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. Before we get started, I'll read our forward-looking statement. During this call, we 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. With that, I'll hand over to Giovanni.
Thank you, Tim, and good morning, everyone. Let's start with our fourth quarter performance on slide four. 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]. 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 deucravacitinib in the U.S., E.U., and Japan, which position us well to grow our presence in immunology. We are excited about the potential of 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 antithrombotic with a $5 billion+ non-risk adjusted revenue opportunity. We presented important updates at ASH on our hematology pipeline. This includes encouraging data for iberdomide and [mezigdomide], 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 benefits compared to the current standard of care. We continue to see Breyanzi as one of the key growth drivers for the company, with over $3 billion in non-risk adjusted revenue potential. Our strong execution helped drive solid financial performance in the fourth quarter.
We reported 8% sales growth and double-digit non-GAAP EPS growth. Our strong cash flow and financial strength provide us with significant financial flexibility. This enables us to continue prioritizing disciplined business development opportunities while paying down debt and expanding shareholder distributions. We also introduced our 2022 guidance last month, and I'll let David speak to the details in a moment.
What's important is that we are guiding to growth this year, with low double-digit growth from our continuing business more than offsetting the Revlimid revenue impact from generics in the U.S. and internationally. Turning to our 2021 execution scorecard on slide five. At the beginning of last year, I outlined a number of milestones that we believed would be important to our future, including opportunities to renew our portfolio and grow our business during the decade.
I am pleased to report we have made great progress. We returned Opdivo's growth, successfully launched multiple new products, and produced key expansion datasets for several assets. This record of execution across the company further strengthens my confidence in our ability to continue to renew our portfolio and grow in the future. We know we must remain focused on advancing our pipeline to accelerate the renewal of our portfolio.
On slide six, you can see there are multiple catalysts ahead during 2022. The 2022 milestones include expected approvals and launches for three exciting first-in-class medicines, mavacamten, deucravacitinib, and relatlimab. We believe that all of these have the potential to further strengthen the commercial opportunity for our new product portfolio and support our growth outlook.
We expect that each of these assets has at least $4 billion revenue potential at the end of the decade on a non-risk-adjusted basis. We look forward to keeping you updated on our progress throughout the year. Looking to the future, slide seven summarizes our perspective of how all of this comes together to support the growth of the company moving forward.
We expect the growth in our continuing business will enable us to more than offset key LOEs through 2025, with continued growth of our in-line brands and $10 billion-$13 billion of additional sales expected from our new product portfolio. In the second half of the decade, with a broad and expanding product portfolio, we will have multiple paths to achieving our growth objective from 2025 to 2029.
As we've said, we expect more than $25 billion in non-risk-adjusted revenue potential from the current new product portfolio in 2029, with additional contributions coming from our pipeline, including assets like milvexian and our exciting CELMoD agents. As we continue our journey to renew our business and grow through the impact of LOEs starting this year, I'm increasingly excited about the future of Bristol- Myers Squibb. With that, I'll turn it over to David to walk you through the financials. David?
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 nine. 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 continues 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 number one 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 one-time favorable true-up in the U.S. of approximately $160 million that will not repeat in Q1 of 2022. 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 see uptake of our new launches in lung and renal cancer in Germany and Japan, and we secured reimbursement in Italy and Spain in the fourth quarter. As we look forward, we continue to expect further growth for Opdivo as we secure additional reimbursement for recent approvals. We're in a strong position to continue to grow Opdivo and look forward to additional approvals this year and in the years ahead. Now let's turn to our Immuno portfolio on slide 12, starting with Revlimid. Fourth quarter revenues grew 1% globally versus prior year and grew 6% for the full year, with sales of approximately $12.8 billion.
As we enter into the first year of generic entry for Revlimid, I want to remind you of our expectations for Revlimid sales in 2022 and beyond. We expect Revlimid sales of $9.5 billion-$10 billion in 2022. Of these sales, we expect roughly 75% to come from the U.S. and the remaining from ex-U.S. markets. As we think about generic entry this year, we expect sales variability quarter to quarter based on the timing of how generic competitors fulfill their annual volumes. For the first quarter, our best projection for global Revlimid sales is approximately $2.5 billion. Beyond 2022 through 2025, although there is still uncertainty due to ongoing litigation, we view an annual step-down of roughly $2 billion-$2.5 billion per year as a reasonable projection. Now on to Pomalyst.
Global sales in the fourth quarter were up 2%. Sales were primarily driven by demand for triplet-based therapies in ex-U.S. markets and fewer selling days in the U.S. We continue to expect growth for Pomalyst as treatments move to earlier lines of therapy and more triplet-based therapies are approved with longer duration of treatment. As it relates to U.S. IP for Pomalyst, we are pleased that there is now no outstanding litigation. At this point, we don't expect generic entry in the U.S. market prior to the first quarter of 2026. Now let's move on to our new product portfolio on slide 13. We are very pleased with the momentum and feedback we're receiving on our new product portfolio. These products contributed over $350 million in the fourth quarter and $1.1 billion for the full year.
Let me provide some color on each launch individually, starting with Reblozyl, which generated global revenues of just over $550 million in 2021. More than doubling its revenues over last year. In the U.S., full year sales grew 87% versus prior year, primarily due to continued demand in ESA refractory MDS patients. Demand continued to grow in the fourth quarter.
Sequentially, revenue was impacted by one-time favorable inventory build in the third quarter of approximately $20 million-$25 million. Our focus remains on treating new patients earlier in their treatment journey upon ESA failure, as well as ensuring physicians titrate their patients up to receive the appropriate dose for sustained benefit. Internationally, we continue to launch in additional countries and expect to continue to do so in 2022, helping more patients and driving additional growth for the brand.
Now moving to our cell therapy launches of Abecma and Breyanzi. Abecma generated revenues of $164 million since its launch in May of last year. Revenues reflect very strong demand for the first-ever BCMA cell therapy. As noted in the past, demand continues to be very robust and we're working hard to expand capacity. We expect first quarter revenues to be largely similar to fourth quarter.
Turning to our CD19 cell therapy, Breyanzi. Physicians continue to recognize Breyanzi's best-in-class profile for relapsed refractory patients. We look forward to moving Breyanzi up the treatment paradigm in the second-line setting with remarkable EFS data presented from our TRANSFORM study at ASH, and we look forward to bringing this treatment to second-line patients in the U.S. this year. Now moving to Zeposia.
Global sales for the year were $134 million, primarily driven by our multiple sclerosis indication. In the U.S., the MS launch continues to go well. Zeposia remains the leading S1P in written prescriptions, and we remain focused on establishing Zeposia not only as the S1P of choice, but also the oral treatment of choice. We continue to be pleased with the progress we have made on patient conversion.
With significant decrease in time, physicians are responding well to the profile, and we are encouraged by their intent to prescribe. We are working on building volume and growing access and reimbursement. We expect to have increased contribution from UC in the second half of this year and expanding in 2023. Internationally, Zeposia continues to gain momentum in MS as the product gets additional reimbursement in more markets and benefited from certain year-end stocking.
We are very pleased with the recent EMA approval of UC in December and look forward to securing access and reimbursement for this indication to drive further growth for the brand. Lastly, on Onureg in the U.S., we continue to make progress on establishing the product for patients in complete remission following intensive chemotherapy. Our focus remains on shaping the maintenance segment and increasing adoption and patient adherence.
Overall, I'm pleased with our new product portfolio performance and look forward to three additional approvals expected this year. We are launch ready for relatlimab and mavacamten with PDUFA dates in March and April, and we're on track for deucravacitinib's launch in September. Now, switching gears to our fourth quarter P&L on slide 14. Having just covered sales performance, let me walk you through a few non-GAAP key line items.
Operating expenses increased versus prior quarter due to timing of MS&A investments that shifted to the fourth quarter, as noted in October. MS&A decreased versus prior year due to some incremental and accelerated investments to support our business in 2020. The fourth quarter effective tax rate was impacted by earnings mix. As a result, the strong performance in the quarter, non-GAAP EPS increased approximately 25% year-over-year. Moving to the balance sheet and capital allocation on slide 15.
We continue to generate a significant amount of cash from operations with approximately $4 billion in the fourth quarter. We ended the quarter in a strong liquidity position with approximately $17 billion in cash and marketable securities. Our capital allocation priorities remain unchanged. Business development remains our top priority to further renew and diversify our portfolio.
We are also focused on reducing debt and returning capital to shareholders. We have executed several business development deals last year, bringing in differentiated early-stage assets. We have the financial strength to be size-agnostic, but we are particularly interested in early science and mid-size bolt-on deals. As it relates to debt, in 2021, we reduced gross debt by over $6 billion and remain committed to maintaining a strong investment-grade credit rating.
Lastly, as it relates to returning capital to shareholders, we recently grew this authorization by $15 billion and plan to execute a $5 billion ASR this quarter. Now turning to our 2022 non-GAAP guidance at current exchange rates on slide 16. As announced last month, we expect 2022 revenues to be approximately $47 billion, representing low- single-digit growth over 2021.
Growth from our continuing business will more than offset the revenue impact from Revlimid and Abraxane LOEs. We expect key LOE brand sales to be approximately $10.5 billion. Our continuing business, which represents our in-line and new product portfolios, is expected to grow low- double-digit and contribute approximately $36.5 billion. As it relates to our line item guidance for the year, we expect our gross margin to be approximately 78% and our total operating expenses to be in line with 2021 expenses. We project our tax rate to be approximately 16.5%. Finally, also communicated earlier this year, we expect non-GAAP EPS to grow faster than sales and be between $7.65 and $7.95.
As it relates to our share count, I'd like to provide a little color as we plan to execute the $5 billion ASR. We ended the year with approximately 2.2 billion diluted shares outstanding. We'll be executing the ASR later this quarter, which means we will get a majority, but not all of the benefit on diluted share count this year. Lastly, given this is the first quarter of generic entry for Revlimid, we thought it'd be helpful to provide some perspective on revenue for the first quarter. In addition to the approximately $2.5 billion of Revlimid sales I mentioned previously, we are projecting total global first quarter sales to range from $11 billion-$11.5 billion.
Before I turn it over to question and answer, I just want to thank our teams around the world for delivering these remarkable results in 2021. These results and our guidance for 2022 demonstrate the financial strength of the business and the renewal of our portfolio, which positions us well for long-term growth. I'll now turn the call back over to Tim and Giovanni for Q&A.
Thanks, David. Alan, could we go to our first question, please?
Certainly, sir. We'll go first to Seamus Fernandez with Guggenheim.
Oh, thanks so much for the questions. First question is just on your Factor XI. Just wanted to, you know, check in on timing of a potential update from your phase II study. 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% to potentially 20% benefit on stroke. You know, how does that sort of fit with your expectations?
Can you guys help us understand a little bit better the opportunity to open up you know this potentially new market and how you see the size of the opportunity should that profile be achieved? Do you agree with those views? Then second, just on. 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 you know for mavacamten versus other competitor compounds? Thanks so much.
Thank you, Seamus. This is Samit. I'll take both of those questions. 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. At the appropriate conference, we'll be able to share that data beyond that.
We are continuing to work with our partners, Janssen, to really execute on the future development of milvexian. As to 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 we 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 antiplatelet agents, as well as to then progress them further into appropriate indications, either as a single agent or as combinations. We just have to wait for the data.
As we saw in the TKR study, there was no increase in the bleeds, but we certainly saw increase in a dose-dependent manner from the efficacy perspective. 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 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. As it relates to 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. 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.
Yeah. The only thing I would add, Seamus, is just on mavacamten. 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. As Samit mentioned, we don't see any differentiated competition on the horizon. 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. So we feel very good about the competitive position for this agent and look forward to launching.
Thanks, Chris. Alan, can we go to our next question, please?
Certainly, sir. Next, we'll go to Chris Schott with JP Morgan.
Great. Thanks so much. Just to follow up on mavacamten, can you 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 need to get reimbursement and familiarizing physicians with whatever REMS program ends up coming out of this one.
My second question was just an update on CAR-T capacity. Just walk through a little bit about how you're expecting capacities to ramp as we move through 2022. I guess when will you be in a position where capacity is not the right limiting factor for the growth of these products? Thanks so much.
Sure, Chris. I'll take both of those questions. With respect to mavacamten and how we think about the shape of the opportunity, this launch will likely progress. It's very much gonna 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 gonna be the initial focus. Beyond this, we'll expand our focus to cardiology specialists and then to the broader cardiology community, where uptake is just gonna be more gradual. 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.
Certainly, there will be a focused effort to get patients on therapy, good drugs, so we feel very good about the long-term potential for the asset. That stepwise approach that I articulated really is in line with the overall opportunity of $4+ 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.
Our efforts are really focused on working with CMOs to accelerate capacity for vector, and then internally, we're focused on slot capacity. 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. As it relates to Breyanzi, the big focus there is on vector supply. It's something we continue to stay focused on, and we fully 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.
Thanks, Chris. Can we go to our next question, please?
Yes, sir. Next we'll go to Geoff Meacham with Bank of America.
Morning, guys. Thanks for taking the question. For some of the new launches, are there any metrics you guys can provide, you know, that show, you know, the wins and access and reimbursement? Mostly talking about, you know, cell therapies and Zeposia.
The bigger picture is just trying to assess, you know, the tipping point for this year, potentially for the launches collectively, you know, versus what we saw last year, which was a lot of lumpiness on a kind of sequential basis. Then the second question, real quick on deucravacitinib. I know there's been a lot of angst about the potential for differentiating labels versus JAK. I just want, now that we have clarity on the latter, to get maybe an updated view from you guys on that. Thank you.
Sure. Maybe I'll start. Geoff, thanks for the question. As we look at access really across all of these launches, we feel very good about where we are from an access standpoint. I'll start with cell therapy. Cell therapy actually I think is a very, very good story. We have seen no issues with respect to access constraints for our cell therapy launches.
You know, we've discussed the supply constraints, but the launches have gone off really without a hitch from an access standpoint. 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. I would say largely, for the class of agents, we've been trending in the right direction.
We see no issues on our cell therapy assets. As we switch gears, and you'd mentioned Zeposia, obviously the focus is on UC. Very quickly on MS, we 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, we have restrictions 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 gonna be on working through those restrictions, and that's gonna 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.
Geoff, I'll take on the question around deucravacitinib. Let me start by saying that we are obviously not going to speculate on the label for what we couldn't and the efficacy and the safety profile that we've talked about before, and we are looking forward to the PDUFA date in September.
Thanks so much. Alan, can we go to our next question, please?
Yes, sir. Next we'll go to Steve Scala with Cowen.
A couple questions. Opdivo was a bit weak in Q4, similar to what we've seen from some of your competitors. Diagnoses still appear to be pre-pressured despite f ewer COVID related shutdowns. Are there any other reasons for weak oncology numbers and what is the outlook for recovery? Does 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. If yes, how are those total stroke and bleeding events trending to what you expected? Thank you.
Maybe I'll start, Steve. 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 IO specifically, new patient volume has been gradually recovering, though I would say, we're where we sit today, we're roughly 5%-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%-10% below where we were pre-COVID. Our hope in terms of the outlook is that we'll continue to see new improvement over the course of the year. As it is, the pandemic has taught us anything, it's that we're gonna 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 grow really through the pandemic, and I think we've demonstrated an ability to execute. Sort of if you level it up, it's still a dynamic situation and one we'll watch carefully.
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'll be presenting the data at the appropriate conference. Really looking forward to it though. Thank you.
Thanks, Samit. Alan, can we go to our next question, please?
Yes, sir. Next we'll go to Chris Shibutani with Goldman Sachs.
Maybe more medium to long-term 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 on a combination of data from [bempeg] plus Opdivo, which I believe could be in the second quarter timeframe, the economics are distinct there. However, help us at all with progress and timelines, that would be appreciated. Then finally, on the IO, we see potential for the entry of lower cost checkpoint inhibitors, PD-1. Can you share with us your initial thoughts at this stage about how you see that influencing, the market dynamics for checkpoint inhibitors in IO? Thank you.
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 IO, that's Opdivo plus Yervoy. That's a very strong position given the sustained OS benefit that we have with that population. You have about 1/3 of patients who are treated with IO monotherapy, roughly split between Opdivo and Keytruda 50/50. 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 two products in one vial. We think the opportunity to offer those patients dual IO therapy in a fixed dose combination offers a significant improvement over single agent monotherapy, and that's gonna 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. 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.
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. I think as a sort of put a finer point on it, we shouldn't underestimate the barriers to sort of broad-based commoditization oncology, particularly for a product like Opdivo, given the breadth of our data and indications.
Chris, on the [bempeg] side, just as a reminder, there are three readouts that we anticipate this year, one in melanoma, one in renal cancer, and one in bladder cancer. The first study, 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 three IO mechanisms already as in, PD-1 as well as CTLA-4, and then anticipating the PDUFA and launch for the last-
Thanks so much. Alan, can we go to the next question, please?
Next, we'll go to Tim Anderson with Wolfe Research.
Hi. Thanks for taking my question. 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 two 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. The second is a mention of [nH] twofold. How realistic is it to expect a tripling of diagnosis rates? 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? Thanks.
Sure. Maybe I'll take both of them. Adam, with respect to how we thought about mavacamten, first of all, you know, this is a market where we see a fairly well defined patient population. There are about 80-100,000 patients in the U.S. and a roughly comparable number ex-U.S. We see significant unmet need for this patient population, and the initial focus at launch is gonna 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, or we think it's feasible to double that diagnosis rate. It is currently, as you note, about 25%.
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. That's how we're looking at it. 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 non-obstructive as well.
On the AdCom question, Adam, we have not been notified of 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're now looking to launch, as you know, in April of 2022, as Chris said.
Thanks so much. Alan, can we go to our next question, please?
Yes, sir. Next, we'll go to Andrew Baum with Citi.
Thank you. A couple of questions. 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 antiplatelets or commonly administered drugs in this patient population.
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 one of the big three formularies. I'm assuming that pricing will offset volume, but if you could talk to whether we expect to be slowing, that would be helpful.
I will start off, Andrew. Thank you for your questions. For milvexian, as you know, that we have, first of all, the study ongoing already with antiplatelet 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 the usual clinical pharmacology package that we prepare in anticipation of future filings in an NDA. At the current time, we do not see any major impact or anything major in terms of DDI.
Yeah. 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. This year, we expect continued strong growth for Eliquis. Eliquis is 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 in NBRx and TRX share Xarelto. As it relates to the Cigna 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 non-medical 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. We're actually very confident that the impact of revenue will be non-material, if any. The last thing I would say just related to that situation is we've said consistently that we're gonna continue to be disciplined on gross to nets and how we manage those, and this is part of that story.
Thanks, Chris. Alan, could we go to the next question, please?
Yes, sir. Next, we'll go to Ronny Gal with Bernstein.
Good morning, and thank you for taking my question. First, just following up on Andrew's question, can you talk a little bit about a benefit from 340 switch, especially from Eliquis? It seems that the net price of Eliquis and 340B was close to nothing, and given the volume estimates that we're seeing, it should be a pretty good benefit for them this year. Can you talk about that? Second, ORENCIA, it seems to be growing together with the RA market. It seems to be in position to grow better, given the JAK inhibitor safety issues. Can you talk a little bit about what you're seeing and what your projection for 2022?
Sure. Let me
Yeah.
Giovanni, you wanna start?
Go ahead, Chris.
Sure. 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. 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 two things. First, BMS and Celgene having different policies around the recognition of contract pharmacies and needing to align those as part of integration. Second, wanting to ensure that the 340B discounts that we pay are valid and appropriate.
We feel this change in policy allows us to do that or for how we think about. Do you mind repeating your second question again?
I think it was about.
Great. If you could quantify from the JAK inhibitors black box label. Sure. We're not gonna 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 labels are updated and their position potentially opportunity. That said I think our focus on really all of our products continues to execute against the strategy that we obviously we'll allow the situation with JAKs to evolve as they do.
Can we go to our next question, please?
Certainly. Next, we'll go to Luisa Hector with Berenberg.
Hello, thank you. I wanted to discuss a little bit more on the 2022 outlook and the impact of Revlimid. I just wondered if there are any particular risks you would highlight around the delivery. I guess, really to confirm the pace of the Revlimid erosion is pretty predictable. Just checking on levels of uncertainty. You know, how you are adapting to Revlimid generic cost base, any color around that, given that you have the ongoing presence in multiple myeloma. The cost side of it. Thank you.
Yes, thanks for the question, Luisa. As we think about Revlimid, we thought it was important this year, number one, to provide guidance on the full year. Secondly, we thought it was really important to provide guidance on the quarter. I'd say one thing is that the contracts are annual volume limitations. As the generics enter, there could be quarter-to-quarter variability based upon how quick the product makes it to the marketplace. 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.
The rest of the generics will come usually about 180 days later, which is pretty typical in a generic entry scenario, so that'd be in the September timeframe. 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 from the standpoint if you think about the nine products that we're bringing to the marketplace, the six that are on the market, and the three that we're launching this year. We're able to move resources within our therapeutic areas and reallocate. We're able to use existing resources to support those launch brands and maintain our cost base where we are. You know, that's why we provide the guidance on operating expenses as we did.
Luisa, this is Giovanni. David referenced Revlimid. Let me just say, this is an important year for us because obviously, it's the first year. What I'm really pleased about is the fact that we've got strong momentum with the inline business. We are making great progress with the launch plans that are already on the market. We're looking forward to three important approvals. 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.
I think that's a clear demonstration that we are confident in the ability to grow through the loss of exclusivity of Revlimid this year and over the next few years, just because of the strength and resilience of the underlying businesses and the fact that we are accelerating the transition of our portfolio to new brands.
Thanks, Giovanni. Alan, could we go to the next question, please?
Yes, sir. Next, we'll go to Evan Seigerman with BMO.
Hey, guys. Thank you so much for taking my question. I'd like to dive a little bit more on the Revlimid, you know, going generic. What do you need to show with these clinical trials to help maybe replace Revlimid and Pomalyst in the treatment landscape? Kind of how do you think about progressing those in clinical trials, understanding that you have the standard of care with your current assets? Thank you.
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 a combination of iberdomide plus dexamethasone and [CC-92480] plus dexamethasone.
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 pomal, comparing to dexamethasone as well as Velcade and CD38 antibody. 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-92480 looking to replace pomalidomide, and that would be a head-to-head comparison versus pomalidomide combinations. In 2022, 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. The ways we are thinking about as we think about replacement of the current IMiD. Let me also ask Chris to comment on the commercial perspective.
I think you've covered most of it, Samit. It's gonna be important, as Samit noted, to generate data that differentiates directly from the IMiDs. There's obviously gonna be a focus to address areas of IMiD unmet need, whether it's renal impairment or look at potentially other populations where-
Go to our next question, please, Alan.
With Barclays.
Brad.
I wanted to focus a little bit on the TI immunology portfolio. You know, last year after the phase II UC data sort of was disappointing. You guys talked about an additional study, and UC that's no longer sort of on your slides in terms of catalyst for 2023 or the 2022 and 2023. Just any additional thoughts on that front, now 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 2022.
Then, maybe a little bit off the radar, cendakimab, we've seen you know 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. Thank you.
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 deucravacitinib. There are two studies that are ongoing, looking at a higher dose in UC in the ongoing study. 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. 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.
Overall, the idea is to get that 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 as a phase II, and that proof of concept can then generate additional indications for further development.
Thanks, Samit. Can we go to our next question, please, Alan?
Yes, sir. Next, we'll go to Matt Phipps with William Blair.
Morning. Thanks for taking my questions. You all announced positive TRANSFORM results in June, a couple of weeks before similar announcement from Yescarta. Yet they have a PDUFA date in April, and we're still kind of waiting on hearing the PDUFA date for Breyanzi. Are there any risks to meeting a 2022 approval milestone there? And then Samit, you know, some three phase IIIs with [bempeg] coming up this year. Do you think those have equal probabilities of success, or is there one indication you think is 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. Very, very pleased with the data that we have, as well as you know that Breyanzi is 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 DLBCL.
For bempegaldesleukin, certainly we as well as in renal cell and as a reminder, these indications were chosen based on those phase II data that we had seen early on, but each study stand on its own and the data will dictate how we proceed further in terms of future development.
When can we go to the next question, please?
Yes, sir. Next, we'll go to Matthew Harrison with Morgan Stanley.
Hi. This is Charlie Allen for Matthew. Bleeding in the stroke prevention study. Second, can you provide more details regarding the REMS plan and what that will look like? Patients need to be monitored. As you kind of walk through the early lines of therapy, can you talk about in terms of the prioritization of these studies versus commercial supply? I guess
I'll start off. First of all, for milvexian, in terms of what amount of bleed is acceptable, look, it is all data dependent. Certainly we don't want to see any increase in bleed compared to the control arm. That's how you have to compare and contrast. We certainly have historical data from other therapies as well as how patients are treated today.
We'll have to put that into context as we look at milvexian program. 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 quote-unquote, "relax too much" and decrease the ejection fraction. That's the intent. The way the patients are currently managed on a continuous or ongoing basis is periodic echocardiographies.
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 a 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. Studies are going to be as important as commercialization. Certainly from a supply perspective, Chris-
Make one comment on the REM. The way that we have approached the REMS, obviously we knew a REMS would be likely with this asset. We worked very closely from a commercial standpoint with Samit's team to ensure that the nature of that REM fits very nicely into how physicians treat patients and particular challenges associated with that as we go into the launch.
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.
Thanks, Chris. Can we go to the next question, please, Alan?
On mavacamten. We've seen biomarker data from MAVERICK-HCM viability of developing in non-obstructive HCM and HFpEF. When do you think the team would be able to outline a plan for plausibility of clinical strategy in either of those indications? The second question would be, when do you think we might have some emergent data from the Dragonfly collaboration on IL-12 that the oncology community seems to be pretty excited about? Thank you.
I can take. Looking forward to initiating the first phase III study in non-obstructive hypertrophic cardiomyopathy within 2022. Over time, 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. That data evolves, which we currently don't have in hand. Those will be presented at appropriate conferences as we look to the future.
Thanks so much. I think we can maybe go to our last question, please, Alan.
All right, our last question will be from Mohit Bansal with Wells Fargo Securities.
Hey, good morning. This is James on for Mohit. Just a couple of quick questions. For deucravacitinib, 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 expecting the S1Ps to be positioned relative to the JAKs? And any thoughts on competitiveness of Zeposia relative to ponesimod?
Let me start with Duclazna. We've already got two phase III studies that have read out and those safety data all the way were part of the submissions in China and Japan for studies that have been conducted in China and Japan with longer term, one-year follow-up. Those are all in line with the safety profiles that we have added.
We certainly do not look forward to doing additional. We've conducted those. Long-term follow-ups will continue and see additional evolution. 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-
Sure, I'll take that one. 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 for Zeposia, both from an efficacy, given the strong clinical remissions as well as the clean safety profile. Our focus continues to be to drive awareness and overall volume. There may be opportunities longer term given to do in order to build volume. 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 those.
Thanks, everyone. I appreciate that. To 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.
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. Thanks for being with us for the call. Our team remains available 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.