is antigen selection. There aren't a set of cell surface privileged antigens in the same way that there are for hematologic malignancies. So you need to look at intracellular antigens, reactivated oncofetal proteins, for example, that we know occur in these tumors. They are processed and presented on the surface of the tumor cells in the context of MHC molecules, and the recognition element for the immune system is the T-cell receptor pair.
We've been working with our colleagues at Immatics to identify antigen and T-cell receptor pairs so that we can create T-cell receptor cell therapies. Interestingly and importantly, Immatics showed data from one of their own programs at SITC this weekend that shows that this approach can be efficacious in melanoma, and that provides an early validation for this type of strategy. Very promising to see that. Another thing that you have to overcome with solid tumors is the suppressive tumor microenvironment. There are a lot of suppressive cells, suppressive cytokines around. One way to do that is through combination with other agents in our portfolio, and we have a tremendous number of opportunities, you'll see some of them later, for those types of combinations. You can also further engineer the cells. You can engineer out receptors that mediate signals from suppressive cytokines like TGF-beta.
You can engineer in proinflammatory signals that can be turned on and off with a simple, safe, small molecule given for short duration to help overcome this suppressive microenvironment. We're working on that, for example, with Obsidian. We're also looking at so-called logic gates with another partner, Arsenal. Beyond that, we are of course seeking to improve the processes, and in particular, looking for off-the-shelf strategies for cell therapy manufacturing. We have our own program of allogeneic cell therapy development in collaboration with Editas, and we continue to monitor and explore the opportunity for iPSC strategies for creating cell therapies. There's lots to look forward to and watch out for here. Looking at some of the biotherapeutic approaches, I'll focus here on immune cell engagers. You're all familiar, of course, with T-cell engagers. They have terrific efficacy.
We have one in our own portfolio in myeloma, for example. They do suffer from a pretty narrow therapeutic index. It's quite a tightrope to walk in terms of developing these agents. We've started looking at other cells in the immune system as potentially being useful in an engager format, and one we're focused on are natural killer cells. We know they have antitumor activity, and preclinical data has shown us that you can get evidence of activity with a reduced potential risk of cytokine release syndrome. We've partnered with Dragonfly, and you can see here that we've built quite a substantial portfolio of natural killer cell engager programs. Two of those were already in phase I development. In the not too distant future, we will be attempting to demonstrate proof of concept for this type of immune cell engager approach.
Beyond our internal efforts, we have been working hard to build up a network of external collaborations. We have a great organization. There are things that we can do really well, some of which I've shared with you. We are still only a small fraction of the whole world of biotechnology innovation, and we recognize that. There's constant innovation, new platforms, new ways to address critical biological questions, and we need to be part of that. We do that through this network of external partnerships in which we take a highly collaborative role. It's not just a license in and take it over. We work very closely with our biotechnology partners. We learn from them, we enable them, until things are ready to come into our pipeline.
You can see here these arrayed by thematic area of interest and different platforms and therapeutic areas. We have over 85 of these kinds of collaborations that are contributing potential assets to our portfolio. In just the last year, we've optioned nine licenses and four of the 15 INDs we had approved this year came through our external network of collaborators. This is already paying off for us in terms of delivering molecules into our pipeline. One area we're particularly proud of is the effort that we have undertaken to build up a neuroscience pipeline. We've done this with a very small internal team who are very expert and a really interesting set of external collaborations, which are shown here. We started this about three and a half years ago, and we've already got assets in clinical development.
In fact, by the end of 2023, five assets will have gone through phase I development, and another two will be actively in phase I development. That is a pretty remarkable accomplishment in a short space of time with a novel type of external strategy. Now, beyond these sort of early development or discovery collaborations, we're of course interested in what comes next in biotechnology. What is 10 or 15 years out? I wish I could predict the future. That would be great. Unfortunately, I can't. The strategy that we take here is try to be broadly involved in a wide range of scientific opportunities. Here are a few of our strategies. First of all, we make a lot of direct equity investments, modest investments in small emerging companies.
In almost all of those cases, we have board observer roles that allow us to work with the company, shape the direction, and very importantly, be in a position to have first mover advantage if something looks really promising. Right now, we have about 75 equity investments under management for this strategic purpose. We also invest in venture capital funds, but we select the funds we invest in very carefully. They are designed to be complementary in terms of geographical region or their type of approach or maybe the therapy area that they're investing in so that they're broadening our outlook on external science. Lastly, we've also over the last couple of years, worked on a network of actively managed academic incubators.
Networks of universities, particularly in Europe, where we enable them through a third party with drug discovery capability to turn those emerging ideas into solid data that can then be invested in terms of company formation. We've already formed one or two companies along this route where we are continuing to be actively engaged. This is our way of scanning and surveying the emerging science landscape and positioning us for the wave beyond the next wave, if you like. Turning now to the application of artificial intelligence and machine learning to R&D. AI and machine learning is everywhere now, everywhere in every walk of life, every facet of our existence, and R&D is no stranger to this as well.
I will say that there is a lot of hype, and you have to sort the wheat from the chaff as you're looking to how to apply this and where to apply it. We have a number of key partnerships that are specifically directed to this type of work, as you can see here. For example, phenotypic screening or mechanism deconvolution for our CELMoD collection. This is a new area of drug discovery, but we're generating an enormous amount of data. There isn't that much experience with these molecules. Computers can hasten that. We've shown through our partnership with Exscientia, for example, that we can dramatically shorten compound optimization times for small molecules, and we're going to be applying the same approaches to large molecules. Biomarker discovery is another important area.
Complex biomarkers like images or histopathological specimens, computers and AI algorithms are better at picking out the key features that are predictive of a patient's response or prognosis than humans alone. Further into development in Samit's area, there's application in terms of trial design, trial simulations, identifying the patient populations, and ensuring that you're enrolling them most efficiently and so on and so forth. This is a concerted effort right across our R&D continuum. Here's a summary of our early pipeline. We continue to evolve it, bring in new things, take out things that aren't working, but we maintain the opportunity for more than 20 proof of concept decisions over the next three years.
I'm gonna talk to you just about four of these assets that are highlighted here in magenta in a little bit more detail in the second part of my presentation. The first of these is CC-99282. This will be presented in detail at ASH in the next few weeks. It's a novel CELMoD drug. It degrades Ikaros and Aiolos, and it's optimized for the treatment of non-Hodgkin's lymphoma. Just to remind you again of the mechanism of action, CC-99282 binds to Cereblon. In doing so, it acts as a molecular glue that attracts in Ikaros and Aiolos to this E3 ligase complex. The proteins are tagged with ubiquitin, and that targets them to the proteasome, where they are chopped up and destroyed and degraded. The result of removing those proteins is twofold.
In lymphoma cells, they are B-cell survival factors, and they result in tumoricidal activity. They also have effects in other immune cells that result in immunostimulatory activity. You can see on the right side of this panel, some preclinical work that we did in selecting this compound, where we took a panel of cell lines that were completely resistant, so lymphoma cell lines completely resistant to lenalidomide, and also quite resistant to an earlier compound that we had been generating as we were learning how to optimize CELMoDs avadomide. CC-99282 has activity against almost all of those resistant cell lines. In preclinical in vivo models, we've been able to demonstrate that this compound leads to deep regressions of lymphoma xenografts, something never seen preclinically with precursor molecules or the original IMiDs like Revlimid.
This is highly differentiated from that point of view. We've also optimized the distribution profile so that it concentrates in target tissues, i.e., lymphoid organs. This is the phase I design. It's early. We've enrolled resistant or relapsed refractory patients, some of whom have had prior CAR T-cell therapy or prior CELMoDs or IMiDs. We've also got transplant non-eligible patients in the protocol. We've dose escalated, and we're just about at the recommended phase II dose, and you can see the next step will be to undertake some expansions in different lymphoma patient populations with and without rituximab. Just having a quick look at the data. As I said, the patients are heavily pretreated with median number of prior lines of three. The primary adverse experience is neutropenia.
This is what we expect when we degrade these proteins. It's manageable through dose adjustment and optimization of the schedule and supportive care. Importantly, we haven't really seen much in the way of febrile neutropenia. A very manageable profile for this asset. What we don't show on this slide are the PK/PD data. I can tell you that right out of the gate with this very potent molecule, we were able to see very rapid and deep degradation of our target substrates. Very good on target activity, and that's translated in just this dose escalation phase to an overall response rate of 40%, which we're excited about. Now we'll be able to further characterize that at the recommended phase II dose with and without rituximab.
We are also looking at a number of other combination opportunities for this agent with some other emerging lymphoma assets in our pipeline and beyond, in fact. The next asset which will also be highlighted at ASH is CC-95251. This is a novel anti-SIRPα monoclonal antibody. SIRPα is part of the CD47 pathway. CD47, I'm sure you're familiar with. It's a competitive field. CD47 is known as the don't eat me signal. It's expressed broadly on normal tissues, and tumors use CD47 as a decoy to prevent engulfment and destruction by macrophages. There's already proof of concept that blocking CD47 itself can have efficacy in lymphoma and in some other tumor types. There are some challenges.
The broad expression means that you have a large sink for targeting CD47. Also the expression on red blood cells, for example, has resulted in hemolysis as a result of administration of these agents. We took a different approach. We targeted the binding partner, which is SIRPα , so a different way of disrupting this access. When we combine it with anti-CD20 as an opsonin for targeting to the lymphoma cells, we have been able to demonstrate interesting early signals of antitumor activity for this approach. Again, here's the phase I clinical trial design. As with the prior study, we enrolled heavily pretreated patients. We administered rituximab according to regular dose and schedule, and then dose escalated weekly CC-95251 on top of that.
Again, we're just at the end of dose escalation and about to move into our dose expansion cohorts. But here are some of the early data. Again, heavily pretreated, median of four prior therapies. We do see some neutropenia with this agent, but I can tell you that this is transient, only tends to happen around the first dose, and then we don't see it with subsequent doses. We're happy with the tolerability and safety profile here. Again, albeit in a relatively small number of patients, we have seen an overall response rate of 41%, and we'll be looking to solidify and flesh this out, and again, look at combination opportunities for targeting this distinct pathway for the treatment of non-Hodgkin lymphoma.
Now, turning away from hematology, just a couple of early solid tumor assets that we'd like to share with you. This one, BMS-986415, is a novel interleukin-12 Fc construct. Interleukin-12, as I'm sure you probably know, is a very important immune-orchestrating cytokine. It's made by cells in the innate part of the immune system, and it activates cells in the adaptive part of the immune system, and consequently, has long been a sought-after agent for enhancing immuno-oncology assets. The challenge with IL-12 in its native form is that it's very short-lived, so you have to dose it very frequently. You get tachyphylaxis, and you also get high peak concentrations, which give you intolerable immunologic side effects. Our partners at Dragonfly took a different approach.
They engineered this as an Fc fusion with the aim of smoothing out the PK profile, managing the immunologic responses to that, and creating a better therapeutic index. Preclinical data using a mouse surrogate suggests that this has been accomplished. The PK profile is more prolonged, and importantly, the PD profile, as evidenced by interferon gamma responses, is extended and without high peaks and tolerated. It also translated in a hard-to-treat CT26 model, which is checkpoint non-responsive, so we could overcome checkpoint non-responsiveness. Importantly, in cases where the tumors had been allowed to grow to a tremendous size, when normally we would not see anything impact those tumors, we were able to demonstrate potent monotherapy activity.
We were impressed with this profile, and we've taken a license to this asset, and we're working on it with Dragonfly in partnership right now. We're in dose escalation, both monotherapy and with nivolumab. I'm pleased to say that so far, the PK profile and the early PD results, systemic PD results, look like they're bearing out the original hypothesis. The aim here now is to get to the right dose to test whether this type of approach can deliver clinical efficacy either as a monotherapy or as a combination therapy. We'll update you on this as we get more data. Then finally, I'd like to talk about this agent. This is in reference to our IL-8 monoclonal antibody. IL-8 is a chemokine.
It's responsible for migration of neutrophils and myeloid-derived suppressor cells, which can aggregate in the tumor microenvironment and cause a highly suppressive tumor microenvironment. People have long been interested in targeting this cellular mixture as a way of reigniting antitumor immune responses. We've actually done quite a lot of translational work. I think this speaks to the power of our datasets and translational organization to help validate this hypothesis. On the left here, you can see some survival curves from CheckMate 067, which studied nivolumab and ipi in melanoma patients. Here, the patients were subsetted according to their baseline interleukin-eight circulating interleukin-eight levels.
You can see that patients with higher levels of circulating interleukin-eight had much worse outcomes, suggesting that this is indeed potentially involved in blunting the effect of checkpoint inhibitor therapy. We went one step further and actually looked at tumor biopsies, quite a large number of tumor biopsies. We were able to show that in tumors where there was a high concentration of IL-8, there's an example here where it's stained in red, that you got colocalization of both neutrophils and myeloid-derived suppressor cells. The markers in white and purple reflect the colocalization of those cells, suggesting that yes, indeed, this is driving some of those key suppressive elements into the tumor microenvironment. Encouraged by that, we performed an initial study combining anti-IL-8 with nivolumab in patients with melanoma who had been refractory to checkpoint inhibitors.
They had really become unresponsive. These data were originally presented at a SITC meeting, but what we saw in this single-arm trial was some evidence that this combination could reinduce partial responses in these refractory patients. Now, of course, we need controlled data in order to firm this up, and that's exactly what we're working on right now in the clinic. We're again back in melanoma here as the test population, and we are looking at nivo, ipi and anti-IL-8 versus nivo and ipi. You can see the endpoints here. I'll also point out that we will be stratifying these patients according to their baseline circulating IL-8 levels to firm up whether that is indeed a patient response prediction marker that will enrich for people responding to anti-IL-8.
This study's ongoing, and we will update you as data become available to us. To summarize, I hope I've shown you that we have a really rich and deep pipeline that is across a wide range of modalities and therapeutic areas, in fact, transformed over the last couple of years within our company. I've shared with you some of our industry-leading internal discovery platforms, our excellence in small molecule drug discovery, our undoubted leadership in the field of protein homeostasis, complex biotherapeutics, cell therapies, both now and next generation. I talked to you about our external network, carefully constructed collaborative network that adds things of high value to our capabilities, and more importantly, is delivering things, tangible assets into our pipeline. I shared with you a few highlights from some early pipeline assets. Just a handful.
There are many others that are very promising in that pipeline, but we just wanted to focus on a few, particularly a couple that are just going to come up at ASH in the next week or two. With that, I'll stop and invite Samit Hirawat up to the stage to talk about the next steps in development. Thank you.
I think he does deserve an applause. That was a whirlwind tour of our pipeline. I think Rupert has done a nice job to show you why we are pioneers in discovery and research. Over the next 30 minutes or so, I will try and do my best to show you why we are also leaders in development. With that in mind, I think we've made a significant progress over the last year or so, generating data that has been showcased in some of the most important medical conferences. If you look at what just happened over the weekend and on Monday, we presented data on milvexian that I'll go through again, as well as long-term follow-up from mavacamten MAVERICK study.
In December of this year at ASH, we'll be showcasing data for the first time looking at a randomized trial in the second-line large B-cell lymphoma studies, comparing it to the standard of care of hematopoietic stem cell transplant. We will also talk about the cell mods that Rupert laid the groundwork for. Earlier this year at EADV, we were able to present the data of the longer term follow-up from the psoriasis trial of deucravacitinib. Overall, our commitment to the therapeutic areas that we are leaders in remains very high. We continue to make progress in cardiovascular medicine, hematology, oncology, as well as immunology, and I'll walk you through some of those. Let's start with cardiovascular medicine. We are leaders in cardiovascular medicine based on what has been shown with Eliquis.
We want to continue to build on that franchise and continue to grow our leadership in that area through additional indications such as cardiomyopathy and heart failure through mavacamten, as well as in the anticoagulation, antithrombotic area through milvexian. These are areas of very high unmet medical need, and new medicines are needed for that. Now, one could say, "What is the high unmet medical need in anticoagulation when we are talking about Eliquis as being the leader molecule here?" Well, we believe there are patients who still need further innovation. Patients who are at a very high risk of bleeding because of bleeding disorders still develop thromboembolic episodes, but they cannot be treated with the currently available anticoagulants. Secondly, there are concerns about being able to combine the currently available OACs with dual antiplatelet therapy as background.
Therefore, there is a significant need to be able to develop new therapies that are equally efficacious or better in efficacy with a lower risk of bleeding. That's exactly where we need to understand the overall coagulation pathway briefly to see where factor XIa inhibitors play a major role. We see factor Xa sits at the cusp of where the two pathways come together. As very eloquently stated yesterday by the presenter at the AHA meeting, factor XIa in this particular case seems to be more dispensable. If you do inhibit factor XIa, the likelihood of bleeding is low because the extrinsic pathway is still open, and that leads to coagulation when you really need it. That is exactly the hypothesis that the team set out to do through two phase II proof-of-concept trials.
The first of that has read out in people who were undergoing total knee replacement therapy and were provided treatment with milvexian for 10-14 days, starting 12-24 hours after surgery. We've got the data, we've got the proof of concept, and I'll go through that one more time. The second study that is currently ongoing is in patients who have recently had a stroke, and we are looking to prevent a second stroke in those patient populations. Once again, this trial will be reading out early part of next year, and we'll be able to share the data with you. With that in mind, here is the trial design for the total knee replacement study. Multicenter, open-label, dose-ranging study, 10-14 days of treatment with milvexian only. We want to demonstrate, can we prevent the VTE episodes from the efficacy perspective?
From the safety perspective, we wanted to see what the bleeding profile is gonna look like. As you can see on the right side, we tested multiple doses and we also tested single daily dose versus a BID dosing pattern. Here are the data that you also heard yesterday if you had a chance. Four very critical things to take away. Number one, robust efficacy in this trial that was shown with a very clear dose response as you see in the first row of that table. Number two, low risk of overall bleeding, as you can see in the second row of this particular table. Number three, no episodes of major bleed with milvexian, as you can see in the highlighted row. Last, but the most important thing, no dose response relationship when it comes to the bleeding.
You see the increasing efficacy with the dose, but no increase in bleeding as you increase the dose per day. Overall, these data are significant and are recognized by the scientific community as the next generation of anticoagulants that should be developed, and that's why the New England Journal of Medicine simultaneously published this paper yesterday, and it's available online. To further our conviction, we have the second study that is ongoing. That is looking at a combination of milvexian with the background dosing of antiplatelet agents. This is also a dose-ranging study, but it allows patients to receive treatment for up to 90 days. It is important to understand that once these data are available in the early part of next year, it will provide us that optionality to choose and pick on a multitude of indications that can be pursued in
As shown on this slide, both as a single agent as well as in combination with the anti-platelet therapy that has become the background standard of care in many conditions that are listed over here. Just to summarize on milvexian one more time, the profile that we see over here is clearly differentiated from the factor Xa inhibitors. We've seen these data in the past, as well as we're looking forward to now moving as soon as the second trial is available to take the collective data and initiating the phase III program in the next year. I will now switch gears to another area of high unmet medical need, and that is hypertrophic cardiomyopathy. A picture is worth a thousand words. The lower part of the picture that you see on the slide very clearly shows a hypertrophic heart.
What that really means is that there are left ventricular pressures that are very highly increased that leads to heart failure. There is also dysfunction in terms of the pathway, electric pathway that the heart needs, and therefore atrial fibrillation can be very common. These patients have symptomatology of shortness of breath, seizures, loss of consciousness, and even sudden cardiac death. If you take that all into account and look at what drugs have been approved thus far, the only approved drug for symptomatic management was propranolol in 1967. There are no drugs approved to date that truly address the underlying mechanism of this disease, and that's where mavacamten comes in. Mavacamten, a myosin inhibitor, has shown activity, and we've shared these data before. We've also seen the long-term extension data from this trial up to 60 weeks.
That has shown that the biomarkers are very much in control over the period of time. We've also seen the left ventricular ejection fraction as well as the overall outflow gradient is very well managed. The echocardiographic changes are very well managed, and they are controlled and remain stable over time. The safety profile doesn't change. We don't see increase in this, in the adverse events. Overall, this gives us high amount of confidence in this drug, and we are really looking forward to the PDUFA date of January 2022. In addition to the first study, EXPLORER, we also have completed enrollment in the second trial called VALOR. In severe obstructive hypertrophic cardiomyopathy patients, the only option left is really septal reduction therapy. This trial has been designed to compare mavacamten versus a placebo in patients who are eligible for septal reduction therapy.
After 16 weeks, the patient would either undergo surgery or could continue on mavacamten with a crossover. This is going to be important data to look forward to next year as we continue to extend our vision of the lifecycle management plan for development of mavacamten. Beyond obstructive hypertrophic cardiomyopathy, we've also seen the data from the MAVERICK trial in the non-obstructive hypertrophic cardiomyopathy. Once again, demonstrating the improvement in the outcomes in terms of NT-proBNP and the long-term improvement in the wall stress in the heart through this trial, and these data were presented at AHA this weekend. Overall, these datasets also provide us confidence to move into phase III in 2022.
If you look at the mavacamten program, it has a very sound lifecycle management program, three of the trials that I already described, and the fourth one that was recently initiated as a proof of concept phase II study in heart failure with preserved ejection fraction. I will now switch gears to hematology. Once again, we will be able to leverage our overall strength in understanding the hematological malignancies because of the long history that we have, not only with Revlimid and pomalidomide, and then the discovery efforts that Rupert described to you, but also with the advent of new molecules that we have recently launched, as in Reblozyl, as in Onureg, and cell therapies that are truly transformational, as in Breyanzi and Onureg.
I will not spend time in the early pipeline because I think Rupert has given you a good flavor of what is evolving and coming very soon, through the early pipeline assets like SIRPalpha as well as other CELMoDs. At ASH this year, we will be showcasing and showing you the data from the second-line large B-cell lymphoma study, as well as the progress that we've made, with CELMoDs, and I'll give you a glimpse of that data right now. Then beyond that, you will see SIRPalpha and CC-99282. This is the most exciting slide for me. Breyanzi, a differentiated CD19-directed CAR T-cell therapy. Over here, the first time we are comparing it to the standard of care of salvage chemotherapy, followed by high-dose chemotherapy, followed by infusion of stem cells.
Comparing that to a single infusion of CD19 CAR T-cell. The results are in front of you. We not only have highly statistically significant improvement, but these are meaningful outcomes for these patients. We have an improvement in median event-free survival as the primary endpoint. We see improvement in progression-free survival, as well as overall response rate. The most important part is at the bottom of the slide, the differentiated safety profile, where we see very low rates of CRS and low rates of neurological toxicity. We are really looking forward to have these dialogues with the health authorities and bringing this medicine forward for this indication as soon as possible, so the patients can continue to benefit. In addition to this trial, we have several other studies that are already ongoing for Breyanzi.
We are looking forward to extending the indications that could be available, could be pursued for Breyanzi. Next year, we'll see the data from the pilot trial, which is in patients who are not eligible for transplant, as well as from the CLL study, the third-line plus patient population, and then following that, follicular lymphoma as well as marginal zone lymphoma. Switching gears from lymphoma to multiple myeloma, a space that we are the leaders because of the current IMiDs that are available to patients. We have a long-term vision. Rupert showed you how we learn from the IMiDs the overall biology and how we can really impact the disease in the long run. Multiple myeloma remains an incurable disease today, so we need to continue to innovate. We have two CELMoDs that are already in development in multiple myeloma.
Our long-term vision is to be able to replace Revlimid with iberdomide in the newly diagnosed multiple myeloma patient population. On the right side, you can see that CC-92480 has the potential to replace pomalidomide in the relapsed refractory multiple myeloma setting. Now to be able to do that, we know the plan that we will need to execute on. Number one, we will need to be able to show the superiority of CELMoDs over IMiDs. Number two, we need to show the combinability of these CELMoDs safely with other standard of care treatments. Number three, we have to establish these combinations so that we can continue to move them early on.
Number four, with the deep and broad pipeline that we have, we will need to develop strategies and demonstrate that these many of these medicines can be sequentially used in patients with multiple myeloma. We have started to put the groundwork for all of these, and some of those will be showcased at ASH. Starting with the doublet of iberdomide plus dexamethasone. You see the brief summary of the trial design over here. Patients who are enrolled in this phase I/B II study are heavily pretreated. All patients have received prior IMiDs, CD38 antibody, proteasome inhibitors. We are focusing specifically on cohort D and cohort I. Cohort I is very important because these are patients who have received prior BCMA-directed therapies as well.
What we see from that trial, that overall response rate is similar to what has been shown in this very late patient population, but very importantly, a 25% response rate in the population who has received prior BCMA-directed therapy. These are the first of their kind as far as I know of the data being presented in that population. On the right side of the slide, you also see the safety profile. Very specific to note the low levels of grade three, four toxicities in the GI toxicity, fatigue, as well as rash, and very low rate of discontinuation due to treatment-emergent adverse events. Doublet over here is not enough. We need to have a triplet to be able to move earlier in the line, and that's what we saw at EHA.
We've shown the data with high overall response rates in combination with daratumumab, dexamethasone, bortezomib, dexamethasone, carfilzomib, dexamethasone, a comprehensive phase I B program that has given us the optionality to look forward to moving in earlier into the lines. How are we going to do that? Well, we have the EXCALIBER study that is already planned in the second-line plus patient population that we intend to initiate in the first half of 2022. Thereafter, we have a dose-finding study that is ongoing right now in the post-transplant maintenance setting. Once that data is available, we'll be able to initiate a head-to-head comparison versus Revlimid in that patient population. Last but not the least, in the transplant non-eligible population, the newly diagnosed multiple myeloma space, we have another opportunity to initiate studies in the future looking at head-to-head comparison versus Revlimid in the combinations.
I will now talk about the second CELMoD, CC-92480, a more potent compound. Over here, we show again the design of the phase I trial, where we're looking at the combinations in multitude of these arms that are planned. Once again, heavily pre-treated patient population. All patients have received IMiDs, refractory to IMiDs, and have relapsed after receiving CD38 antibodies as well as proteasome inhibitors. On the left side, you see the outcome for a patient with extramedullary disease, which is very hard to treat. Even with a doublet of a CC-92480 plus dexamethasone, we see the outcome on the right side scan, where there is improvement in that plasmacytoma that was present pre-treatment. On the right side of the slide, you see the triple combination of CC-92480, bortezomib plus dexamethasone.
Very high response rate in the early part of the study that we've seen, as well as a well manageable safety profile. Once again, as these data emerge in the triplet combinations, we have a plan to move those also in the earlier line setting. We have the doublet study that is ongoing, as well as the triplet combinations, which will set us up to initiate the phase III program starting late next year, early 2023, looking at CC-92480 plus Velcade plus dexamethasone or CC-92480 plus Kyprolis plus dexamethasone. More to follow, more to come on the cell mods as the data continues to emerge, but certainly I encourage you to pay attention to the data being presented at ASH. Cell mods are not the only things that we have as we think about multiple myeloma.
There are multiple other modalities to target BCMA that are in development. We've talked about previously about the T-cell engagers that we initially tested as an intravenous therapy. We saw high response rates, but we also knew that there are safety liabilities with the intravenous administration. Therefore, we switched to the subcutaneous formulation, and that trial is well underway in its dose escalation phase, and soon the data would be available, and we'll be able to share that next year. As Rupert said earlier, we have an NK cell engager, which is in phase I, and that is also proceeding quite well in the dose escalation phase. In the middle of the slide, you see, ADC against BCMA that we are also developing.
It is also in phase I and showing a good safety profile that we'll be able to take forward once we have the recommended phase II dose. On the right side, once again, cell therapy. First BCMA-directed cell therapy that has shown efficacy in late-line. We have finished enrollment in the KarMMa three trial, which is in the third-line+ patient population. We also have other KarMMa trials ongoing in the earlier-line setting that we are looking forward to have the data readout and then proceed further to test it out in the earlier lines. Having said that, as Rupert mentioned, we are continuing to improve how we manufacture. We are continuing to improve how we develop newer targeted targets in the CAR T cell space.
Some of that, as was mentioned earlier, will be showcased at ASH again, such as the GPRC5D CAR-T cell therapy from a Memorial Sloan Kettering collaboration. Overall, we have the CELMoDs that have made tremendous progress over the last year in terms of generation of data and showcasing not only the activity, but also the efficacy, safety aspect. We have the cell therapies that have progressed as well as other BCMA-directed therapies that have made progress. We are now looking to see how we can start the combinations of these to move forward to implement and showcase and achieve the vision we have for overall multiple myeloma program. Beyond that, we have a robust pipeline. You already heard about some of those molecules early on.
As they move forward, we'll have the robustness that will be built in into our overall development plan. With our excellence in execution, we are going to bring those forward in an accelerated fashion. Now switching gears to oncology. This remains a key strategic focus for us. We already have the leadership with Opdivo plus Yervoy. We continue to want to evolve beyond Opdivo and Yervoy with newer molecules that are entering into the registration space as well as into our pipeline. We have the fixed dose combination of relatlimab plus nivolumab, the first LAG-3 inhibitor to have shown positive outcomes in the melanoma phase III study. We also have another IO mechanism, which is regulated IL-2 with a large phase III program that is underway.
We want to differentiate ourselves even beyond the immunotherapies, and that's why we have molecules such as MORab-202, which is the folate-directed antibody drug conjugate that we are also partnering with Eisai on to build that overall data set. With Opdivo and Yervoy, we've seen tremendous results, truly transformative results for patients with metastatic disease. We've got 30+ approvals for the two agents across 11 tumor types. We have the adjuvant registrations already in melanoma, in bladder cancer, as well as in esophageal cancer. We have more to do. We have a long way to go in the adjuvant space. We're just scratching the surface. Just as an example of that, let's talk a little bit about non-small cell lung cancer.
We have four trials ongoing in the early space, looking at the adjuvant setting as well as the peri-adjuvant setting and in the unresectable population, and very importantly, in the neo-adjuvant space. We already showcased the data for the CheckMate 816 trial, looking at the primary endpoint of pathological complete response, a very successful, statistically significant, we believe, meaningful outcome from a clinical perspective as well. From a regulatory perspective, we needed to demonstrate that there is also a translation of the pathological complete response rate into an event-free survival improvement. Well, it's a pleasure of mine to share with you, we have the EFS data in hand, and now we are on our way to discussing those with the health authorities and bringing this to patients as soon as possible.
The other combination of relatlimab plus nivolumab as a fixed-dose combination, we've seen the data in first-line melanoma. Really proud to be the only company with a third IO mechanism, and everybody else was also looking for it. We knew how to design this trial, how to select these patients, and how to conduct this to be able to get to these results. I'm also proud to say we've seen the overall survival data, and we are very happy with what we've seen thus far. Obviously, I can't share the data with you because they will be presented at the appropriate medical conference, but we are happy with the results that we've seen. Based on the data that we have seen in the melanoma trial in the metastatic setting, we have initiated the adjuvant program in melanoma.
We already have the phase II trials ongoing in non-small cell lung cancer as well as in hepatocellular carcinoma. We intend to initiate the first-line non-small cell cancer study in the first half of 2022, as well as a phase III program in colorectal cancer based on the emergence of data that we've seen from competitive molecules as well as our internal efforts. As I said earlier, our story in IO doesn't end with nivo, ipi, and rela. We have pegylated IL-2, sorry, and that is a program that is currently ongoing in five phase III trials. We'll be looking at the readout of three of these trials in 2022, which will pave the way for further extension of this as we work with our collaborator and partner, Nektar, on these trials. In addition to that, we've recently added MORab-202 to our pipeline.
This antibody drug conjugate is differentiating itself, first of all, by the payload that it carries, which is eribulin and different from others. Second, we've seen activity already in the dose escalation phase across a multitude of tumors, including ovarian cancer, endometrial cancer, non-small cell lung cancer, as well as breast cancer. If we see activity in low expressers of folate receptor, that could truly differentiate this molecule as we think of initiation of the phase II, phase III program in the near future. More to come on that as we finish out the dose escalation portion of this trial. Beyond that, we have a robust oncology pipeline, two of these assets you already heard about early on from Rupert. As those data evolve, we'll be able to move those along and develop them in an accelerated fashion.
Now let me switch gears to immunology, one of the very important therapeutic areas that we have in our franchises. The foundation is very strong because it's based on Orencia as well as Zeposia, which was added on last year, the first indication with multiple sclerosis. Then we have expansion opportunities with the recent approval in UC for Zeposia, as well as other molecules. I'll talk a little bit more about deucravacitinib as well as sindaximod. Then if you look at the future, we again have a broad, deep breadth in our pipeline that we look forward to bring forward as we look to the future. Let's start with deucravacitinib. We have shared the data from the phase III trial in moderate to severe psoriasis with you before. These responses that we saw in that trial are deep, durable, and sustained.
We do believe that it has a future to potentially be the oral medication of choice for patients with moderate to severe psoriasis. I'm happy to share with you that we have filed an NDA with the U.S. FDA, as well as we've submitted the application in Europe. We are looking forward to a formal declaration of PDUFA date imminently, and as that is available, we'll be able to share that with you as well. The data for the longer-term follow-up for patients with moderate to severe psoriasis were already shared at EADV. If you look at PASI 75, PASI 90, PASI 100, SPA 0-1, all of these endpoints have maintained and sustained the outcomes for these patients with moderate to severe psoriasis.
Now, I know that there has been a lot of speculation around combining the data for TYK2 inhibitors and seeing them as a JAK inhibitor. Well, let me just start by saying that this is a very selective TYK2 inhibitor with very specific downstream effects on IL-12 and IL-23. This is not the profile of a TYK2 inhibitor. JAK inhibitors, we know, do cause anemia, thrombocytopenia, dyslipidemia, as well as changes in liver functions, and these are evident very early on in the treatment time period of use of JAK inhibitors. We shared at EADV that that is not the profile that we see with a TYK2 inhibitor. We've got data all the way out to 52 weeks. We don't see anemia, we don't see thrombocytopenia. We've not seen the liver dysfunction. We've not seen dyslipidemia.
These findings have been replicated in another trial now that has just finished in Japan and has been included in the filing in Japan for those patients as well. Overall, those are not the only data that we have. We are continuing to make progress to develop deucravacitinib in multitude of other immune-mediated diseases. We've shared this data before in phase II study of psoriatic arthritis, and that has formed the basis for initiation of two phase III trials in that indication. We look forward to readout of those studies in 2024. We have additional opportunities for development of deucravacitinib. Yes, the phase II trial in ulcerative colitis, the first one that read out, did not meet the proof of concept criteria that we had set out.
Having said that, we do know that these diseases, IBD, requires doses that are two to three times higher than what have been used in other diseases in rheumatological space or dermatological space. There are two trials that are ongoing, one in ulcerative colitis, one in Crohn's disease, and we look forward to those readouts as those will pave the way for future development of deucravacitinib in IBD. In addition to that, as you know, we have the study ongoing in systemic lupus erythematosus. The phase II study will read out early next year. That would be very critical. Beyond that, we're looking forward to initiation of a phase II study in mild to moderate psoriasis with a topical formulation in 2022 as well.
Overall, I would say deucravacitinib has a very important place in the treatment of a multitude of immune-mediated diseases, and we are really looking forward to the breadth of the program, and execution is going on very well. For Zeposia, as I said earlier, we have the approval for MS, as well as in the U.S., it's approved for our patients with ulcerative colitis. We have a positive CHMP opinion in Europe as well, and we are looking forward to rounding out the Crohn's disease study and produce that data and present it in 2024, so that we can extend the treatment benefit for patients with IBD beyond that single indication that we have today. Within the immunology franchise, we also have cendakimab, our IL-13 R alpha 2 inhibitor.
That is gonna be very important because in the phase II study, we not only saw the reduction in the eosinophil count in the esophagus, but also a truly impactful improvement in the endoscopic outcomes for these patients. That phase III study is also ongoing and enrolling well. We look forward to the results in 2024. A very busy year, I think, 2024 is going to be. We have another phase II study ongoing in the atopic dermatitis. Those data will read out next year and will pave the way for future development in that indication if supported by data. Of course, like all other therapeutic areas, here again, we have the depth, we have the breadth, and we have multitude of these studies also ongoing.
Those readouts will then progress these molecules from early development to late development and hopefully to patients in the commercial setting in the future. Overall, as I wrap up, I think we have a busy year ahead of us. If you look at cardiovascular disease, we have the data in hand for mavacamten, and we remain committed to be able to bring this medicine to patients as soon as the approval comes, and the PDUFA date is January, as you know. For milvexian, we've got data that is very, very helpful in defining how we'll move forward next year once the SSP data are available into the phase III programs. In oncology, we are continuing to expand beyond Opdivo and Yervoy with the relatlimab and nivolumab fixed-dose combination and differentiating our pipeline by also adding non-IO mechanisms in the pipeline.
In hematology, cell mods have made tremendous progress, as well as the cell therapies are truly transforming the lives of patients with these life-threatening diseases. Last but not the least, in immunology, we have deucravacitinib that we are bringing forward very quickly, very soon, and then of course, continuing to build on the pipeline assets that we have in our hand. 2022 is going to be a very busy year. This slide just starts to scrape the surface. We have a lot more to do beyond that because we do know that additive therapies are not going to be enough. We will need to really bring transformational outcomes for patients for these diseases.
2023, 2024, as Giovanni has already said, as Rupert has already said, are going to set us up for the second part of the decade as well as we look towards overcoming the challenges that we have from an LOE perspective. Now, I know that Chris will be able to give you a lot more in terms of how these patient benefits are also going to translate into successes for the company, but that will have to wait for 10 minutes, and so now we go to the break. Thank you.
Yes. We're gonna take a quick break, just 10 minutes. There's coffee outside, bathrooms downstairs. We'll see you in 10 minutes. Okay. All right, folks. I think we're ready for Chris. Whenever you're ready, Chris. Terrific.
Thank you, Tim. Good morning, everyone. I'm going to pick up where we left off before the break and walk through the commercial potential for the portfolio, and I'm gonna hit on a number of the assets that Samit just walked you through. As Giovanni referenced at the beginning of his presentation, the core elements of our commercial business are really threefold. First, we have a very strong book of inline products. These are products that have significant sales today, and relevant to the discussion we're having this morning, we believe they have significant potential to continue to grow in the years ahead. I'm gonna talk a bit more about a couple of these very important assets on the next slide. Second, we have a swath of new medicines across therapeutic areas.
These are going to be critical as we think about the growth profile for the company throughout the decade, so I'm gonna spend the bulk of my presentation on a number of these products. Then finally, as you saw in Samit's presentation, we have a very exciting set of late-stage clinical assets, which have the potential to have meaningful commercial sales, particularly as we get into the latter half of the decade. Let's double-click on each of these, and we'll start with our inline business. As all of you know, we have a significant and robust business in immuno-oncology today. Roughly $9 billion in sales spread across 11 core tumors. Importantly, this is a business that's not only a large business today, but it has significant growth potential through the middle of the decade.
You can think about that growth coming in three broad areas. First, we have the potential to continue to grow in metastatic tumors, where we have a significant presence today. You can think about renal cell carcinoma, for example. We have seen very good growth with Opdivo plus cabozantinib in the first-line setting. In fact, O plus C has become one of, if not the leading IOTKI regimen for first-line renal cell patients. Of course, that's built on top of the significant business that we have in renal with Opdivo plus Yervoy. Many of you will recall that when the first IOTKI data emerged, we received a lot of questions about what that meant for the future of Opdivo and Yervoy.
Thanks to very strong commercial execution as well as the continued evolution of our mature durability data with Opdivo plus Yervoy, not only in renal cell, by the way, but really across tumors. Opdivo plus Yervoy continues to be an important treatment approach for first-line renal patients, and we consider it to be foundational going forward. The second area for growth in IO is in metastatic tumors where we have less of a presence today. We've talked at length about the opportunities that we have in upper GI cancers, as well as the incremental growth opportunities that we have in first-line lung cancer. Finally, we have a very exciting set of programs in early-stage cancers, as evidenced by the recent approvals in bladder and adjuvant gastric, as well as the very exciting data that Samit referenced with CheckMate 816 in early-stage lung cancer.
This is a big business today, and we see it as having considerable growth potential going forward. It's a very similar story when we think about the cardiovascular business. We obviously have a very large business with Eliquis today, and this too is a business that has significant momentum behind it. You'll recall that we have taken a very disciplined and stepwise approach to how we've grown our cardiovascular business. We started by focusing on leadership in the NOAC class, initially with cardiologists and then expanding into a broader PCP network. Once we established leadership within the NOACs, we focused on growing that class. Once we established leadership within the OAC category, only then did we focus on patients who were undiagnosed.
It is really this very disciplined approach to how we decided to grow that business that has enabled us to build such a strong presence with Eliquis and that continues to give us momentum with this business. If you look across our major markets, we continue to see Eliquis growth rates exceeding that of the OAC market as a whole. In a number of our key markets, including the United States, you see this nice delta between new-to-brand share and total share, and that's indicative of a product that continues to have strong growth potential. Now, Eliquis is important not only because of the growth that it provides itself, but also because it's a springboard for future cardiovascular products.
As I think you all know, and as Samit alluded to, BMS has a long history in the cardiovascular space going back to the Plavix days, and it's this history, along with the existing Eliquis business, that creates a strong foundation for future cardiovascular products. I think you all know we have built a very broad commercial and medical infrastructure in the cardiovascular space. The Eliquis business is a very competitive business. It's in a highly managed category in the United States. That's enabled us to build very strong commercial muscles. We know this disease state well. We have well-established relationships. Importantly, we have experience operating in large global partnerships as we did with Sanofi and Plavix, and as we're doing today with Pfizer, with Eliquis. Many of these capabilities are gonna be absolutely critical as we think about launching the next wave of cardiovascular medicines.
The first of those expansion opportunities in cardiovascular is mavacamten. Since we completed the acquisition of MyoKardia about a year ago, we have engaged with a broad set of stakeholders to really help to refine the opportunity that we have with mavacamten, and a few things are clear. What we hear from patients is just how devastating hypertrophic cardiomyopathy is. It is a disease that is frequently misdiagnosed, and when it is diagnosed, it leaves patients with a panoply of symptoms ranging from stress and anxiety all the way to arrhythmias, the risk of sudden cardiac arrest, and heart failure. The reason for that is that there are no therapies that treat the underlying cause of HCM. Current standards of care are nonspecific, they're not well-tolerated, and they really do simply treat the surface-level symptoms.
There continues to be significant unmet need from a patient standpoint in HCM. From physicians, we hear three things very clearly. First, mavacamten is the first medicine to mechanistically treat the underlying cause, causes of HCM, and you see that highlighted in the quote on the left-hand side of this slide. Second, the data that we have with the Explorer trial represents a significant step forward for these patients. The efficacy improvements are meaningful, the drug is very well-tolerated, and this has the potential to significantly improve outcomes, and you see that highlighted in the quote on the right-hand side of the slide. Finally, for those physicians who have direct experience with the product through the clinical program, you hear about the significant improvement this drug is providing for their patients.
That shows up clinically in the quality of life data that we see coming out of the Explorer trial, but more poignantly, it shows up in the stories that these physicians tell about their patients and the impact that this drug has had on those patients' lives. It is really this feedback that gives us increased conviction in the significant and meaningful commercial opportunity that we see with mavacamten. HCM is a large patient population with over 1.3 million patients diagnosed across our largest markets. Roughly 60%-70% of these patients are diagnosed with obstructive disease, and of course, that will be the initial indication when we're approved.
Of those that are diagnosed today, roughly 60%-80% of those patients are symptomatic, and many of these patients are treated in a relatively small set of centers of excellence, and it's these centers of excellence that are gonna be the focus of our initial promotional efforts. Over time, though, we see the possibility to significantly increase the number of patients who can benefit from this product. First, by expanding beyond those centers of excellence into the broader cardiology community, and then ultimately expanding the diagnosis rate. The diagnosis rate for obstructive HCM today is roughly 20%-25%, and we see the potential of possibly doubling that over time. Finally, I would highlight that this is a disease where there is no obvious differentiated competition on the horizon.
Certainly includes products that are used to treat the disease today, and it also includes follow and follow-on myosin inhibitors, at least based on the data that we've seen thus far. If you combine the opportunity that we see that we have in obstructive HCM, along with lifecycle management opportunities that Samit highlighted, notably in non-obstructive disease, we see this asset as having upwards of $4 billion in potential. A second product with upwards of $4 billion in commercial potential is deucravacitinib. Since the phase II data, and certainly since we saw the POETYK phase III data, we have been engaging with key opinion leaders on this product as well, and the feedback that we get on deucravacitinib is very consistent. It is a unique mechanism of action. I think Samit highlighted the reasons that are played back to us in that regard.
The efficacy data from the POETYK studies are very compelling. The PASI 75 scores themselves are very compelling. They are clearly differentiated from Otezla, which remember will be the primary focus competitively at launch. The response rates are deep and durable, and the safety data is entirely consistent with a unique mechanism of action. It's favorable to Otezla, and it is clearly differentiated relative to JAKs. This profile we see as fitting a unique space in the moderate to severe psoriasis market. There is clear unmet need in this market for more efficacious and tolerable oral options. What we have with deucravacitinib is a drug that has biologic-like efficacy, but one that is more tolerable from a safety standpoint than the biologics that are typically used to treat these patients. We see durable responses through one year in a convenient once daily dose formulation.
We see clear potential for deucravacitinib to become the new branded oral of choice for these patients. How that translates into commercial potential is sketched out on this slide. Like mavacamten, we have here a large, well-defined patient population. The oral market as it exists today will be the first opportunity for us. However, over time, we see deucravacitinib as potentially changing the treatments landscape by expanding the space for highly efficacious orals. For example, you could think about deucravacitinib being used earlier in the treatment algorithm or potentially delaying the switch to biologics. Now, unlike mavacamten, this is a much more competitively intense space, but I would remind you that the pivotal efficacy data that we have is clearly differentiated against the main competitor that we will have at launch.
Again, we have a more favorable safety profile than JAKs, as well as biologic agents that are used to treat these patients. We think it's this profile that yields significant commercial potential. Over time, we have the potential to expand into a broader set of indications, initially in psoriatic arthritis, followed by lupus, and potentially, as we get into the latter half of the decade, in IBD. You can see the associated patient numbers with each of these potential indications. And collectively, these add up to significant commercial value. Let's switch gears and talk about hematology. We see Reblozyl as an important long-term asset for the company. As I think many of you know, we are currently approved in a subset of second-line MDS as well as in beta thalassemia. At a macro level, we see potential with this asset in two areas.
First, we clearly have incremental sales opportunities in our current indication. I'm gonna talk more about that in a moment. As Samit referenced, we have the opportunity to expand, and I would note here the opportunity to move into first-line MDS with the COMMANDS study as well as potentially into other diseases, notably myelofibrosis. let's take a deeper dive into our current indication. There are roughly 8,000 patients in our current indication. These are second-line patients who have lower risk disease with RS positivity. we think for these patients, Reblozyl is an important new treatment option. Moreover, we know that approximately 50% of patients treated with ESAs either get no response or are being suboptimally treated. we see an opportunity for these patients to benefit from Reblozyl earlier.
We've already seen a reduction in the time that patients are on ESAs from roughly 18 months prior to our approval to roughly 10 months today, and we would anticipate a potential continued reduction in that time on ESAs based on the recent NCCN updates, which in light of Reblozyl being on the market, is encouraging physicians to test for ESA response sooner in the treatment algorithm. Our commercial focus is very clear here. First, we have to establish Reblozyl as the standard of care for patients post-ESA. Second, we have to get more suboptimally ESA-treated patients onto Reblozyl. Then, of course, we have to ensure that patients are treated with the appropriate duration of therapy consistent with our clinical trials, such that they get maximal benefit from the product.
Again, beyond the current indication, we see significant opportunities through lifecycle management, and I will note again the importance of the COMMANDS study. That's particularly important because it more than doubles the patients who are available to us today in MDS. Then again, as you get into the mid-decade, you see the opportunity there with myelofibrosis. Beyond mavacamten, deucravacitinib, and Reblozyl, each of which we see having upwards of $4 billion in commercial potential, there are other new or near launch assets with meaningful sales potential. Notable among those is Zeposia. Zeposia is currently approved in the U.S. in two indications. The MS launch continues to progress well. We're the number one SP in terms of written scripts.
We're en route to becoming the number one SP in terms of commercial dispense and have begun to shift our focus to stealing share from the broader oral class. UC, again, also going well. Still very early days. The execution of that launch continues to go well. This, we believe, is the larger opportunity for Zeposia, so I'm gonna spend more time talking about that on the next slide. But our focus today continues to be on, first and foremost, delivering on these two very important launches. Then as Samit referenced, we have the opportunity to expand into the broader IBD market, pending the outcome of those clinical programs. First things first, we've got to deliver on the opportunity in ulcerative colitis. This is a large market with roughly 1.1 million patients diagnosed across our largest geographies.
We have a very compelling profile here. This is a novel mechanism of action that's critically important in a disease like ulcerative colitis, where patients are gonna cycle through multiple modalities. The efficacy is very compelling. What physicians play back to us is the remission rates, particularly for patients who have experience on other therapies and have failed those therapies, are particularly impressive. Again, this comes with a tolerable safety profile in a convenient dose form. We see clear potential to drive utilization first at the expense of other orals and then potentially grow the oral class. Now, how we go about building this brand is articulated on this slide and is very similar to what I described with Eliquis, which is to take a very disciplined stepwise approach. This year is all about building volume.
That means continuing to add new trialists to begin to build additional depth in those trialists as a means of building volume. Over time, we have the opportunity to leverage that volume to gain broader access, ultimately moving this product into earlier lines of treatment. You can see how the patient opportunity expands as you go from multiple sclerosis to UC, and then potentially as you get into the broader IBD market in the latter half of the decade. Another set of important growth drivers for the company are cell therapy. With the approval of Breyanzi and Abecma, we're the only company with two cell therapy assets across multiple targets. At a macro level, what we've seen with these launches is, first and foremost, very significant demand for both assets. With Abecma, we've spoken about how the demand is currently exceeding our abilities to supply.
We anticipate those supply constraints will ease as we get into the first half of next year. Even as those supply constraints ease, and we have the potential of a competitor moving into this space, what the demand that we've seen for Abecma clearly illustrates is that in multiple myeloma, there's room for multiple cell therapy assets in these later line settings. We're very excited about the opportunity we have with Abecma. It's a similar story when we think about Breyanzi. Again, very strong demand for this asset based on what we see as a best-in-class profile for the drug. Exciting opportunities for both of those assets. One of the things that's also clear with these launches is the potential that cell therapy has to significantly improve the lives of patients.
Nowhere is that more evident than with the TRANSFORM data that Samit referenced, which really does speak to the opportunity to expand cell therapy to a broader patient population. It is really this ability to expand the patient population beyond the initial indication, particularly for a product like Breyanzi, that we think yields significant commercial opportunity. What this slide shows are the potential patient populations that we see as potentially benefiting from this drug. What I would highlight is that in each of these patient populations, we have strong clinical rationale and in fact, clinical data to support the use potentially of Breyanzi here. If you add that up, we see significant commercial opportunity upwards of $3 billion with this asset. Before I close, I wanna highlight the potential for relatlimab plus nivo in as a fixed-dose combination.
As Samit referenced, the initial opportunity for relatlimab will be in the first-line metastatic melanoma population. We would anticipate the commercial focus will be on those patients who are today treated with PD-1 monotherapy. That's roughly a third of the market. Obviously, as data mature, there's a potential to expand in first-line metastatic melanoma. Given the activity that we see in the metastatic setting in melanoma, there's clearly a potential that this drug could be important in the adjuvant setting, and we have a phase III ongoing to test that hypothesis. There's potentially broader applications across a number of tumors, and you see some of those highlighted on the bottom of this slide. Together, pending the outcome of those studies, this could be a very meaningful opportunity for our immuno-oncology business.
Before I close, let me just summarize here by saying the launch products that I've discussed are important because they drive growth potential through the mid-decade and beyond. In addition, we have a number of smaller but still very important drugs, and you see two of those highlighted at the top of this slide. As Samit referenced, we have a very exciting set of late-stage clinical assets across therapeutic areas. Those are highlighted at the bottom of this slide, and they have the potential to have meaningful commercial sales, particularly as we get into the latter half of the decade. It's together, these assets show the sustained growth potential that we have as a company, and importantly, these assets are gonna be critical as we go about renewing our portfolio.
With that, I'll thank you for your time, and I'll turn it over to David Elkins. Thanks.
Thank you, Chris. Nicely done. Well, good morning, everybody, and thank you for being here in person as well as virtually. It's my pleasure to share my excitement with you about what you heard here today this morning, both from a scientific perspective, pipeline perspective, and as well as from a commercial perspective. Let me just say by summarizing, you know, we've really strengthened the innovation engine, as you heard from Rupert. On the portfolio side, as you saw earlier today, we've de-risked that a lot, and I'll share with you our scorecard to demonstrate how we've been doing that, but also the depth and breadth of our portfolio.
As you heard from Chris, the size of the market opportunities that we're participating in, there's large unmet medical need, and this provides, you know, significant potential for the company to continue to grow through 2025, but as well into the second half of the decade. We're really excited about that. The other that I'll share with you here is we shared the scorecard with you at the beginning of the year. As you can see, there's a lot of check marks here, and I'm incredibly proud of the organization and all the people within it that have delivered against this. I can honestly say, you know, in my 20 years career, I've never seen an organization execute as well as we are here from a pipeline perspective.
Even one earlier with neoadjuvant lung cancer and CheckMate 816 coming through is just another proof point of the ability to continue to grow our IO franchise as well as the other follow-on compounds that you heard about. With that, we're not only executing against the pipeline, but we're also continuing to execute against the financial objectives that we laid out after closing the Celgene transaction. First and foremost, the growth of this business has been tremendous, as you've seen over the past two years. Particularly this year, as you see that launch portfolio continue to grow, gives us confidence in our ability to replenish the pipeline as well as renew and have a younger product portfolio that we're gonna be taking into next year.
That replenishment, as you heard, you'll see in a minute, it's $10 billion-$13 billion of risk-adjusted sales that we'll have in 2025. That non-risk adjusted with the expansion opportunities there, it's $25 billion just on the products that we're gonna be launching, and I'll share a little bit more about that. The financial strength of this organization. We continue to generate significant cash flow, which I'll share with you. We've over-delivered on the synergy commitments related to the Celgene transaction. As a result of that, we have significant cash flow for business development as well as other corporate needs. You can see here, Giovanni shared with you earlier, how we're gonna grow through the Revlimid LOE.
You have the LOEs that are coming through, primarily the growth coming from both not only the launch brands, but also, as you heard from Chris, the significant potential with Eliquis on where we stand with that, not only to grow share, but also to grow the class. The IO with the follow-on indications that we have that are advancing both this year and in the next year gives us confidence to continue to grow that business. Just to put a finer point on that, this year we will grow the business by about $4 billion. 75% of that growth is coming from that continuing business.
That's what gives us confidence as we head into next year with the Revlimid generic entry coming, that we'll be able to grow not only the top line in next year, but also the bottom line. It also gives us confidence on the launch portfolio as we see how well we've done this year with that, and also the trajectory as we head into next year, our ability to achieve that $10 billion-$13 billion by 2025. How will we get there? This really lays out our objective over the next couple of years of how we're gonna build $10 billion-$13 billion of risk-adjusted revenue by 2025. You can see that this is largely de-risked. We have nine products, six of which are already approved. As you heard earlier, three of those are well on their way. They're filed.
We have mavacamten coming in January, relatlimab in March, and deucravacitinib in September. As you saw with Chris, significant potential, and you can see there to the right, leading to that $10 billion-$13 billion. Very strong performance and huge potential for us. We get a lot of questions about profitability of business. As you know, we have top-tier profitability, and we're confident in our ability to continue to maintain that. First, it all starts with revenue growth, and as you can see with the potential of the portfolio, we're gonna be able to continue to grow with that, with the potential of these brands. Gross margins will decline during the Revlimid LOE.
However, remember, a lot of the products that you just heard about in our launch portfolio are small molecule, which have high margins themselves, so that will temper that gross margin decline. But also, as you know, you know, our operating expenses as a percentage of sales have been one of the lowest in the industry. We have a very disciplined approach to expense management, and we've done an incredible job this year of reallocating resources from the mature portfolio to our launch business. As a result of that, we'll be able to lower our expenses as a percentage of sales over the next few years, and that will enable us to maintain that profit margin, as we've been talking about, in the low to mid-40s% during the period through 2025. Then on to cash flow.
This organization is generating significant cash flow. As we shared with you before, $45 billion-$50 billion of free cash flow. You know, we're sitting today with $16 billion of cash on the balance sheet, so performing well. Our number one priority remains business development, and I'll share with you what we've accomplished recently with that. We've made a commitment to strengthening the balance sheet. We've done that, and we're now at 2.5x debt to EBITDA, so on a very strong position, strong investment grade. What I'd say on top of that, we have about $10 billion of planned maturities, which will further strengthen our balance sheet, putting us in a very strong position with strategic flexibility as we move forward.
We've been consistent in returning cash to our shareholders. We know this is important to our shareholders. We got 13 years of dividend increases. In the last two years, they've been double that, double digit. Also what I'd like to say is since we closed the Celgene transaction, we returned $12 billion in cash to our shareholders through share repurchases. Very disciplined approach, but it also, we have significant flexibility from a business development perspective. We've been busy this year. As you can see here, we have the ability to further complement what you saw between Samit and Rupert today with further business development. We've closed 10 deals over the past 18 months, and those deals have yielded 8 development candidates, which we'll continue to bring forward. That excludes MyoKardia.
MyoKardia is a huge opportunity, as you heard from Chris, from a mavacamten perspective, and our willingness to invest in brands that we know and that have been de-risked. We look forward to doing more of those transactions, similar to the ones that we've done historically. The other thing I'd like to say is that we've been very successful in executing transactions across multiple therapeutic areas, but as well as multiple modalities. This just gives you a bit of an insight into what Rupert shared with you with those 85 collaborations that we have and what we've been able to demonstrate and execute, most recently. With that, really excited. Elizabeth Mily and her team working closely with Rupert and Samit have evaluated a lot more deals than the ones you see here.
You're only seeing the ones that we completed, but we remain very financially disciplined. We do see this as an important opportunity to further complement the portfolio. In summary, you know, the business, all I can say is the business continues to execute extremely well, both from a pipeline, but as well from a commercial, and that flows through in the financial results that you've been seeing over the last two years. This gives us significant confidence in our ability to navigate the waters of the LOE, that the first one we're facing with Revlimid, but even just as important, one of the LOEs that we're facing in the second half of the year. You can see the pathway there with the $10 billion-$13 billion being further de-risked to $25 billion of non-risk-adjusted revenue by the time we get to 2029.
with the business development capabilities that we have to further complement the strong pipeline that you heard earlier today, gives us every confidence that we're gonna be able to continue to grow throughout the decade. With that, it's my pleasure to turn it back over to Giovanni, who will close us out and open us up for Q&A. Thank you, everybody.
Thank you, David. Thanks very much. Thanks, everyone. Let me just make a couple comments to go to close the session before we go to the Q&A. You know, if you look at this slide, I'm really proud of the diversification of our business. Across every one of our therapeutic areas we have strong in-line businesses with leadership positions in the marketplace. Our business is growing. We're launching new medicines in every one of the four areas, and interesting and very exciting is the development in our pipeline. When you look at the dynamics in the R&D pipeline, is extraordinary. Our pipeline is broad, it's deep, it is advancing both with the life cycle management of launch medicines and with the progression of new medicines in the pipeline.
You know, I look at this scorecard, it's gonna be two very important years for us. At the same time, as you've seen the 2021 scorecard that David presented, the company's executing really well, and so I look forward to continuing to see the science behind our key assets advancing and to many of those milestones beginning to be clear, so that we can advance those medicines and opportunities next year, and obviously into the next following couple of years. You know, as you've seen, we have a clear confidence in our ability to navigate the Revlimid loss of exclusivity between now and 2025. Our attention has expanded to really focus on the second half of the decade.
As you look at 2025, I see a company with a much more diversified portfolio, with a rapidly growing and dynamic portfolio of new medicines that will have $10 billion-$13 billion in sales and will be growing rapidly. That positions us very well for the second half of the decade. I wanna say again very clearly what I said this morning. I see 2029 sales as higher than 2025 sales. I see multiple paths and avenues to grow, and significant optionality. Obviously, the strength of our commercial execution, which Chris reviewed, and the financial flexibility we have as a company are integral part of our strategy to successfully navigate the headwinds of losses of exclusivity and continue to grow the company through the rest of the decade.
Some elements of our strength, clearly the significant growth potential of the new product portfolio, the excitement in the early pipeline and our science capabilities, clearly the financial flexibility of the company, the strength that we have to continue to invest in innovation. I feel we are in a very strong position to again renew our business and grow through the period of losses of exclusivity. With that, let me close the presentations. Team, we're gonna start the Q&A. Let me invite the rest of the team here with me to be able to address your questions. Thank you.
Thanks, Giovanni. While we're getting set up for Q&A, a couple of things. You know, for folks who are here in the room, if you want, just putting your hand up, we'll get a microphone over to you. Wanna make sure that the people who are participating remotely can hear your question. We know that there's several people who are gonna be asking questions remotely as well. If you are, just press star one on the telephone, so we know that you wanna ask a question. By the way, we have, as Rupert said, we have some members of Rupert, Chris, and some of its leadership teams here to help answer questions if necessary as well. Let's go. I think I see Seamus has his hand up. We'll get a microphone over to Seamus.
Oh, thanks. Just a couple of quick questions. Maybe first off, Samit, you mentioned some enthusiasm for where the relatlimab data is headed. You know, just wanted to get a little bit of a better sense of your enthusiasm for the broader opportunities outside of melanoma, and your conviction in adjuvant melanoma, in particular. Then separately, obviously a lot of questions around the JAK labeling dynamic, the questions around there. I think it's pretty clear what was explained, that allosteric is definitively different from a catalytic inhibitor. But how important is differentiation in the label to the commercial success of this product, Chris?
I'll start off with the real question that you asked, and thank you for asking that. Data are strong, as you just saw. We have preclinical science, as well as the clinical science that goes along with it. In melanoma, we've had our experience for many years now, and we understand how metastatic setting works and the adjuvant setting works. Therefore, we are very confident, and that's why we have launched a phase III program in the adjuvant setting for melanoma, as well as the evolution of the data is telling us to go into additional indications. That's why the box study that we have in hepatocellular carcinoma, intention to start a phase III study in non-small cell lung cancer, as well as the colorectal cancer program because of the evolution of the data that we continue to see.
We are very confident and very excited about relatlimab going into the additional and broader indication population. On the JAK side, I'll just start off and then I'll pass it on to you. I've shown you the data from how we are differentiating it from a in vitro perspective, in vivo perspective, phase I, phase II trials, as well as the phase III trials and the long-term follow-up data that we have now. All of that is part of the package that we've been able to submit to the FDA, and we just showed you that the file has been accepted, but both in the U.S. we filed, in Japan we filed, in Europe we filed, and now we're looking forward to those discussions and dialogues. Implications, I know that our commercial team thinks about it, so maybe you wanna add that.
Differentiation is critical in any commercial launch, and I think what's clear to us in everything that we have seen both clinically, pre-clinically, and it's 100% clear in what we hear back from customers in that we have a differentiated label with deucravacitinib. We have data that are incredibly compelling in the phase III program directly targeted against the initial competitor that we'll have with launch. It shows clear differentiation on efficacy, shows a favorable safety profile. Just to this broader JAK question, as Samit highlighted and as I alluded to in my presentation, it's entirely clear that the safety profile is differentiated from JAKs, and we hear that consistently from the customers we talk to.
That's Geoff Meacham over there. Give the mic to Jeff.
Hi, guys. Thanks for hosting the event, too. It's been super helpful. Just have a couple for Samit. You know, myeloma is a core franchise for you guys, and you have a pretty high bar set from Revlimid in first line on both cost benefit and risk benefit. When generics come into the mix here, it's a high bar. So the question is, what do you see as the biggest attribute of some of the assets in your myeloma pipeline that could maybe be convincing or persuasive to both payers and to docs? Then for Chris on mavacamten, you're super close to the launch. You talked a little bit about the awareness and where maybe it could go, but how would you characterize the visibility today?
What needs to happen from, you know, a diagnosis perspective, from a payer perspective, you know, just to help with the early stages of the launch? Thank you.
Samit.
Thank you, Jeff, and I'll start off with the myeloma side of things. As I said earlier, and also Rupert showed you how CELMoDs have evolved from our understanding of how IMiDs work. We took that preclinical understanding into the clinical side of things and saw if these CELMoDs are active when the patients have a disease that is refractory to IMiDs, and is there activity there? We've consistently seen that when we look at the response rates in patients who have a disease that is refractory to prior treatment with Revlimid, pomalidomide, et cetera. The second thing then is, as I talked about earlier, that our plan is to see if they are combinable, and we do see that they are combinable with the current standard of care, daratumumab, Velcade, as well as carfilzomib.
That is the reason why we can move earlier. The first test, of course, of this hypothesis of a head-to-head comparison will come through the 92480 study that we plan, which will compare it head to head versus pomalidomide in the phase III study that is gonna start next year and/or early 2023. Looking at pom Velcade dex versus 92480 Velcade dex. The second one that will be is in the post-transplant maintenance, again, comparing iberdomide to Revlimid. Now, these studies will tell us, of course, we'll need this superiority to get to the point that you're getting to, how do you convince the prescribers and payers?
These are the kinds of data that will be important, but we look at these, the raw evolution of the data, the emergence of the data, and that is what is giving us the confidence to move into the earlier lines.
Maybe I'll start with the mavacamten question, then I'm gonna turn it over to Adam Lenkowsky, who leads our U.S. business and spends the majority of his time thinking about the launch preparations that we have across assets. With, with mavacamten, as I said, I think it's gonna be important that we stay very disciplined in how we execute against this launch. The initial focus, as I mentioned, is gonna be for centers of excellence. That's where many of these diagnosed patients, particularly those who have more significant disease, are being treated today. We think there will be a bolus of patients there. Then we'll be very stepwise in moving beyond that. We've got a nice infrastructure that's been established in the cardiovascular to move into the broader cardiology community, so we'll be disciplined about how we do that.
We've got a lot of efforts really across the organization focused on how we increase the diagnosis rates. There are a number of interesting approaches that the team is investing in, really not only on the commercial side, but also partnering with our medical and development colleagues. I'll let Adam speak more to how the preparations are going.
Sure. Thank you, Chris, and Jeff, thanks for the question. Our teams are launch ready for mavacamten, very excited with our PDUFA date coming up at the end of January. Our teams are working diligently to raise awareness of the disease state of HCM because as Chris mentioned, the diagnosis rate is very small today. It's modest at 20%-25%. We think we can significantly increase that over time. We also know that these patients are in these academic centers that are HCM centers of excellence. There are about 250 centers in the U.S. that capture the majority of these patients at launch.
We do think there will be a bolus of patients at launch that will be appropriate for treatment, but the key is gonna be over time reinforcing the efficacy and safety profile of mavacamten, making sure that patients have a frictionless experience as they go on to treatment, and ultimately expand out beyond those centers of excellence into the broader cardiology community. Our field footprint is in place. We have coverage with Eliquis, and those are the same teams that will be launching mavacamten over the next couple of months. It also reminds me of, there's a slide that with Plavix, because we have an opportunity now to recreate a new category like we did with clopidogrel several years ago. The teams are ready to go and very excited about the opportunity. Thank you, Geoff.
I think Steve Scala has a question over here, Nina.
Thank you. Steve Scala from Cowen. I have three questions. First, Giovanni, you provided many milestones for financial progress. It's not clear how these milestones compare to what the company has said in the past. For instance, new product potential was stated to be $25 billion in 2029. In the June 2020 meeting, a $20 billion number was provided for 2025 through 2029. Has the potential gone up 25% or are the numbers looking at something different? Secondly, in the past, the company has said Sprycel, Abraxane, Pomalyst, and Revlimid would represent 10% of revenue in 2025. Apologies if I missed it, but I don't think the company said that today. In fact, I don't think it's said it for a while. Has the guidance changed?
If so, how has it changed? Lastly, Chris, it's clear Bristol does not view deucravacitinib as a JAK and therefore should avoid a JAK label, but there's a real chance that FDA gives you a JAK label anyway. What happens to the $4 billion+ potential if that is the case? Thank you.
Thank you, Steve. Let me start on the financial targets, and I'll ask David to comment. I'd like to focus on one number you described, the $20 billion-$25 billion we discussed earlier this year. Today, we didn't mention 25+, and that's just because the outlook for the launch portfolio has improved. As the data has matured, relatlimab, as an example, has come into the picture, and we see significant potential for relatlimab in melanoma. The launch portfolio has just strengthened. You know, we're really confident that we are continuing to execute on the plan, and we have more visibility and optionality in terms of the growth. David, do you wanna comment on the continuing business versus total business?
That's right. The continuing business, as we said, I think your first question was related to the LOEs. That's all the LOEs that we're gonna be facing that we include in that number to be all inclusive. Then as you can see there, the inline business, both from the IO as well as the hematology is continuing to grow. As a percentage of the total, as we said, reaffirming that, approximately up to 30% of that business will be from the new portfolio. We haven't changed anything and from the previous guidance that we provided.
Yeah, that includes what percentage of the total company's continuing business versus the LOE portfolio.
Maybe I'll pick up on the question on deucravacitinib. As I said in the presentation, we see significant opportunity for this for this asset. We have a very strong team that's ready to deliver it. We scenario plan really across different label scenarios. We do that for every launch, and then that's inclusive of what we're doing with deucravacitinib. The team's gonna be ready irrespective of the scenarios that come our way. I'm not going to speculate on where the FDA could net out, but I think what is very clear from what the drug is telling us and what customers are telling us and what folks who have experience with the product through the development program are telling us, and that is it is a very differentiated profile.
The phase III data are very clearly differentiated against the main competitor that we're going to have at launch, and the safety profile is absolutely favorable relative to Otezla and clearly differentiated from JAKs.
Great. Let's go to one more in the room. I think Ronnie has his hand up, and then we'll take some from the phone.
Good morning, and thank you for being the pioneers in terms of us returning to in-person meeting. Thank you very much for the great presentations. I've got three kinda like specific questions around product. The first, Zeposia. You've mentioned that you're gonna do well with it in 2022. Given we're already in November, if you could share with us the commercial coverage in UC that you're seeing, both overall and in first line without a prior branded step. Second, on milvexian, one of the questions, the comparison to apixaban. Would you conduct as part of the pivotal program a head-to-head trial against the apixaban in any indication? Third, great expectation for Reblozyl.
Can you just share with us what you're seeing right now in terms of duration of treatment in the field now that the product is approved? Thanks.
Chris, w hy don't I hit Zeposia and Reblozyl, and then I'll turn it over to Samit on milvexian. For Zeposia, as I said in the presentation, this year is all about building volume and then driving additional access based on that volume. It's a bit early to provide any additional context on sort of how those discussions are going. What I will tell you is we are having very good success in terms of the execution of that launch. We feel very good about what we're doing in terms of driving awareness of the product. In fact, unaided awareness is upwards of 70%, aided awareness is over 90%, and importantly, all of those customers that we talk to who are aware of the product have an intent to use the product in ulcerative colitis.
That's a very important leading indicator as we think about the opportunity to, again, build that volume this year going into next year and then leverage that for broader access. On Reblozyl, maybe I'll turn it over to Winslow Tucker, who leads our hematology business in the U.S., and he can give you a sense of where things stand on Reblozyl.
Thank you, Chris, and thank you for the question. With Reblozyl, I think you asked specifically around the duration of therapy. What we've seen, and we said earlier this year, we had a bolus of patients. That bolus of patients has actually declined. What we're seeing is long-run patients, and those patients have a better duration of therapy. Additionally, as we're getting patients, and Chris identified this, we're focused on getting patients earlier in their treatment journey, and we see that as evidenced by the fact that patients are moving quicker from ESAs onto Reblozyl. Secondly, we're focused on the right duration of therapy through ensuring the patient physicians optimize the dosing. What we would expect over time is that duration is gonna continue to build as we get patients earlier and as those patients stay on longer.
Excuse me. When patients are extending past eight months, getting much more further, we see very few patients dropping off at the eight-month period. As we go further and further, get earlier patients, also with the NCCN guidelines in our favor, we expect that duration to continue to increase. Thank you.
The third question that you had was around milvexian, and whether we'll do a study versus apixaban. Look, it'll all depend on what indications are chosen to be taken forward, what are the regulatory requirements, and what do we need for a registration trial. We are certainly going to be ready to do that if required by regulation, and if the trial needs it, because we do believe that the profile that we've already started to see and emerge is differentiated from a bleeding perspective and efficacy perspective.
Thanks so much. I just wanna check. I think Luisa Hector may be on the phone. Luisa, if you're there, do you wanna go ahead and ask a question?
Hi, Tim. Yes. Can you hear me?
We can.
Great. Sorry not to be with you. I have a couple more on milvexian. Just to understand any potential advantages of an oral approach versus, say, antibodies over and above the convenience. Curious to understand your thoughts around dosing once daily, twice daily, and how you're thinking now about that combination with DAPT for the secondary stroke prevention study. Do you feel more confident on the safety profile with the knee replacement data in-house? Secondly, a broader question on the approach to R&D investment and productivity, because it's very clear from all of your presentation that the phase I and II pipeline is full and exciting. Industry success rates tell us that more assets will fail than succeed at that stage.
Can you give us any confidence that, at Bristol- Myers, you will have higher success rates or confidence that you do have good stop mechanisms in place to make sure that you're not over-investing in failures? Thank you.
Thank you. Let me maybe start from the second question. If you don't mind, I'll ask Rupert and David to comment. Then, Samit, you can address the milvexian question. You know, I think when I look at our R&D organization, I look at R&D pipeline, you know, I'm really impressed with the depth and breadth of the pipeline. Of course, we know that many programs in phase I and phase II will not work. That's the nature of our business. It's the nature of our industry. It's the reason why, you know, very early on, you cast a broad net and you invest beyond a number of different strategies at the same time.
I think obviously what you're referring to is, do we have the right strategies in place to look at proof of concept trials early on, so that we maximize the opportunity to success. Rupert, why don't you comment on that?
Yeah. It's a really good question, and I think there are several things that we do to try to mitigate that risk, and certainly to try to avoid things going into large, expensive trials and having, you know, late-stage failures. First of all, in the selection of the targets that we choose, certainly in the non-oncology indications, we place a heavy weight on human genetic validation. I wanna refer you to both milvexian and to deucravacitinib, that both target biological targets that have extremely strong genetic validation. We know that when you do that, it's not a guarantee of success, but it does bias things in your favor.
In fact, Robert Plenge, who's here in the audience, is a trained geneticist as part of his background and looks after most of the non-oncology part of our portfolio. Obviously, on the oncology side, we use a range of other approaches to try to improve the success rates at the target selection stage. The next thing I would say in answer to your question is that we invest extremely heavily in translational medicine. In the time in my career in industry, this is an area that's advanced dramatically because there are so many technologies that you can use for assessing whether your drug is having the biological activity that you really want it to have.
We don't allow any molecules to enter the clinical phase of development without a validated and clear biomarker strategy to enable us to correctly interrogate the drug mechanism. We actually hold things back if they don't have that. The other feature of our translational work is the aggregation of datasets. I showed you just one example of that in my presentation, but that extends broadly to all the areas that we work in, where we have aggregated and collected large datasets, and we try to use these through computational methods to best select the patient populations in which to test our medicines. So that we can get signals as to whether things are working as early as possible and as nimbly as possible in a focused population.
We also have very rigorous governance around the transition of molecules from early development into full scale late development. Samit and I work extremely closely on this. For every program- We define a clinical proof of concept paradigm. It does vary depending on the disease or the mechanism, but every single one has that defined, and we recognize that if we achieve those bars, we have something that is worth investing in heavily in global drug development. That's a really important part of our drug discovery and development process. All those things are in our favor, I think, in terms of trying to optimize our success rates.
Thanks, Rupert.
I think, Lisa, your second question was around milvexian in terms of the oral formulation versus looking at it from an antibody perspective. Two things that are gonna be important here to remember. One is just the convenience of delivery, oral versus subcutaneous or any other parenteral way of administering it. Second is about the half-life. The T-half for milvexian is about 12 hours. So if it were to be that the patient or a person gets into trouble from a bleeding perspective, withdrawal of that oral agent leads to that reversal very quickly as we look to the future. The second question was around QD versus BID dosing. As you know, we've done a dose-ranging study, both in the TKR study as well as ongoing the SSP study.
I think that the combinability or combined dataset from the two trials will ultimately define whether we go forward with a QD dose or a BID dose. It's too early to pick that schedule at this time.
Great. Tim Anderson, I think you're on the phone.
On mavacamten, a topic I've probed on before, regarding just getting a standard review and not a priority review, despite you know very robust results from the Explorer trial. You know, I wondered if a CRL could be the outcome at the January PDUFA, but maybe your comments about the teams being launch-ready answers this question, and you're saying you're highly confident. I'm surprised there's no FDA advisory panel for this product, and I've just wondered if FDA would wanna see more data from something like the VALOR trial before approving the drug. Those results come out in 2022, but just not by the PDUFA date. On milvexian, in the past at least, you've described the target product profile seeming to center mostly on chronic anticoagulation, really going after things like the factor Xa.
Today, you seem to be casting a broader net potentially, but is the main focus here and the main value proposition really just in that chronic anticoagulation setting? Thank you.
Yeah, Tim, let me start with mavacamten. You know, I know you've asked the question before. We've articulated that very clearly today. Our teams are launch ready. Of course, we are in discussion with the FDA as part of the regulatory process, as you would expect us to be. But we're really confident in the profile of the medicine from an efficacy perspective, from the safety perspective. Our perspective is that it's well-characterized and, you know, there is really not much more I can add versus what we've said in the past. You've seen our excitement and enthusiasm today. Samit, on milvexian?
Yeah, milvexian. Look, I think what you're hearing from us is there are opportunities that are there, both on the arterial side as well as on the venous side, both as a single agent as well as combination with the background therapy of antiplatelet agents. We have those choices to pick from with our partners, Janssen. We haven't picked the indications themselves, and we will be able to communicate that once we have the data available, and we are able to make those decisions and then be ready to convey. At this time, I wouldn't say it's a chronic anticoagulation or a broader net, but rather these are all the options we have on the table.
Great.
Thank you.
I guess, Matt Phipps had a question.
Thanks, Tim, and thanks, everyone, for hosting us. On deucravacitinib, you know, you mentioned the second UC trial. Samit, you've said a couple times the potential to expand that trial. Now, there's only 50 patient enrollment listed on ClinicalTrials.gov. Wondering what you need to see or what's the gating factor, and is that just expanding enrollment or adding dosage arms? Then also, I just wanted to confirm, I know you said deucravacitinib filing is checked off. You mentioned a PDUFA date. Has the filing been accepted? Sorry if I missed that. Yeah.
Yeah, I'll start with the second one because that's straightforward. Yes, the filing has been accepted, and as I think you saw on my slide as well as David said, the potential PDUFA date will be in September. The exact date, we are still waiting to hear back from the FDA. Imminently, we should be hearing it. On the UC side, we have two trials ongoing, and I'm not gonna go deep into the doses and all of that, but all I can say is we do have a very good eye on it. We have the expansion, meaning in terms of the number of patients to be enrolled in there, and we will be looking forward to that proof of concept when available. We're looking forward to end of 2022, 2023 to be able to get to that.
Great. I think I see Carter has his hand up.
Great. Thank you for doing this. Carter Gould with Barclays. I guess first for Chris on mavacamten. I recognize it's too early to get into details on pricing, but there are a lack of good comps, and you could drive a whole fleet of trucks between Entresto, PCSK9s, and Tafamidis. Can you offer any color that you've internalized some of the learnings from prior CV launches that maybe didn't live up to hype and your confidence that pricing won't limit access at launch? Then maybe for Samit, just in terms of EXCALIBER, particularly the study post transplant, in the past Celgene and Bristol had talked about other kind of surrogate endpoints beyond PFS, to the extent that maybe this could include, you know, minimal residual disease or something like that as an endpoint. Any thinking or color you can provide there?
Just a clarification, not EXCALIBER. You're talking about TRANSFORM, I guess.
the other frontline study with
iberdomide.
iberdomide, yeah.
Oh, iberdomide. Okay. EXCALIBER study. Got it.
Yeah. Maybe I'll start. As you said, it's too early to talk specifically about price, but what I would tell you is that we have invested heavily over the years in this space, in particular, to build a very strong market access capability, and that includes understanding pricing dynamics. I feel very good about our ability to manage through the pricing environment with this asset, and I don't anticipate that it's gonna be a great limiter to our ability to get access.
On EXCALIBER for iberdomide, as we look to the regulatory landscape, at this time, the minimal residual disease is not a validated endpoint. We certainly look at it in every trial that we are conducting. We will have that as an exploratory endpoint in this trial as well. We'll see if it graduates to a secondary endpoint if the data are supportive. At this time, I don't think it's an endpoint that is validated for use as a primary endpoint. We'll see how that evolves with the conversations with the FDA.
Great. I know we're running a little over, but we have time maybe for a couple more. I think, on the line, I think we have Andrew Baum. Andrew, are you there?
Thank you. A couple of questions. Firstly, just following up on milvexian. Could you talk to whether you believe that the key market opportunity is atrial fibrillation, despite there being a generic NOAC in the market even after you would launch, or whether indications like ESUS and ACS are gonna be the area that's gonna be the biggest revenue generator? Obviously, the data's evolving, I take that, but interested in your view at this point anyway. Second, in relation to deucravacitinib, could you talk to whether you had any interaction with the FDA? I hear your very positive statements about the anticipated label, but the FDA, I'm sure, will be aware of the increase in viral infections in patients with loss of function TYK2 mutations. You see the label which Opdivo got, even though it's a cream.
The mechanism of thromboembolism is still not defined as far as I know, in relation to the JAK family, of which this is a member. I accept entirely allosteric inhibition, but it just would seem directionally the risk aversion of the derm division in particular would make a boxed warning more than likely, and I wondered if you had already had any feedback or discussions with that division since you filed?
Thanks, Andrew. Chris, why don't you start with opportunities for milvexian, and then we'll cover your question, Andrew, on deucravacitinib.
Sure, Andrew. As you mentioned, you know, it's obviously difficult to talk about the commercial opportunity absent the data. What I would say is that the nice thing about the development program for milvexian is that it actually has a focus on two areas that continue to be an unmet need generally in the space. The first is bleed rates. With Factor Xa, that continues to be a consideration in patient selection and how patients are treated. Second is the risk of secondary events. We know that patients who have a stroke are at significant risk of a secondary event within months of the primary event. Both of those are areas of significant unmet need here, and they're the primary focus of the two phase II studies that Samit referenced in his presentation.
Beyond that, I think we'll have to wait and see how the data continue to evolve, and as the development program materializes, we'll be able to speak more to that.
Yeah. Andrew, as it relates to deucravacitinib, of course, I'm not gonna comment on the conversations we've had or we will have with the regulatory agencies, as we've never done that before. What I can tell you is if you look at the data for deucravacitinib, not only from the psoriasis trial, but as we continue to evolve in terms of learning from our data of other indications as well, look at the profile from a thrombotic perspective or MACE events perspective, we don't see it. Those are the conversations that are gonna be important for all of us to understand and take forward.
I think this is Matthew Harrison on the line?
I'm here. Thanks. Thanks very much for taking the questions. I guess two from me as well. One on milvexian. Again, I was wondering if you could just comment on the SSP study. Excuse me, the SSP study. And two questions there, just on how you're thinking about doses and how you're thinking about powering of that study, given the number of arms and the need to really differentiate on efficacy and safety there. And then secondly, maybe one for Rupert on protein degradation. You obviously gave us one of the targets that you're focused on there. Maybe you could just talk about the breadth of your protein degraders platform and how you're thinking about targets. Thanks.
I'll ask Roland Chen, who's the head of the cardiovascular therapeutic area in my team to take on the milvexian question.
Thanks for the question on milvexian. So what we're doing is somewhat similar to what we've seen with the AXIOMATIC-TKR study. We're studying a range of doses, both BID and once daily doses in the SSP study specifically. What we're looking at is for a primary outcome, looking at events of recurrence of stroke or covert brain infarction. This endpoint was chosen because it would allow us to see the number of events to try to understand the dose-response profile with respect to efficacy as well as the safety profile in the SSP study. Thank you.
From a statistical perspective, each of the arms will be compared to the placebo arm, similar to what was done in the AXIOMATIC-TKR study. We will have adequacy in terms of reflecting on that as the data come out.
Rupert?
Yeah. No, I'm glad you asked me that question 'cause it's one of my favorite topics, so this should fill up the rest of the available questions without any trouble whatsoever. The programs that we have that are visible in clinical development, obviously we have optimized Aiolos, Ikaros degraders. We have the GSPT1 degrader, and we have a brand new one, which is a CK1α selective degrader. Those are the disclosed degraders. You saw on the slide that I also listed seven additional molecular glue targets that are in what we would call full discovery. They are marching towards development candidates. I'm not gonna disclose the specific targets of those degraders, but I can tell you that they're all different from the ones that are in development today.
Behind that, just to give you a little bit of perspective as to why people are so excited about this and why we're seeing a lot of investment. Over the last seven years or so, we have made investments to fully understand the range of degradable proteins by the Cereblon modulating collection of compounds. This has been a back and forward between undertaking full proteome analysis and then expanding the library of compounds, which in that time has gone from about 5,000 compounds that all look rather similar, to now, many tens of thousands of compounds that all look extremely diverse. I can tell you that there are literally hundreds of degradable proteins that can be brought into that complex in numerous different structural configurations.
The challenge for us is not that we don't have enough targets to go after in this space, it's making sure that we pick the right ones. There are a range of things that are really desirable, have been undruggable, that are coming into our discovery pipeline very rapidly. Then there's another tier where we need to add to the biological validation. Then there are others where actually people don't know very much about the function of the proteins because there has been no means of studying it. Those are in a sort of third bucket, where we need to kind of watch and wait. There's way more than enough to sustain an ongoing set of programs here, probably at the level of, you know, 7-10 discovery programs for a number of years to come.
Thanks, Rupert.
Rupert, I think maybe we have time for two more quick ones. I think Dane is on the phone. If you're still there, Dane, do you wanna ask your question?
Hi, thanks for taking the questions and congratulations on the updates. Just two quick ones from me. Firstly, a pipeline question. As we look at your pipeline and even the deeper pipeline, in oncology, especially within solid tumors, a missing component of your pipeline continues to be targeted oncology. I would just like to get your thoughts in terms of maybe that strategy, if you're interested in filling in targeted oncology as a part of that portfolio, over time. Then how defensible you think the IO portfolio is, given you will start to have some at least biosimilar competition towards the latter part of the decade from drugs such as Keytruda. The second question is very easy.
Can you just comment in terms of more specifically what might be improved in the manufacturing and deliverable abilities for Abecma into the first half of 2022? As we've heard that there's some frustration in the clinical community with manufacturing and cell expansion failures with the commercial product as it stands now. Thank you.
Thank you. Let me ask Rupert to start on targeted oncology, and then Chris will mention.
Yeah. Thank you for your question. Over the last two years, we've actually reconfigured our research efforts. We have four research teams that are focused on different aspects of oncology. Our team in Redwood City works on the tumor microenvironment, so that's really next generation IO. We have our cell therapy team. I talked a little bit about going after solid tumors with cell therapy. We have our protein homeostasis team, so we've talked about that. Many of the targets that I just referenced without naming them are all targeted small molecule therapies using degradation as a way to go after solid tumors. Then the fourth component is our team in Cambridge, who are definitely working on different aspects of targeted oncology therapy.
We have a number of collaborations in the DNA damage repair space, and we've converted some of our resources to start focusing on things like next generation KRAS inhibition. We have an active business development effort seeking to supplement that with additional targeted therapy. I think we've really rebalanced our portfolio, managed to maintain our core strength in immuno-oncology, but built in two brand new research units that we'll be seeking to broaden out that portfolio in the way that you asked.
Regarding Abecma supply, I would say there are a number of efforts underway, and I'd maybe just highlight three. The first is there's obviously a focus internally on continuing to build our capacity to meet the demand in the marketplace for Abecma. Those efforts are well underway and are going well. Second, as we've highlighted repeatedly, there is a broader issue affecting cell therapy around vector supply. We have an ongoing work stream to make sure that we are doing everything we can to build up our supply of vector, leveraging internal and external opportunities to do so. The third thing related to Abecma, as we've engaged with customers and as referenced your out-of-spec point, is that we are working with customers to understand the patient types that are more likely to yield an out-of-spec.
We're hoping to optimize the type of patients who go on to these therapies. I think that's gonna be important as well.
Thank you.
I think we'll go to our last one. I think Evan has his hand up.
Thank you. One on deucravacitinib. Can you just talk about some of the key learnings from the Otezla launch? I think there's a few of us here who remember some of the challenges on what you're doing to ensure both, you know, proper positioning and, you know, effective contracting, given the competition. Thank you.
Sure. Yeah. I mean, I think you've hit on both of them. One of them is that making sure that you position the product well at launch and clearly differentiate. I think the advantage that we have here is that we have very strong data relative to Otezla. The phase III program is very clear on efficacy and differentiation versus that asset. We compare favorably on safety as well. I think that from a positioning standpoint, we feel good that the data is supportive. We're building a very strong team in the U.S. under Adam's organization. A lot of experience in this space, which I think is also gonna be very important and is a lesson learned from Otezla.
The other thing is, we have focused a lot of energy on making sure that we're building the right patient support services and market access capabilities, and that was one of the impediments to the Otezla launch.
Thanks, Chris. Well, look, we've run over, but lunch is still available outside. Thanks, all, for coming and thanks for participating online.
Thanks, everyone.
Thank you.
Thank you.