Good day, everyone, and welcome to the Bristol-Myers Squibb 2021 Fourth Quarter Results Conference Call. Today's conference is being recorded. At this time, I'd like to turn the call over to Mr. Tim Power, Vice President, Investor Relations. Please go ahead, sir.

Thank you, Alan, and good morning, everyone. Thanks for joining us this morning for our Fourth Quarter 2021 Earnings Call. Joining me this morning with prepared remarks are Giovanni Caforio, our Board Chair and Chief Executive Officer; and David Elkins, our Chief Financial Officer. Also participating in today's call are Chris Boerner, our Chief Commercialization Officer; and Samit Hirawat, our Chief Medical Officer and Head of Global Drug Development. As you'll note, we posted slides to bms.com that you can follow along with for Giovanni and David's remarks. And before we get started, I'll read our forward-looking statement. During this call, we'll make statements about the company's future plans and prospects that constitute forward-looking statements. Actual results may differ materially from those indicated by these forward-looking statements as a result of various important factors, including those discussed in the company's SEC filings. These forward-looking statements represent our estimates as of today and should not be relied upon as representing our estimates as of any future date. We specifically disclaim any obligation to update forward-looking statements, even if our estimates change. We'll also focus our comments on our non-GAAP financial measures, which are adjusted to exclude certain specified items. Reconciliations of certain non-GAAP financial measures to the most comparable GAAP measures are available on bms.com. And with that, I'll now hand over to Giovanni.

Thank you, Tim, and good morning, everyone. Let's start with our fourth quarter performance on Slide 4. I'm pleased to report we delivered another strong quarter, building on our very good performance throughout 2021. Our commercial results were strong across the portfolio with robust performance in our continuing business, driven by Eliquis and accelerated growth for Opdivo as well as continued demand growth for our new products. The launch of Zeposia in ulcerative colitis is progressing well in the U.S., and we obtained European approval during the quarter. We are pleased with continued demand growth for Reblozyl in ESA refractory MDS and transfusion-dependent beta-thal. And our cell therapies, Breyanzi and Abecma, continue to see significant demand while we remain focused on broadening supply and expanding indications over time. We are advancing our strategy and delivered key pipeline milestones in the fourth quarter. This enables us to help more patients, accelerate the renewal of our portfolio and support our growth outlook. Let me highlight some key achievements. We submitted applications for the deucravacitinib in the U.S., EU and Japan, which position us well to grow our presence in immunology. We are excited about the potential of the deucravacitinib as the oral standard of care in moderate to severe psoriasis and various other autoimmune diseases. We are expanding our cardiovascular portfolio and presented exciting data at AHA for Milvexian, which we see as the next-generation anti-thrombotic with a $5 billion-plus non-risk-adjusted revenue opportunity. We presented important updates at ASH on our hematology pipeline. This includes encouraging data for iberdomide and 480, our exciting new multiple myeloma CELMoD agents. These have the potential to replace Revlimid and Pomalyst over time. Importantly, the TRANSFORM data for Breyanzi in second-line B-cell lymphoma showed practice-changing benefit compared to the current standard of care. We continue to…

Thank you, Giovanni, and thank you all for joining our call today. I'd like to start with our strong top line performance on Slide 9. We closed out the year with another great quarter across our key franchises. Revenues grew high single digits versus prior year, which was driven primarily by increased demand for our in-line and new product portfolios. Now let's turn to some product specifics, starting with Eliquis on Slide 10. Eliquis continued to deliver extraordinary growth, with global sales up 20% for both the fourth quarter and the full year. In the U.S., fourth quarter sales increased 22% versus prior year, driven primarily by total prescription growth of 13%. Internationally, Eliquis sales growth continues to be driven by increased share across all key markets, and the brand remains the #1 OAC in multiple countries. Looking forward, the growth outlook for Eliquis remains strong as we continue to grow the oral anticoagulant class and increase our share within the class. As a reminder, the first quarter of 2021 did experience a onetime favorable true-up in the U.S. of approximately $160 million that will not repeat in Q1 of '22. Moving to Opdivo's performance on Slide 11. We are very pleased with the accelerated momentum, growing 11% globally versus prior year. This is driven by strong demand, particularly for our new launch indications. In the U.S., fourth quarter revenues were strong, up 16% versus prior year. Growth was primarily attributable to demand in metastatic indications, including first-line lung, first-line renal and first-line gastric cancers as well as adjuvant indications with the approvals of adjuvant esophageal and adjuvant bladder cancers in 2021. Internationally, fourth quarter revenues grew 5% versus prior year, driven largely by demand for new indications and expanded access primarily in emerging markets. More broadly, we continue to…

Thanks, David. Alan, can we go to our first question, please?

Certainly, sir. We'll go first to Seamus Fernandez with Guggenheim.

So first question is just on your factor XI. Just wanted to check in on timing of the potential update from your Phase II study. And just wanted to get a sense of where your expectations are. As we've spoken with thought leaders in the space, the hope is that the increase in the dosing or the stepped-up dosing would result in no bleeding increase, but with roughly a 15%, potentially 20% benefit, on stroke. How does that sort of fit with your expectations? And can you guys help us understand a little bit better the opportunity to open up this potentially new market and how you see the size of the opportunity should that profile be achieved? And do you agree with those views? And then second, just on your -- we just had the filing of the Cytokinetics competitor compound. Can you just talk a little bit about the competitive landscape as you think about the opportunity for mavacamten versus other competitor compounds?

Thank you, Seamus. This is Samit. I'll take both of those questions. So for factor XIa, as we have talked about, the second Phase II study, which is in secondary stroke prevention, we expect to have the data in-house around the middle of the year. And at the appropriate conference, we will be able to share that data beyond that. And we're continuing to work with our partner, Janssen, to really execute on the future development of Milvexian. As your question related to what the data would show and what the acceptance and availability would be and applicability would be from a bleed perspective or efficacy perspective, I think you just have to wait to see the data. The primary goal for these studies is to be able to isolate what the impact is on the bleed as we look to combine it with the background therapies of anti-platelet agents as well as to then progress them further into appropriate indications, either as a single agent or as combinations. So we just have to wait for the data. But as we saw in the TKR study, there was no increase in the bleeds. But we certainly saw increase as a dose -- in a dose-dependent manner from an efficacy perspective. So let's wait for the middle of the year to see the data, and then we'll define the future trajectory for the development of that. Coming on to the mavacamten and the competitor compound. We remain very focused and very confident in the data for mavacamten. As you know, we are launch-ready, as David spoke earlier, for the PDUFA date coming up soon. And as it relates to the additional data, we are waiting for the readout of the VALOR trial as well in the short time frame. Now of course, we've seen the small amount of data that has been talked about from, I think, 13 patients looking now at a different cohort in combination with disopyramide. Certainly, we, in our EXPLORER trial, have looked at the commonly used background therapies of beta blockers and calcium channel blockers. In the VALOR trial, we do have patients who are going to be receiving the background therapy of disopyramide as well. So we do not see a differentiated profile at this time from a competitor perspective. We certainly are confident that we already have a Phase III trial that has been submitted and the second Phase III trial that is going to read out in the short term.

The only thing I would add, Seamus, is just on mava. As we've discussed previously, the current standards of care for these patients really aren't focused on targeting the underlying nature of the disease. So we feel good about the competitive environment when we launch. And as Samit mentioned, we don't see any differentiated competition on the horizon. And certainly, based on the public data that we've seen thus far from competitors, it's entirely consistent with what would be expected from a myosin inhibitor. And so we feel very good about the competitive position for this agent and look forward to launching.

We'll go to Chris Schott with JPMorgan.

Just to maybe follow up on mavacamten. Can you just help set some expectations about how we should be thinking about the launch here? I guess, is this a product, given the current standard of care, where there could be kind of a bolus of already identified patients you could go after? Or should we be thinking about maybe a more gradual ramp as you to need get -- we think about reimbursement and familiarizing physicians with whatever REMS program ends up coming out of this one? And then my second question was just an update on CAR T capacity. Just walk through a little bit about how you're expecting capacity to ramp as we move through 2022. And I guess when will you be in a position where capacity, I guess, is not the rate-limiting factor for the growth of these products?

Sure, Chris. I'll take both of those questions. With respect to mava and how we think about the shape of the opportunity, I would think about it as more of a gradual opportunity. When we look at the way this launch will likely progress, it's very much going to be in a stepwise fashion. We expect that there will be strong interest in treating the most severe patients, particularly in the centers of excellence where these patients are being treated today. That's going to be the initial focus. Beyond this, we'll expand our focus to cardiology specialists and into the broader cardiology community, where uptake is just going to be more gradual. And one other thing I would say about -- as we think about really all of these segments, we have an educational effort on that will be initiated at launch as to how physicians should initiate and treat these patients. And certainly, there will be a focused effort to get patients on therapy quickly. But just those efforts in and of themselves will take some amount of time. The good news is we have a very strong team with an established presence in this space. We have a very good drug. So we feel very good about the long-term potential for the asset. And that stepwise approach that I articulated really is in line with the overall opportunity of $4-plus billion that we see for this asset. Moving to cell therapy supply constraints. As we've said previously, the supply constraints that we're seeing right now are mainly related to Abecma. And our efforts are really focused on working with CMOs to accelerate capacity for vector. And then internally, we're focused on flat capacity. And there are a number of things across both of these efforts that we're focused on, including training and qualifying new staff, increasing our operational efficiency and increasing site capacity. On Abecma, we would anticipate being in a much better position for supply as we get into the middle of this year. And then as it relates to Breyanzi, Breyanzi, the big focus there is on vector supply. It's something we continue to stay focused on. And we fully -- we expect to be in a position to support demand as we get later into this year and certainly by the time that we would have any label expansions for that product.

So next, we'll go to Geoff Meacham with Bank of America.

For some of the new launches, are there any metrics you guys can provide that show the wins in access and reimbursement? Mostly talking about cell therapies and Zeposia. The bigger picture, is just trying to assess the tipping point for this year potentially for the launches collectively versus what we saw last year, which was a lot of lumpiness on a kind of a sequential basis. And then the second question real quick on deucravacitinib. I know there's been a lot of angst about the potential for differentiating labels versus JAKs. I just want -- now that we have clarity on the latter, just wanted to get maybe an updated view from you guys on that.

Sure. Maybe I'll start, Geoff. Thanks for the question. So as we look at access really across all of these launches, we feel very good about where we are from an access standpoint. And I'll start with cell therapy. Cell therapy actually, I think, is a very, very good story. We've seen no issues with respect to access constraints for our cell therapy launches. We've discussed the supply constraints. But the launches have gone off really without a hitch from a supply -- from an access standpoint. And in fact, if you look at the class of agents more generally, if you go back a couple of years, as you well know, access and reimbursement were significant areas of concerns. And I would say largely for the class of agents, we've been trending in the right direction. But we see no issues on our cell therapy assets. As we switch gears and you mentioned Zeposia, obviously, the focus is on UC. But very quickly on MS, I feel very good about the access position there. We have very broad coverage in MS, so really not a significant concern on the MS side. In UC, we've been very clear that we have to execute a diligent effort around access over the course of this year. What I can say coming into 2022 is we have very broad formulary coverage for Zeposia. Now how restrictive that formulary coverage is, it varies by plan. And for the course of this year, for those patients with less restricted access, the focus is going to be on converting those patients from starter or bridge programs to commercial drug, and do so very quickly. For patients with more restricted access, which unsurprisingly for our first full year in the market, most patients have multiple step edits, the focus is going to be on working through those restrictions, and that's going to take more time. What I can say, though, in any case, is that on Zeposia, we're continuing to build volume over the course of this year. The plan has been and continues to be to then leverage that volume to move Zeposia into an earlier access position as we head into 2023, and we're very much on track to do that.

And Geoff, I'll take on the question around deucravacitinib. So let me start by saying that we are obviously not going to speculate on the label for what we will see. But we certainly remain very confident in the efficacy and the safety profile that we've talked about before. And we are looking forward to the PDUFA date in September.

Next, we'll go to Steve Scala with Cowen.

I have a couple of questions. Opdivo was a bit weak in Q4, similar to what we've seen from some of your competitors. Diagnoses still appear to be pressured despite fewer COVID-related shutdowns. Are there any other reasons for weak oncology numbers? And what is the outlook for recovery? So that's the first question. The second question is for Samit. Samit, do you or anyone else at Bristol know the total number of stroke and bleeding events in the Milvexian stroke study to date. So both arms combined, not each one. And if yes, how are those total stroke and bleeding events trending to what you expected?

Maybe I'll start, Steve. With respect to -- let me just say at the outset, with respect to Opdivo, we're actually very happy with the performance we saw for Opdivo in the quarter. As David and Giovanni mentioned, we saw a return to growth for Opdivo and actually saw an acceleration of Opdivo in the latter half of the year. As it relates to COVID, we have generally seen some improvement in a number of markets. But as you would imagine, the situation remains quite dynamic. As it relates to I-O specifically, new patient volume has been gradually recovering. Though I would say, where we sit today, we're roughly 5% to 10% below pre-COVID levels in terms of patient volume. There's just a considerable amount of variability across tumor types as well as in academic versus community. But on net, it's about 5% to 10% below where we were pre-COVID. Our hope in terms of the outlook is that we'll continue to see an improvement over the course of the year. If the pandemic has taught us anything, it's that we're going to have to continue to be flexible and agile. What I can say definitively is that the impact will likely vary by product and market. From our standpoint, I think we've shown our business is resilient, and our ability to really through the pandemic. And I think we've demonstrated an ability to execute. But sort of if you level it up, it's still a dynamic situation, and one we'll watch carefully.

And on the Milvexian trial, Steve. The study is ongoing, and we will not be talking about data, whether it's a pooled analysis or unblinded. We'll just have to wait for the data. And as I said earlier, we will be presenting the data at the appropriate conference. Really looking forward to it though.

So next, we'll go to Chris Shibutani with Goldman Sachs.

If I could ask a question about the immuno-oncology franchise, maybe more medium to longer term. There's a couple of dynamics that are happening. One, I think we have a PDUFA coming up in March for the LAG-3 combination fixed dose. Anything that you could share in terms of how you're thinking about positioning this so that you have success commercially, given the anticipation for competition, not just from other players, but also from other regimens, like TIGIT? Could you also comment, with a combination of data from bempeg plus Opdivo, which I believe could be in the second quarter time frame. The economics are distinct there. However, help us at all with progress and time lines, that would be appreciated. And then finally, on the I-O, we see potential for the entry of lower-cost checkpoint inhibitors, PD-1s. Can you share with us your initial thoughts at this stage about how you see that influencing the market dynamics for checkpoint inhibitors and I-O?

Sure. Maybe I'll start and I'll hit your first and third question. We're very pleased with the opportunity to potentially launch relatlimab. As we've said, if you look at the first-line metastatic melanoma market, it's really divided into thirds. You've got 1/3 of patients who are treated with dual I-O, that's Opdivo plus Yervoy. that's a very strong positon, given the sustained OS benefit that we have with that population. You have about 1/3 of patients who are treated with I-O monotherapy, roughly split between Opdivo and KEYTRUDA 50-50. And then you have 1/3 of the market which is really focused on targeted therapies. We see the opportunity for relatlimab to really go after that 1/3 of the market, which is single agent PD-1 therapy. We think that the data are very compelling relative to that population. Remember that relatlimab is 2 products in 1 vial. And so we think the opportunity to offer those patients dual I-O therapy in a fixed-dose combination offers a significant improvement over single-agent monotherapy, and that's going to be the initial focus at launch. As it relates to your question on low-cost entries of PD-1 agents. We don't see a significant threat to our business in the near to medium term from these products. We -- in our larger markets, like the U.S., evidence continues to be the most important dimension of choice. Physicians want to see data in a specific tumor and patient type. And so there may be markets where these sort of low-cost me-too drugs are able to piggyback on innovation and drive use, but those historically have not been our larger markets. Obviously, things can evolve and we'll continue to monitor and adjust as necessary. But I think as a sort of put a finer point on it, we shouldn't underestimate the barriers to sort of broad-based commoditization in oncology, particularly for a product like Opdivo, given the breadth of our data and indications.

And Chris, on the bempeg side, just as a reminder, there are 3 readouts that we anticipate this year, 1 in melanoma, 1 in renal cancer and 1 in bladder cancer. The first of it, as you very well pointed out, is in melanoma. We are anticipating the data within the first half of this year. With that said, we are certainly very pleased to have 3 I-O mechanism already, as an PD-1 as well as CTLA-4. And then anticipating the PDUFA and launch for relatlimab, as you also mentioned earlier. And we're looking forward to continuing work with Nektar in progressing the program as the data continues to evolve.

Next, we'll go to Tim Anderson with Wolfe Research.

This is Adam on behalf of Tim. On mavacamten, you've described this as being a $4 billion-plus product by 2029. It seems that there are 2 main drivers of this. One of which is that the forecast assumes a tripling of diagnosis rates for OHCM, going from about 25% today to 75% in the future. And the second is the mention of NHCM and other indications. My question is twofold. How realistic is it to expect a tripling of diagnosis rates? And second, what portion of the $4 billion is due to NHCM and other indications that you have not talked about as much? Separately, can we assume that an FDA Advisory Committee meeting is unlikely with this drug before approval happens?

Sure. Maybe I'll take both of those questions, and then -- or at least the first 2 questions. So Adam, with respect to how we thought about mava, first of all, this is a market where we see a fairly well-defined patient population. There are about 80,000 to 100,000 patients in the U.S. and roughly a comparable number ex U.S. We see significant unmet need for this patient population. And the initial focus at launch is going to be focused on treating those patients who are symptomatic, diagnosed, and where there's a real urgency to treat. Now what we have said is that, over the longer term with obstructive HCM, the focus will be on increasing the diagnosis rate. What we have said is that we plan on, where we think it's feasible, to double that diagnosis rate. It is currently, as you note, about 25%. And we think, with significant efforts, which we certainly have the skill set in the field to do, we think we can double that over time. So that's how we're looking at it. And in terms of the overall opportunity, the majority of the opportunity that we see is in obstructive disease. But certainly, we are looking forward to potentially seeing data in nonobstructive as well.

Yes. And on the ADCOM question, Adam, we have not been notified for a potential ADCOM. We do believe in the strong profile of mavacamten and benefit it provides in patients that we have enrolled in clinical trials for obstructive hypertrophic cardiomyopathy. And we are now looking to launch, as you know, in April of 2022, as Chris said.

Next, we'll go to Andrew Baum with Citi.

A couple of questions. So first on Milvexian. I'm mindful of the dose-dependent interaction of aspirin with Plavix. You have a number of trials ongoing and completed looking at potential drug interactions with Milvexian. Perhaps you could comment on level of reassurance in terms of either interaction with anti-platelets or commonly administered drugs in this patient population. And then second, you've already highlighted the Q1 -- inflation in 2021 for Eliquis. Perhaps you could talk more generally to the trends, particularly for U.S. Eliquis growth for 2022. I seem to remember that you've been excluded from 1 of the big 3 formularies. I'm assuming that pricing will offset volume. But if you can talk to what we expect for this year, and that would be helpful.

So I will start off, Andrew. Thank you for your questions. And for Milvexian, as you know, that we have, first of all, the study ongoing already with anti-platelet agents in the SSP, so we'll get to see that data when that reads out. In terms of the other drug-drug interaction studies, that is part and parcel of usual clinical pharmacology package that we prepare in anticipation of future filings and NDA. At the current time, we do not see any major impact or anything major in terms of BDI.

Yes. On the Eliquis questions, first of all, we're very happy with the performance that we saw with Eliquis, obviously, coming out of the fourth quarter. And then this year, we expect continued strong growth for Eliquis. Eliquis is going to likely going to be the key driver of the overall OAC market. We're seeing a nice delta in share between our new-to-brand share and total brand share, which is roughly around 7% now. That gives us confidence in the near-term growth trajectory. And we really do expect to see Eliquis NBRx and TRx share growth this year, both at the expense of warfarin and Xarelto. As it relates to the zinc situation, we see no meaningful impact on revenue. There are a few things to consider here. First, it's a relatively small part of our overall business. You certainly won't lose all of the volume. What we know in this space is that there's significant risk for nonmedical switching of patients who are on Eliquis. We know also that downstream accounts, in light of that, many of them will not adhere to the change that's been proposed at a macro level. And so we're actually very confident that the impact of revenue will be nonmaterial, if any. And the last thing I would say just related to that situation is we've said consistently that we're going to continue to be disciplined on gross to nets and how we manage those, and this is part of that story.

Next, we'll go to Ronny Gal with Bernstein.

First, just following up on Andrew's question. Can you talk a little bit about the benefit from 340 switch, especially from Eliquis? It seems to -- the net prices, Eliquis and 340B was close to nothing. And given the volume estimates that we are seeing, it should be a pretty good benefit for them this year. Can you talk about that? And second, Orencia. It seems to be growing together with the RA market. It seems to be in a position to grow better, given the JAK inhibitor safety issues. Can you talk a little bit about what you're seeing and what's your projection for 2022?

Sure. Let me -- Giovanni, do you want to start?

Go ahead, Chris.

Sure. So on 340B, let me just say, at a macro level, we remain committed to ensuring the eligibility of patients for 340B, those patients who can directly benefit from the program. And what I would say, there's really no change in our stance with respect to 340B as it relates to the program. We're committed to it, and we're committed to patients maintaining access to our medicine. The change that we announced really was reflective of 2 things: First, BMS and Celgene having different policies around the recognition of contract pharmacies and needing to align those as part of integration; and then second, wanting to ensure that the 340B discounts that we pay are valid and appropriate, and we feel this change in policy allows us to do that. And so that's really been the focus for how we think about the 340B program. And then do you mind repeating your second question again?

It would be great if you can quantify -- hello? It will be great if you can quantify the 340B impact. And the second question was around Orencia trends and the potential to benefit from the JAK inhibitors black box label.

Sure. We're not going to comment on any impact of 340B. Again, I think we've given the rationale for having made that change. As it relates to Orencia, look, Orencia continues to perform well in the RA market. The way we've thought about any potential change from a label update on JAK as it relates to Orencia or, frankly, any of our products, is that those changes will likely continue to push JAKs into later lines of therapy as they are -- as labels are updated and their position continues to evolve. So we think there's potentially opportunity. That said, I think our focus on, really, all of our products continues to execute against the strategy that we have, for those assets to continue to compete effectively in those markets. And obviously, we'll allow the situation with JAKs to evolve as they do.

Next, we'll go to Luisa Hector with Berenberg.

Just wanted to discuss a little bit more on the '22 outlook and the impact of Revlimid. So I just wondered if there are any particular risks you would highlight around the delivery of your sales target. Anything, just anything of note. And I guess really to confirm the pace of the Revlimid erosion is pretty predictable, so just checking on levels of uncertainty. And then specifically around how you are adapting to Revlimid generic entry in terms of your cost base. Any color around that, given that you have the ongoing presence in multiple myeloma. So just trying to understand kind of the cost side of it.

Yes. Thanks for the question, Luisa. As we think about Revlimid, we thought it was important this year, #1, to provide guidance on the full year. And secondly, we thought it was really important to provide guidance on the quarter. And I'd say one thing is that these are -- the contracts are annual volume limitations. So as the generics enter, it's all -- there could be quarter-to-quarter variability based upon how quickly the product makes it to the marketplace. So that's why we thought it was important to provide that. The first generic entry is occurring in March, so there could be variability between the first and second quarter. And then the rest -- remainder of the generics will come usually about 180 days later, it's pretty typical in a generic entry scenario, so that would be in the September time frame. But for the full year, we feel very confident in the guidance that we provided for the full year as it relates to Revlimid. As far as the expense base is concerned, I mean, this is a really fortunate thing for us. And the standpoint is, if you think about the 9 products that we're bringing to the marketplace, the 6 that are on the market and the 3 that we're launching this year, we're able to move resources within our therapeutic areas and reallocate the resources to the launch brands. So as you think about our hematology sales force, being able to move those resources out of Revlimid and into like cell therapy with the Breyanzi and Abecma, we're able to use existing resources to support this launch brands and maintain our cost base where we are. So -- and that's why we provided the guidance on operating expenses as we did.

Luisa, this is Giovanni. Let me just make another comment there. You mentioned about our level of confidence. David referenced Revlimid. Let me just say this is an important year for us because, obviously, it's the first year in which there will be generics of Revlimid. And what I'm really pleased of is the fact that we've got strong momentum with in-line business. We are making great progress with the launch brands that are already on the market. We're looking forward to 3 important approvals. And this year, as you know, we've guided to growth, both in terms of our revenue base, but also in terms of earnings per share. So I think that's a clear demonstration that we are confident in the ability to grow though the loss of exclusivity of Revlimid this year and over the next few years, just because of the strength and resilience of the underlying business and the fact that we are accelerating the transition of our portfolio into new brands.

Next, we'll go to Evan Seigerman with BMO.

I'd like to dive a little bit more on the investigational CELMoDs, understanding Revlimid's going on generic. What do you need to show with these clinical trials to help maybe replace Revlimid and pomalidomide in the treatment landscape? And kind of how do you think about progressing those in clinical trials? Understanding that you have the standard of care with your current assets.

Sure. Thank you, Evan, for the question. From a CELMoD perspective, the way we are thinking about development, and as we continue forward, we've generated the data in the late lines looking at the combination of iberdomide plus dexamethasone and CC-480 plus dexamethasone. And we have early data in triplets as well looking at combinations with VELCADE, dexamethasone as well as CD38 antibodies and dexamethasone, et cetera. As you will see later this year, we are initiating a Phase III trial of iberdomide plus VELCADE plus dexamethasone, comparing to -- sorry, iberdomide, daratumumab, dexamethasone comparing to dexamethasone; as well as VELCADE and CD38 antibody. So that's the first foray into the second-line plus patient population for the CELMoD. The other trials that you will see in the short while coming up will be the Phase III trials of CC-480 looking to replace pomalidomide, and that would be a head-to-head comparison versus pomalidomide combinations. And in 2022 -- sorry, 2023 and beyond, you will see trials of iberdomide looking into the post-transplant maintenance head-to-head comparison versus Revlimid; as well as the newly diagnosed patients who are transplant-non-eligible, to again, replace Revlimid in the first line or front setting. Those are the ways we are thinking about as we think about replacement of the current image. But let me also ask Chris to comment on the commercial perspective.

Yes, I think you've covered most of it, Samit. It's going to be important, as Samit noted, to generate data that differentiates directly from the IMiDs. There's obviously going to be a focus to address areas of IMiD unmet need, whether it's renal impairment or a look at potentially other populations where IMiD's underperformed. And then ultimately, from a commercial standpoint, we're going to need to establish a strong value proposition versus generic, but all of that will be part of the plan.

Next, we'll go to Carter Gould with Barclays.

I wanted to focus a little bit on the GI immunology portfolio. Last year, after the Phase II UC data sort of was disappointing, you guys talked about an additional study in UC. That's no longer sort of on your slide in terms of catalysts for '23 and -- '22 and '23. Are -- just any additional thoughts on that front and how you think about sort of being able to revisit UC? And if we'll be able to get an answer to that question here in '22. And then maybe a little bit off the radar, cendakimab. We seem to sort of expand the development program there and then recently add sort of a Phase III study in Japan, so in eosinophilic gastroenteritis. Wanted to see if there were broader plans to run a pivotal study in the U.S. in that indication, and maybe how some of the other kind of competitor data in the recent history kind of maybe has shaped that viewpoint.

Sure. Thanks, Carter. This is Samit again. For deucravacitinib, UC as well as Crohn's Disease, both of those Phase II studies are ongoing. As we said earlier, that we do not have a proof of concept based on the first trial that we conducted with deucrava. But there are 2 studies that are ongoing, looking at a higher dose in UC in the ongoing study. And when those data are available, we'll certainly be able to analyze those and take that program forward once we have a proof of concept. So it is not off the charts, but more about looking to generate the data to make decisions as we look forward. For cendakimab, the U.S. study -- or the global study in eosinophilic esophagitis is already ongoing and enrolling patients as we speak. The Japan part is in addition to that, as you have already noted. So overall, the idea is to get the antibody to IL-13 into patients with eosinophilic esophagitis and look for additional indications. As you know, that we have a study ongoing in atopic dermatitis is a Phase II, and that proof of concept can then generate additional indications for further development.

Next, we'll go next to Matt Phipps with William Blair.

You all announced positive TRANSFORM results in June a couple of weeks before a similar announcement from YESCARTA. Yet, they have a PDUFA date in April and we're still kind of waiting on the PDUFA date for Breyanzi. Are there any risks to meeting the 2022 approval milestone there? And then, Samit, some 3 Phase IIIs of bempeg coming up this year. Do you think those have equal probability of success? Or is there one indication you think that's more likely based on where high dose IL-2 has been more effective?

Thanks, Matt, for the questions. On Breyanzi, as you know, we don't necessarily declare our filings until we have heard from the FDA from the acceptance perspective. So as time goes, we will certainly be able to share more in terms of the filing and the PDUFA dates, et cetera. And we are certainly very, very pleased with the data that we have. As well as that Breyanzi has a large development program. So additional trials are already ongoing in CLL, follicular lymphoma as well as for additional indications in indolent NHL. We're certainly looking forward to launching the second-line indication, as Chris mentioned earlier during the call, in that indication as well, in the second line of BCL. For bempeg, certainly, it is data dependent. We are working with Nektar as well to read out these studies in melanoma as well as in renal cell and bladder cancer. Just as a reminder, these indications were chosen based on those Phase II data that we had seen early on. But each study stands on its own, and the data will dictate how we proceed further in terms of future development.

Next, we'll go to Matthew Harrison with Morgan Stanley.

This is Charlie Yang on for Matthew. First on Milvexian, can you say what amount of incremental bleeding in the stroke prevention study is acceptable clinically? And second, can you provide more details regarding the REMS and what that would look like? So for example, how frequent might patients need to be monitored. And lastly, on Abecma, as you kind of walk through the earlier lines of therapy, can you talk about in terms of the prioritization of studies these versus commercial supply? And I guess what are the commercial opportunity relative to kind of current indication?

Okay. I'll start off. So first of all, for Milvexian in terms of what amount of bleed is acceptable, look, it is all dependent. And certainly, we don't want to see any increase in bleed compared to the control arm. So that's how you have to compare and contrast. And we certainly have historical data from other therapies as well as how patients are treated today. So we'll have to put that into context as we look at Milvexian program. But there are no numbers that I can share today with you as to how to start looking at or projecting out those numbers. From the REMS perspective for mavacamten, once again, we are not going to get into specifics. But as we have spoken before, what we are looking forward to is how patients are really managed in the clinic today. We have to go back to what Chris talked about earlier, the basic mechanism of the drug for mavacamten is myosin inhibition. And we want to ensure that the patients are treated in a safe way so that we don't cause the heart to "relax" too much and decrease the ejection fraction. And that's the intent and the way the patients are currently managed on a continuous or ongoing basis, is periodic echocardiographies. So more to follow on that as we get to the PDUFA date and final approval and full package of REMS and overall NDA approval. From an Abecma perspective, certainly, the continuous progress in looking at the data from KarMMa and then KarMMa-3 and KarMMa-2 proof-of-concept this year will dictate the further evolution in terms of the overall development program. And studies are going to be as important as commercialization. So certainly, from a supply perspective, Chris has spoken before. But certainly, I'll ask Chris to comment further on Abecma supplies for the clinic as well as commercial.

Sure. And maybe I'll just make one comment on the REMS program, Charlie. The way that we have approached the REMS, obviously, we knew a REMS would likely -- would be likely with this asset. We've worked very closely from a commercial standpoint with Samit's team to ensure that the nature of that REMS fits very nicely into how physicians treat patients. And so we don't anticipate that there will be any particular challenges associated with that as we go into the launch. And I think Samit's last point is particularly relevant as it relates to Abecma, which is that the way we've approached looking at clinical and commercial supply, is that, obviously, commercial supply is critically important. But it is equally important that we continue to prosecute our development program. And we're going to continue to make those trade-offs with both of those priorities in mind.

Next, we'll go to Dane Leone with Raymond James.

Two quick ones for me. Firstly, on mavacamten. We've seen biomarker data from MAVERICK that suggests the possibility of developing in nonobstructive and HFpEF. When do you think the team would be able to outline plan for plausibility of running a compelling clinical strategy in either of those indications? And then the second question would be, when do you think we might have some emerging data from the Dragonfly collaboration on IL-12 that the oncology community seems to be pretty excited about?

Sure. I can take both of those, Dane. Thank you. For mavacamten, we are looking forward to initiating the first Phase III study in non-obstructive hypertrophic cardiomyopathy within 2022. And for HFpEF, the Phase II trial is now ongoing and looking forward to that proof-of-concept readout over time. And then that will dictate the future development in Phase III as well. For Dragonfly, once again, it's an early phase development right now in Phase I, looking at single and then combination as well for our I-O platform. And as that data evolves, which we currently don't have in hand, and those will be presented at appropriate conferences as we look to the future.

Thanks, Samit. I think we can maybe go to our last question, please, Alan.

Our last question will be from Mohit Bansal with Wells Fargo Securities.

This is James on for Mohit. Just a couple of quick questions. For deucrava, I know we're exploring new doses, but will you be rerunning the lab safety analysis to differentiate or rule out any JAK-like signals? And then for the S1Ps, how is BMI -- or BMY expecting the S1P to be positioned relative to JAKs? And any thoughts on competitiveness of Zeposia relative to etrasimod?

So let me start with deucravacitinib. So we've already got 2 Phase III studies that have read out. And those safety data are all the way with a follow-up of 52 weeks, we've already shared. And we'll to continue to evolve as we look forward. We've also looked at the data and will be part of the submissions in China and Japan for studies that have been conducted in China and Japan with longer term, 1 year follow-up. So those are all in line with the safety profile that we have added. So we certainly do not look forward to doing additional analyses on the same data because we've conducted those. Long-term follow-ups will continue and see additional evolution. And certainly, those similar sorts of exercises of continuing to generate data at higher doses for other indications that we are studying will be evaluated when data are available. From an S1P perspective, Chris, do you want...

Sure, I'll take that one. So James, as I said earlier, we do expect that there's going to continue to be an evolution of JAK labeling that could continue to push those assets into later lines of therapy, if you will. From our perspective, we continue to be very happy with the profile from Zeposia, both from an efficacy, given the strong clinical remissions, as well as the clean safety profile. Our focus Continues to be drive awareness and overall volume. There may be opportunities longer term given the evolving JAK situation. But we're going to continue to be disciplined in how we approach this launch and executing against what we need to do in order to build volume. And with respect to differentiation against other future S1Ps in that space, again, I would just say that we're very confident in the profile that we have, and it's important that we execute effectively with the launch in UC. And that's where our commercial focus is.

Thank you. Thank you, Chris. Thanks, everyone, and I appreciate you participating in the call. Let me just close by saying we're really pleased with our performance in the quarter. And much more broadly, our performance in 2021 positions us really well to deliver growth this year, in 2022, and beyond. We have built a solid foundation, and I'm confident that, as our portfolio renewal gains traction this year, our company is well positioned to reach new heights, both for patients and shareholders. And I want to thank our employees for supporting very strong growth. Thanks for being with us for the call. Our team remains available to ask -- to answer any additional questions you may have. And I wish all of you a good day. Thank you.

That does conclude today's conference. We thank everyone again for their participation.