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Greetings, and welcome to the Incyte Third Quarter 2025 Earnings Conference Call webcast [Operator Instructions]. As a reminder, this conference is being recorded. It's now my pleasure to turn the call over to Alexis Smith, Vice President and Head of Investor Relations. Please go ahead, Alexis.
Thank you. Good morning, and welcome to Incyte's Third Quarter 2025 Earnings Conference Call. Before we begin, I encourage everyone to go to the Investors section of our website to find the press release, related financial tables and slides that follow today's discussion. On today's call, I'm joined by Bill, Pablo and Tom, who will deliver our prepared remarks.
Steven, Dave, Matteo and Mohamed will also be available for Q&A. I would like to point out that we will be making forward-looking statements, which are based on our current expectations and beliefs. These statements are subject to certain risks and uncertainties, and our actual results may differ materially. I encourage you to consult the risk factors discussed in our SEC filings for additional detail.
I will now hand the call over to Bill.
Thank you, Alexis, and good morning, everyone. On our last call, I told you I'd be taking a fresh look at the company with a focus on getting the core business right, our R&D priorities right and our cost base right. This, of course, is a continuous process and one that is well underway and on track. In terms of the core business, my assessment has reinforced my confidence in the growth potential of our key products.
As we announced today, we had a strong quarter with total revenues of $1.37 billion and product sales of $1.15 billion. This represents a 20% and 19% increase, respectively, versus prior year. The fundamentals around Jakafi, Opzelura and our hem/onc business, Niktimvo and Monjuvi namely remains strong. Our job right now is to keep it that way and to identify effective ways to optimize the promotional strategies and investment for these products to drive future growth.
Jakafi Q3 sales reached $791 million, a 7% increase with strong demand growth of 10% year-over-year. Growth was broad-based across all 3 indications. In MF, Jakafi utilization continues to increase, and we are maintaining market share leadership despite competition. Growth in GvHD remains strong, supported by our portfolio strategy with Niktimvo, which is helping identify patients across multiple lines of therapy, and PV is our largest growth driver, fueled by compelling MAGIC PV data showing impressive thrombosis-free survival.
Based on this momentum, we're raising our full year guidance for Jakafi to a new range of $3.05 billion to $3.075 billion. Opzelura growth was exceptional in the third quarter and continues to be a significant contributor to revenue with $188 million in sales, a 35% increase versus prior year. Of this, $144 million in net sales came from the U.S., which represented a 21% increase versus prior year. The increase was based on strong prescription demand across both indications and more favorable formulary placement at the 3 top PBMs.
In July, we reorganized the Opzelura sales force into 2 dedicated sales teams, one for AD and one for vitiligo to ensure execution and sustained growth. The market for branded non-steroidal topical continues to expand at a 20% rate as more patients migrate off and away from topical corticosteroids. Given the efficacy of Opzelura in terms of rapid itch relief and skin clearance, our broad prescriber base and formulary coverage, we're well positioned to take advantage of this market dynamic. Internationally, sales for Opzelura and vitiligo totaled $44 million, representing a 117% increase from last year.
France, Spain, Italy and Canada account for over 80% of our sales and growth, and we plan to file an application for ruxolitinib cream in moderate AD in the EU by year-end with a potential approval in the second half of 2026. Now in its third quarter post launch, Niktimvo continues to outperform expectations across all launch metrics. Sales in the third quarter totaled $46 million, an increase of 27% versus the second quarter. 90% of BMT centers have adopted Niktimvo with all centers placing repeat orders year-to-date. Importantly, 80% of patients who started treatment in the first quarter of launch are still on therapy today.
And we've captured 13% of the third line plus GVHD opportunity in just the first 9 months on the market. In line with expectations, Niktimvo is primarily being used in the fourth line with increasing preference and utilization in the third line. Feedback from BMT centers has been positive with real-world efficacy and safety being equally as impressive as the clinical data. Finally, we're actively studying Niktimvo in combination with ruxolitinib and steroids in earlier line settings.
Our combination study with Jakafi is designed to enable a steroid-free regimen in GvHD, which could shift the standard of care. And our combination study with steroids in the frontline setting has the potential to deliver benchmark efficacy and steroid tapering. This franchise strategy has the potential to significantly increase our addressable market and strengthen our leadership position in GvHD. Our broader hematology and oncology portfolio also performed well this quarter.
Sales from Monjuvi in follicular lymphoma and Zynyz and SCAC, both launched this year, saw strong growth and contributed to our raised guidance. These products will be incremental contributors to our portfolio and collectively can deliver meaningful sales growth over the next several years. We have 3 important new product launches next year, ruxolitinib XR, Opzelura AD in Europe and povorcitinib in HS. I've completed a thorough review of the launch plans and believe these products have the potential to contribute significantly to Incyte's future growth.
Strategically, ruxolitinib XR upon approval offers the same therapeutic benefits of Jakafi and a more convenient once-daily dosing regimen. The stability data are on track to be submitted to the FDA before end of the year with an anticipated launch in mid-2026. As it relates to Opzelura AD, as mentioned, we plan to submit our application in the EU with an anticipated launch next year. Assuming approval, Opzelura has the potential to contribute meaningfully to future sales in the EU4 and Canada and to overall growth given its clinical and economic value proposition. With the moderate AD indication in Europe, we could potentially increase our international topical business by 2 to 3x over the next several years.
And finally, povorcitinib could be the first oral option for patients with HS, which is perhaps the most challenging disease in dermatology. It's a multi-cytokine disease involving many pathways, making treatment more complex and results more variable. A treatment option like povorcitinib, which has shown rapid pain relief and skin clearance scores of over 50% will be very marketable. We believe there's a substantial opportunity in HS, which is the first step for povo.
Our ongoing developments in PN and vitiligo will come into focus next year, and if positive, further strengthen the position of povo and our derm portfolio. Together with Opzelura, we could provide a topical to oral offering for patients across HS, vitiligo and PN. Launch activities for each product remain on schedule, including preparations for the sales force, payer engagements and medical education initiatives. We'll share more details in early 2026. Turning to R&D.
Our ongoing pipeline review is providing us with absolute clarity about which high-value programs are core to future growth and have the greatest potential to create value and outsized returns. We want to configure a balanced pipeline that is not consumed by either safe, low-value projects or moonshots. We've set clear go/no-go criteria for moving key projects forward. We will invest and take calculated risks in key programs rather than thinly spreading investments across many programs.
In other words, fewer, smarter investments versus diffuse spending. We'll fund what matters and importantly, watch out for false positives and negatives. As it relates to our developing pipeline, the first call on capital is hem/onc. This is the central identity of the company and an area where we have differentiated knowledge and capabilities and an asymmetrical advantage.
This includes targeted therapies for MPNs, including mCALR, 617, our mCALR bispecific and discovery programs. We have a window of opportunity here to trigger an innovation-based shift in MPNs from nonspecific symptomatic therapies like Jakafi and HU to targeted mutation-specific therapies like 989. Next steps for 989 and 617 will be shared later this year and next year. In terms of our solid tumor program, the cornerstone of our cancer strategy is novel biological pathways, high incidence cancers with substantial medical need that miss the IO revolution and immunotherapies and targeted therapies that can be used frontline in combination with standard of care regimens.
As you know, we have 3 programs in early development, KRAS G12D for pancreatic cancer, TGF-beta x PD-1 bispecific for MSS CRC and CDK2 for ovarian cancer. Over the next several months, we will collect more data on these programs in terms of response rates, duration of response and safety, particularly in combination with standard of care. We'll move forward without delay, providing our data, continue to be objectively competitive, and we can be early to market and defend our position long term. Now in terms of our operating expenses and overall cost structure, we're conducting a review of the entire business, which focuses on prioritization and data-driven trade-off decisions.
Our objective is to manage costs but not underfund critical initiatives and compromise growth prospects. We'll strike the right balance between financial discipline and long-term strategic investments, which can be achieved by controlling costs in low-value areas to free up capital either for reinvestment in high-value opportunities or to improve margins. Our framework for the 2026 budget and beyond will be based on the following: first, define and ring-fence our strategic growth drivers. This means the new product launches that I touched on as well as key R&D projects, which we have earmarked as nonnegotiable, fully funded programs.
Once we predict the growth drivers, we're looking to control costs in areas that add less or minimal strategic value. From there, the savings we've identified and achieved will either be reallocated or banked. This will be a continuous process, not a one-and-done exercise. It's a mindset.
As our business evolves, so will our resource allocation. Finally, business development. BD works when you have strong strategic leadership, high throughput and a framework for rapidly triaging opportunities and making decisions, which requires a skilled search and evaluation team and a deep network. To be successful, we need to operate inside the loop in our focus areas.
Accordingly, Dave Gardner joined Incyte as Chief Strategy Officer in September, and one of his priorities is to build out this capability. He will play a central role in developing our long-term growth strategy and ensuring external business development opportunities and internal portfolio decisions are strategically sound and financially compelling. We will share more details about our strategic review early next year. Now I'd like to turn the call over to Pablo.
Thank you, Bill, and good morning, everyone. As shown on Slide 14, our pipeline is strategically focused with numerous high-impact programs currently in development. Over the past few months, we have conducted a thorough pipeline review to ensure we're concentrating our efforts and resources on the projects that are essential to the future growth of the company. As Bill mentioned, this process was guided by a clear set of go/no-go criteria, enabling us to make strategic decisions about which programs to advance.
As a result, we have decided to pause or stop several preclinical and early clinical stage programs, including INCA34460, our anti-CD122 program, INCB-57643, our BET inhibitor program and the development of povorcitinib in chronic spontaneous urticaria. By continuing to streamline our pipeline, we will be able to accelerate and prioritize the programs with the greatest potential impact to patients and to drive future growth. Now I'd like to focus on key updates from the quarter, highlighting recent advancements with povorcitinib and our solid tumor franchise. I will also discuss what's expected for the remainder of 2025 from our mutant-CALR antibody program.
For povorcitinib, last month, we presented longer-term data in hidradenitis suppurativa at the European Academy of Dermatology and Venereology Congress, which further reinforced the differentiated profile of povorcitinib. The 24-week data demonstrated deep and sustained improvements across key clinical endpoints, including HiSCR 50, 75, 90 and 100, resolution of draining tunnels and effective reduction in flares. Povorcitinib also showed a rapid and robust reduction in skin pain with 62% to 70% of patients reporting mild or no pain by week 24. Physicians experience in the management of HS emphasize that their primary focus when they treat patients with HS is on 2 elements: help patients feel better by addressing the pain related to HS and to effectively control flares.
The data presented show that povorcitinib provides rapid and sustained pain relief and reduces the frequency of flares. These positive Phase III results demonstrate the potential of povorcitinib to address the significant medical needs of the more than 300,000 people living with moderate to severe HS, offering a novel, effective and convenient oral treatment option for this underserved patient population. Moving to Slide 16 and the near-term opportunities for povorcitinib. As you know, HS is the most advanced program, and we're on track with our regulatory submissions by the end of the year in the EU and early 2026 in the U.S. with potential approvals and launches in late 2026, early 2027. In addition to HS, we're studying povorcitinib in 3 other indications, underscoring its potential to become a major growth driver for the company.
Povorcitinib has been evaluated in Phase III programs in vitiligo and prurigo nodularis as well as a Phase II proof-of-concept study in asthma. We anticipate pivotal data readouts for vitiligo and PN in 2026 with the goal of potential initial regulatory approvals in 2027, 2028. Next, I would like to highlight 2 recent updates from our solid tumor portfolio, beginning with our TGF-beta x PD-1 bispecific antibody program. This month, at the European Society of Medical Oncology Annual Meeting, we presented initial Phase I data for INCA33890, which I'll refer to moving forward 890, our first-in-class TGF-beta receptor 2 x PD-1 bispecific antibody in patients with solid tumors.
This is an Incyte discovered compound and one that is truly differentiated from other TGF-beta and PD-1 approaches. The Phase I trial evaluated 890 in solid tumors with a focus on microsatellite stable or MSS colorectal cancer patients. 890 demonstrated durable single-agent antitumor activity and a manageable safety profile in heavily pretreated MSS colorectal cancer patients, a population with limited treatment options and where anti-PD-1, PD-L1 antibodies have historically produced response rates from 0% to 2%. In patients with MSS colorectal, 890 achieved an overall response rate of 15% and most notably, responses were observed in patients with and without liver metastases.
The majority of treatment-related adverse events were low grade with no dose-limiting toxicities reported. We have also completed dose escalation of 890 in combinations of 4 cohorts, FOLFOX plus bevacizumab, FOLFIRI plus bevacizumab, bevacizumab and cetuximab. No evidence of additive toxicity has been observed in any of the combination cohorts and dose expansion is ongoing. The initial results provide a strong rationale for advancing 890 into a registrational program.
We're planning to start a pivotal Phase III trial evaluating 890 in combination with standard of care chemotherapy and bevacizumab in first-line MSS colorectal cancer patients in 2026. Turning to our KRASG12D program on Slide 18. We recently presented encouraging clinical data from the Phase I trial of INCB161734 or as I'll refer to moving forward 734 in heavily pretreated patients with advanced or metastatic solid tumors harboring the KRAS G12D mutation, including pancreatic ductal adenocarcinoma, among others. Results demonstrated a manageable safety profile with no dose-limiting toxicities observed and predominantly Grade 1 treatment-related adverse events.
Importantly, in pancreatic adenocarcinoma patients, 734 showed promising antitumor activity with an objective response rate of 34%, disease control rate of 86% at the dose of 1,200 milligrams. These results are particularly notable given that only 8 of the patients were treated in the second-line setting. To summarize, both our TGF-beta x PD-1 and our KRASG12D programs represent significant opportunities to address large patient populations with high medical need, specifically MSS colorectal cancer and pancreatic ductal adenocarcinoma. As Bill noted, our strategy in both cancers will be to win in frontline in combination with standard of care.
For 890, we have demonstrated durable single-agent activity in heavily pretreated MSS colorectal cancer patients, including those with liver metastases and a favorable safety profile and combinability with first-line standard of care regimens. As previously mentioned, we're planning to initiate a Phase III study in first-line MSS colorectal in 2026. Similarly, 734 has shown promising antitumor activity and manageable safety profile in advanced solid tumors with particularly encouraging results in PDAC. We'll share more updates on this program next year. Now to Slide 20. 2025 has been a pivotal year for Incyte, highlighted by multiple new product launches, pivotal trial readouts, Phase III study initiations and proof-of-concept results.
These accomplishments reflect the solid progress we've made so far towards the milestones we established at the beginning of the year. As we look at the remainder of the year, we plan to share data for the first time on 989, our mutant CALR antibody in patients with myelofibrosis. We are evaluating 989 in a broad population of patients with MF. There are 3 actively enrolling cohorts.
First, intermediate to high-risk patients who are intolerant, ineligible or resistant to a JAK inhibitor. This cohort is evaluating 989 as a monotherapy. Second, intermediate to high-risk patients who are on ruxolitinib, but experienced a suboptimal spleen response after at least 12 weeks of treatment. In this cohort, we are evaluating adding 989 to ruxolitinib.
And finally, we're enrolling patients with intermediate to high-risk treatment-naive MF in a cohort evaluating 989 compared to a combination of 989 and ruxolitinib. This will allow us to see how 989 performs as a monotherapy and in combination with ruxolitinib in treatment-naive patients. Our update later this year will include early data from the first 2 cohorts. For the monotherapy cohort, we plan to share data from roughly 50 patients, approximately 2/3 of them will have more than 24 weeks of follow-up.
Additionally, data will be presented for the combination cohort and at least 15 suboptimal responders to ruxolitinib. More than half of these patients will have a minimum of 24 weeks of follow-up. Importantly, the update will include response data used in traditional endpoints, SVR25, SVR35, TSS50 and anemia and molecular endpoints like effects on the VAF in whole blood, CD34 positive mutant CALR cells in peripheral blood mononuclear cells and mutant CALR-positive megakaryocytes in the bone marrow. Additionally, we'll provide an update on 989 treated patients with essential thrombocythemia as a follow-up to the encouraging results presented earlier this year.
As you'll recall from EHA presentation, 989 demonstrated a rapid and sustained normalization of platelet counts and was well tolerated with only 1 patient discontinuing due to an adverse event. We look forward to sharing updates on the remaining 2025 milestones and to provide further visibility into our 2026 catalysts as we continue to advance our pipeline. With that, I'll turn it over to Tom for a financial update on the quarter.
Thanks, Pablo. As Bill mentioned earlier, our total revenues and product revenues were $1.37 billion and $1.15 billion, respectively, increasing 20% and 19% from the prior year. Our total GAAP R&D expenses were $507 million in the third quarter. Excluding onetime expenses in the prior year, R&D expenses increased 7% year-over-year, driven by continued investment in our late-stage development assets.
Moving to SG&A. Total GAAP SG&A expenses were $329 million in the third quarter, increasing 6% year-over-year, primarily driven by international marketing activities to support product launches. Ongoing operating expenses in the third quarter increased 8% year-over-year compared to an 18% increase in ongoing revenues during the same period, leading to a continued increase in operating leverage and margins. Based on the growth of our product portfolio, we raised 2025 full year net product revenue guidance to $4.23 billion to $4.32 billion.
We maintain our prior OpEx guidance of $3.25 billion to $3.31 billion, which reflects combined R&D and SG&A GAAP expenses. I'll now turn the call over to Bill.
Thanks, Tom. That concludes our prepared remarks. Please open the line for Q&A.
[Operator Instructions] Our first question today is coming from Tazeen Ahmad from Bank of America.
I wanted to focus on the upcoming mCALR data. You've given us a good preview of how many patients worth of data to expect. I think most people are going to be focused on the monotherapy arm. How important is that going to be for people to believe that you have convinced efficacy as a stand-alone because there could potentially be the view that it could be synergistic when added to Jakafi.
So can you maybe level set for us what level of efficacy you're going to think is going to be convincing enough to move it forward even if it's in combination with Jakafi?
Thanks, Tazeen. I'll turn it over to Pablo.
Thank you for the question. So I think it's important to remember a couple of things about our mutant CALR antibody program. The first is this is the very first targeted therapy for patients with MPNs, and we're talking about MF, but broadly speaking, for myeloproliferative neoplasms, both MF and ET in this case, this is the first truly targeted therapy as opposed to nonspecific therapies in the past, including ruxolitinib that were mostly symptomatic improvements with very little effect on disease modification. Now you're asking specifically about the update at ASH.
I think it's very important for us to demonstrate that there is single-agent activity with 989. That's why the update will include a large number of patients, as I mentioned, 50 patients with somewhat significant follow-up to really prove convincingly that 989 has single-agent activity. The focus will be not just on clinical endpoints, which we believe are critical, spleen reduction, symptom improvement, anemia, but also a set of translational endpoints, which we think are really important to confirm our view that this new medication has potential disease-modifying effects. So in terms of benchmarks around efficacy in previously treated patients with JAK inhibitors, I think the best benchmark we have recently is momelotinib.
As you know, momelotinib has an SVR35 of between 7% and 22% in different studies with the TSS50 improvements in the 25% to 26%. Those are some reasonable benchmarks in the second-line setting to look at. But it's very important for us to confirm the single-agent activity of 989 in MF patients, Tazeen.
Tazeen, thanks for the question.
Next question today is coming from Andrew Berens from Leerink Partners.
Congratulations on the execution during the quarter. I was wondering if you could give some more color on the decision to terminate the povo program in CSU following your announcement in April that this Phase II is successful. Are we going to see the data at a medical meeting as you previously guided?
Yes, Andy, I'll start off and then turn it over to Pablo. As it relates to povo for CSU, it came down for us to priorities. We have to and we are prioritizing projects with better returns profile. It was a good Phase II program, but we have better Phase III programs.
And the factors that went into the decision included differentiation, competitive intensity, timing to market and market potential, among other factors. And Pablo, do you want to just comment on the release of the data?
Certainly, we are -- we haven't decided with investigators whether to release the data, but we'll almost certainly do that at some future conference, Andy. The one other point I would add to Bill's point is that in addition to those factors, the regulatory bar in CSU, we discussed with FDA and the requirements for potential pivotal program in CSU were pretty onerous, and we decided we had other priorities to focus on.
Okay. And then if I could, just a question on the PD-1 TGF-beta. I was at ESMO. I thought it was really encouraging and you guys are advancing into Phase III. Are we going to see combination data before you make that decision to advance? Is there like -- I think there's like a run-in looks like on the clinicaltrials.gov?
So the decision to advance the TGF-beta receptivity by PD-1 program in combination with chemotherapy in first-line colorectal is made. We're moving forward in that direction. In parallel with that, we're generating data with the combination, and we will release that data at some point next year, Andy. But those 2 things are happening in parallel.
We think speed is of the essence here in executing this Phase III trial. So we're advancing this rapidly, and we'll generate the data and release it at some point.
Next question today is coming from Stephen Willey from Stifel.
Just 2 quick ones for me. So on 989, I was just wondering if you could give a little bit of color around what we should expect to see within the abstract publication next week just relative to the presentation itself. And then just a quick one on Niktimvo. Curious how you're thinking about Sanofi's failed frontline trial with Rezurock steroids in terms of read-through to the ongoing Phase III trial with Niktimvo and just whether you think that might say anything about the biology of the disease being different in a newly diagnosed patient.
Yes. Thanks for the question, Steve. I'm going to turn the second question about Niktimvo over to Steven Stein, and then Pab will grab the first question.
Yes, Steve, thanks for the question. In terms of first-line graft versus host disease in combination with steroids, there's really a little bit of controversy around how you measure the primary endpoint and event-free survival. And there's some nuances there on what you call events. So we think our definition is robust and is powered to adequately show the difference we need to beat steroids.
And as Bill said in his prepared remarks, to also show something doctors very much desire, steroid withdrawal as rapidly as possible to avert side effects. But you're right in the sense that it shows the difficulty in this arena of beating steroids, which are active, but we really think it's around the definition of the endpoint, and we -- our endpoint is robust and meets the need for our program, and we're confident about it.
Thanks, Steven. The only other thing I would add, Steve, here is we, fortunately, with Niktimvo have 2 shots on goal. We have the combination study with steroids and with Jakafi. Obviously, these are calculated risks.
You get a combination study with Jakafi that's positive and you're going to 2x the addressable population and then you have a steroid-free regimen. Obviously, we want both these programs to work. 1 of 2 work, it could change the trajectory of Niktimvo fairly significantly. Pablo, do you want to address the first question?
Certainly. With 989, I think it's important to focus on the presentation we'll have before the end of the year. That's a later data cut. It's going to have more patients.
It's going to have longer follow-up. So I realize that the abstracts will be released, but I would ask you to wait for the update we'll provide before the end of the year and focus on that because it's more substantial and particularly follow-up is substantially longer.
Next question today is coming from Jay Olson from Oppenheimer.
Congrats on the quarter. Can you describe the rationale behind terminating the BET inhibitor program? Was that mostly related to your strategic focus on targeted therapies like mCALR in myelofibrosis? And as a follow-up to that question, since the BET inhibitor was on track to begin registrational studies, how soon can you move mCALR into registrational studies?
Jay, thanks for the questions. I'll take the first part and then turn it over to Pablo. As it relates to the BET inhibitor, the risk-benefit calculus, as you know, for BET inhibitors right now is complex, differentiating class-wide risks from molecule-specific ones is challenging. And so in general, we're prioritizing programs with a higher PTRS and a clearer path to market.
And that was fundamentally why we stopped the BET inhibitor program, and then I'll let Pablo comment further.
So I don't have anything to add in terms of the reasons for terminating that program. In terms of the CALR antibody program, Jay, the goal is to start one or more pivotal trials in 2026. As we mentioned during our EHA update in ET, ET will likely be the first pivotal trial to start, and that should start at some point in the first half of the year. In parallel with that, we are having regulatory interactions and continue to review the data in order to decide the right trials and the timing for implementing Phase III trials for patients with myelofibrosis that most likely start at some point in the second half of 2026. I think that one thing that I would like to emphasize is the termination of the BET program in no way reduces our ambition in MPNs.
As I mentioned earlier this year, our goal by the end of the decade is to have a solution for every single patient with a myeloproliferative neoplasm. We're building a pipeline of targeted therapies to address that need, and we intend to continue to advance those programs.
Next question today is coming from James Shin from Deutsche Bank.
First one is for Pablo. Pablo, appreciate 989 is a targeted therapy for MPNs. But can you say whether or not we should expect SVR, TSS and anemia burden, at least on the kinetics front to look similar to rux? And a follow-up for Bill, Jakafi's COMFORT-I and II set a high bar for frontline myelofibrosis.
So from a timing, financial and regulatory perspective, can you share Incyte's progress on gaining certainty for 989's frontline MF development path? And will that development path align with Jakafi's LOE?
Yes. All right. Pablo, you can take the first part of the question.
So thank you for the question. It is very important for us, to address your question directly, it's very important for us to demonstrate that 989 has an effect on clinical endpoints in myelofibrosis. That's why the presentation will include SVR25, SVR35, TSS50 effect and effects in anemia. We realize those are -- a combination of those are the approval endpoints in MF and showing efficacy in those endpoints is critical for this program.
So those will be part of the update we provide before the end of the year. Let me pass it back to Bill.
Yes. And as it relates to both 989 in ET and MF and how we think about the business post 2029, filling a revenue gap is not what 989 does. What 989 does is build a long-duration revenue and cash flow stream well into the next decade. So we don't see the end of the road.
And here's how I think about second line, first line. And Pablo commented on this. There are targeted treatments available in many other cancers. That is not true in MPNs.
And so for hematologist, there is intrinsic appeal to the first targeted therapy. And when you take a look at ET, hydroxyurea is a standard of care. It's the most widely used cytoreductive agent in ET, but it achieves only a partial response, not a complete response in most patients. And there's 3 consequences to that.
The first one is residual symptoms, not as significant as it is in MF, but residual symptoms. The second consequence is residual thrombotic risk. And the third consequence is residual transformational risk. 989 solves the problems that HU created. And even in a second-line single-agent study or with those data, I expect that 989 will reshape the use of hydroxyurea where patients transition off of therapy rapidly because 989 is targeting disease-causing cells.
It's better tolerated. For example, HU has got 7 warnings and precautions, and it's easier to dose. The market for ET is about $5 billion, ET/mCALR patients. Roughly half of them are resistant or intolerant to therapy.
And so I think there's a clear glide path to growth in ET with the first study. And then as it relates to MF, it's, of course, a completely different type of MPN. The risk of transformation to leukemia is real. It's more aggressive.
It's more symptomatic. As effective as Jakafi is, as you know, the SVR35 is between 30% and 40%, right? Symptoms are in the mid-50s. Everybody on Jakafi progresses.
And so even in the second-line setting, there is going to be, just like in ET, a move to either add 989, we'll have to, of course, produce that data or use 989 after Jakafi. And I think that the opportunity in both MF and ET is fairly significant. And what we're looking to is build the business well into the next decade. If we start the studies in the middle of '26, give or take, we should be getting out sometime in that '29, '30 period.
Thanks for the question.
Next question today is coming from Salveen Richter from Goldman Sachs.
You've highlighted VAF as an important part of the mCALR story in terms of the MPN story in terms of the drug being a functional cure. And just remind us what you want to see on VAF reduction and level set us on how well understood the ultimate correlation is between VAF and clinical outcomes. And just a second question here, Bill, on your -- you've highlighted your focus on managing operating expenses and streamlining the company. How are you thinking about the evolution of the company's target margin profile over the next few years and also through the Jakafi LOE?
Great. I'll turn the first question, Salveen, about molecular response over to Pablo, and then I'll address your question about OpEx after that.
Thank you for the question, Salveen. So we have 3 -- and it's important to remember, we have 3 molecular endpoints that we're going to report data on before the end of the year. One is VAF in whole blood. The other one is CD34 positive mutant CALR cells in peripheral blood mononuclear cells.
And the third is malignant megakaryocytes or mutant CALR megakaryocytes in the bone marrow. And the reason why emphasizing those 3 is because VAF is a -- it's in a way, a lagging indicator of what's happening in the bone marrow, which is what truly matters. The disease originates in the bone marrow and reducing malignant megakaryocytes in the bone marrow, which is something we showed for ET at EHA this year is the critical disease-modifying effect. That then will translate into reduction of CD34 positive mutant CALR positive cells in peripheral blood.
And that, in turn, over time will be reflected in a reduction in VAF. So I think I would emphasize that it's important to look at all 3 components of the translational endpoints, and we'll talk about all 3 before the end of the year. In terms of correlations, look, we know that how VAF is a bad thing, and we've shown some data in ET that patients with lower VAF -- with slightly higher VAF reductions over time have better hematologic responses in ET. That data are important.
We still believe that more likely than not, initial approvals for 989 will be based fundamentally on clinical endpoints, traditional clinical endpoints, a combination of the endpoints that we know, which are spleen, symptoms and anemia. And that's the way we're building the pivotal trials for next year. I'll pass it back to Bill.
Yes. Thanks, Pablo. And as it relates to OpEx, Salveen, it's a good question. I spent a lot of time thinking about it.
And as you implied in your question, we have to take a multiyear view of the budget. And I'm not necessarily hard coding for OpEx as a percentage or R&D as a percentage of sales, but I do expect that the quantum of at least spending growth or the percentage is going to come down. And I expect it to come down because of an increase in sales and leverage. Here's what I will say, every R&D dollar and every SG&A dollar has to serve a business strategy.
And budgeting is about distinguishing the high-value projects, as you know, from the low-value projects or another way to put it is good cost from bad costs. What we're really solving for, though, is creating the steepest growth curve possible post '29 and a long-duration revenue and cash flow stream. We will streamline costs where possible, but not underfund critical initiatives and compromise growth. And that is -- those are the principles as I think about OpEx.
And I do expect our margins to improve over time in part due to increasing sales and good cost control. Thanks for the question.
Next question today is coming from Peter Lawson from Barclays.
On Niktimvo, kind of how sustainable is the trajectory on that growth? It's really impressive this quarter. And I wonder if you could also talk around the profitability of that franchise.
Peter, could you just repeat the question? It was a little hard to hear.
Yes. Sorry. On Niktimvo, if you could talk through the sustainability of the trajectory. It was really impressive this quarter. And if you could talk through the profitability as well.
Yes. I'll start off and if Mohamed, who runs that business has any additional comments, he can contribute too. You're right, it's off to a very, very good start. We're annualizing almost at $200 million a year.
I think the important point about the launch right now is you have virtually every BMT center in the United States using and purchasing Niktimvo, which I think is very, very encouraging. All the feedback we've got from transplanters is very, very positive. As you know, we're in the third, fourth quarter of a launch and launches early on can be unpredictable from quarter-to-quarter. All I can tell you is I think the growth trajectory of this is solid right now.
If you look at the Rezurock curve, when it launched, we're virtually right on top of it. That product -- they had a tough quarter, but it's roughly a $500 million business. So I think the prospects for growth next year are solid. We'll, of course, share guidance in early 2026. But I don't see any red flags right now other than launches can be a little bit unpredictable and uncertain.
But I like the way it looks. The next comment I would make as it relates to profitability, one of the nice things about this product is it's a specialty product. And we're not covering 10,000, 20,000, 30,000 physicians or several thousand hospitals. We have a very targeted audience of BMT centers across the United States.
And so when you look at the margin profile of a product like this, it's very healthy. That's what I can tell you about profitability. I wish more of them were as profitable as Niktimvo. Mohamed, do you have anything you want to add?
Yes. Thanks, Bill. Maybe just to complement and give you some color on the sustainability of the growth. As Bill mentioned, a really broad penetration with 90% of transplant centers picking up Niktimvo, but we're seeing all of them have repeat orders year-to-date, which speaks not only to the trial utilization, but the repeat utilization within these accounts and the feedback continues to be positive.
Another point on the sustainability of the trajectory is in line with our expectations, most of the utilization today is happening in the fourth line, but we're seeing a lot more preference and increasing preference in the third-line setting, which gives us a lot of headroom left to go. And maybe one last point on the sustainability. Our goal that we communicated on the last call was to have about 1,000 active patients on therapy by the end of the year. Through the first 9 months, we have about 800 or so patients, well on our way to that 1,000 patient goal by the end of the year, and that continues to be promising as well.
And then from a contribution margin, maybe just the last note is this contribution margin for the Niktimvo P&L is one of the higher in our portfolios, and we expect it to continue to be such given the level of focus that we have on the product and the level of focus from a commercial execution.
Great. Thanks, Mohamed. Thanks for the question, Peter.
Next question is coming from Evan Seigerman from BMO Capital Markets.
Great to see a lot of you at ESMO. So I think we'd all agree that mCALR is a very critical juncture for Incyte, but I want to take it out of the picture for a second. So can you walk me through how the current pipeline needs to mature to drive growth to the Jakafi LOE? And then what type of business development, you're not going to be specific, but would you have to do to help also supplement that growth?
Essentially, I want to understand what Incyte looks like with and without mCALR by the end of the decade.
Thanks for the question, Evan. Yes, and it was nice to see you at ESMO, too. Here's how I would look at the pipeline. We're focused on 7 drivers, 7 projects that I think have the potential to create very meaningful value.
And not all of them have to work. Not all of them will work. We're not going to be perfect. But we have povorcitinib, which is a 3-indication product.
We can build a JAK-anchored franchise in dermatology, where we have differentiated knowledge and capabilities and a very solid data set. The second project is 989, and I can't take it out of the picture, Evan, okay? That's an important project. We have 617F, which is still in early stage, a little bit more opaque.
But as we derisk that asset, that could be as big or bigger than 989 in MPNs because it's covering a mutation that's much more frequent. In fact, it could be 2x the size of a 989. Then we have 3 solid tumor programs, which we derisked at ESMO. We still have more data to collect. We have G12D pancreatic cancer, TGF x PD-1 for CRC and CDK2 for ovarian cancer.
What I would say here is that we're systematically and deliberately and at least up until ESMO, quietly building a high-impact oncology portfolio. There is a lot of substrate there. I don't expect all these necessarily to work, all right? But if 1 or 2 of those hit, they could be very, very meaningful.
As we talked about at the start of the call, novel compounds against novel biological targets in cancers that have missed the IO revolution where there's significant medical need, and we're positioning all 3 compounds frontline in combination with standard of care chemo. And then the seventh project that I focus on is Niktimvo. And as Mohamed talked about, we're off to a good start. And there was a question about sustainability.
We have 2 combination trials in place. If one of those combination trials hit, we're 1 for 2, we move this into the second line. If it's the combination trial with Jakafi, we have a nonsteroid regimen and you could 2x the value of that business. And so when you think about the flow across all of our 3 verticals, I&I, hematology and oncology, there's some real substrate there, and we don't need to be perfect.
We just need 2 or 3 of these out of the 7 to hit, and we'll build a business that's bigger than the one that we have post 2029. Thanks for the question.
Next question today is coming from Derek Archila from Wells Fargo.
Just curious for 989's pivotal trials in MF and ET expected next year, will these be with IV or with the on-body pump from enFuse? And then just a quick follow-up. In terms of a potential XR launch and kind of the commentary around the launch plans in the prepared remarks, I guess, how do you plan to position with payers? And I guess what's your base case in terms of the amount of shares you can convert from Jakafi pre generics?
Yes. Good question. I'll make a few comments about Enable and XR and then ask Pablo and Mohamed. First, we're really pleased to strike a partnership with Enable.
They specialize in high-volume subcutaneous administration with products with a range of 5 ml to 25 ml. We also like the device because it's at-home, self-administered, comfort, the efficiency of their manufacturing operation. And I think it's a high-quality company. They're expanding their manufacturing site, which is an FDA-approved manufacturing site.
And they have commercial devices, I think, in roughly 25 countries and about 8,000 units. And so this is a high-quality company. Pablo can talk more about the program. As it relates to XR, -- let's just -- Pablo, why don't you speak and then we'll go to XR.
So in terms of the plan to incorporating enFuse into the pivotal trials in MPNs, ET is pretty far along. We showed an update at EHA a few months ago on the data. The data has continued to mature. We have already initiated regulatory interactions around that.
So we're probably going to be ready to start pivotal trial in ET before we're ready to deploy the enFuse device. For MF, the goal is to as quickly as possible, make the enFuse device available and ready to go so we can start those studies with the subcu administration. However, I can't be firm at this point. We need a little bit more time to really figure out the timing for the implementation of this, but that would be our goal for MF.
Mohamed, do you want to talk about XR?
Yes. If I can put that in frame for us real quick, Derek. Jakafi XR, as you know, represents a great addition to the portfolio, expected to launch in the middle part of 2026. HCPs and patients now are going to have a convenient once-daily formulation of a brand that they know and trust. We expect about 15% to 30% conversion from the IR by 2028. And with a slower erosion curve than IR, XR can be a solid incremental contributor to top line sales through 2030 and beyond.
And as you mentioned, look, our launch strategy is focused on securing quick formulary access, accelerating HCP adoption and patient preference to maximize that uptick in the short term for that long-term value. And if I can just point to our ability to launch Niktimvo, FL in Monjuvi and Zynyz and SCAC, I'm just proud of our team's ability to execute on these launches, and I think XR won't be any different.
Next question today is coming from Ash Verma from UBS.
So yes, a lot of focus on 989. Maybe just like looking at the Slide 20, a few different settings that you're exploring in ET and MF, but just wanted to confirm at this point, are you able to pursue first-line or naive patients in registrational studies? And then secondly, on the formulation, like where are you able to get the volume down to like how many ml? And is this something that can be a home subcu injection and not just an on-body formulation?
Thanks, Ash. Pablo, do you want to take that?
Thank you for the question. So I think the first part was about first-line MF. And the answer is we fully intend to develop 989 for first-line patients with myelofibrosis. That's why we're running the combination with ruxolitinib in treatment-naive patients.
That work is ongoing. We're not going to disclose results on that before the end of this year, but I'm confident that we will find a path there. We have very clear preclinical data showing synergy between 989 and ruxolitinib in the right models of MF. So I'm confident that we will find a path there.
In terms of the subcu, our goal is to have a device that patients can use at home for self-administration of 989 subcutaneously. That's the goal. That's why we put in place a collaboration with Enable, and we think we're going to find a path to that in 2026.
Next question today is coming from Reni Benjamin from Citizens.
Congratulations on a great quarter. I guess just a follow-up with rux XR. There was a strategy way back when about combining it with a pipeline product to help kind of fight this LOE. Are you looking at any potential combinations to move this forward with either the pipeline or in-licensing a product and staving off this erosion curve for rux?
And as a follow-up, you're starting this registrational program with TGF-beta. I'm kind of curious as you think about how large the study is, the delta that you need to show to have a positive study, how you come to the calculus given the kind of limited data that you have so far?
Ren, thanks for the question. I'll take the first one and turn the second one over to Pablo. Right now, our focus for XR is launching it for the Jakafi indications. We're not working on any combinations in development, and we don't plan to right now.
I know that there was a history there, but we're just focused on the once a day and preserving some portion of that revenue stream and getting a more convenient dosing regimen out. As it relates to your second question, I'll turn it over to actually Steven Stein.
Ren, thanks for the question. So it's first-line microsatellite stable colorectal cancer. The combination we'll be advancing there, as we alluded to at ESMO is with FOLFOX and bev. That's used across the board, independent of RAS mutant versus wild type, independent of left or right side of tumor.
The enabling safety work has already progressed well and will continue. There's benchmarks available both for progression-free survival as well as overall survival. The primary endpoint, as we alluded to at ASH, will be PFS because OS takes a little longer to get there. And the size we'll put up when we launch the study.
But you can estimate it's probably north of 500, and we'll be well powered to show the PFS advantage we want.
Your next question today is coming from Jessica Fye from JPMorgan.
I had a couple more on 989. So I guess for Pablo, recognizing that we won't have frontline data for 989 by year-end, can you talk about what elements of these data in post-Jakafi patients and Jakafi suboptimal responders could make us come away confident that 989 could be successful in the front line? And I guess, specifically for that combo data set, I know it's smaller, but what are you going to be looking for as proof points that 989 is offering clear clinical benefit on top of Jakafi in the absence of a control arm? I guess is there like a certain magnitude of change from baseline on those key measures that you think would exclude any natural variability in the endpoints over time had the patients just remained on their Jakafi monotherapy?
And I have a follow-up.
Thanks, Jess. So I think that the elements -- look, like with any early development program, early-stage development program, I think looking at the totality of the emerging evidence is important. So the first part here is obviously looking at the safety profile. We showed that in ET early this year.
We'll show it in MF before the end of this year. And because of exclusively targeted nature of 989, we think that the safety profile, the really excellent product that we've shown so far is a key element for the future development. So the second part is obviously efficacy. The 2 components, as I mentioned earlier, are obviously the classic clinical endpoints.
We need to see as monotherapy in patients that are resistant intolerant or ineligible for Jakafi, we need to see clear evidence of impact on clinical endpoints, spleen reduction, improvement in symptoms and anemia improvements in addition to translational endpoints. Now when you look at the add-on cohort that we're going to show some data, I think it's important to remember that those are the hardest patients to treat. Those are patients that did not respond to Jakafi in an ideal way despite a minimum of 12 weeks of treatment and being 8 weeks on a stable dose. So any improvement on classic endpoints in those patients, we think, is highly meaningful.
When you look at what's available in second-line MF, the benchmarks are pretty low, as I mentioned earlier, between 9% and 20% for SVR35, for example. So in our view, when you combine the monotherapy data in second line, together with the ability to combine 989 with Jakafi, together with the safety profile, I think it's very easy to put a story together that increases our confidence in our ability to move 989 to the frontline setting as quickly as possible. Obviously, at some point in 2026, we'll provide an update on the treatment-naive patients, as I mentioned earlier, and that sort of will be the definitive element of that story.
You mentioned looking at SVR25 in addition to SVR35. How do you incorporate SVR25 data into your decision-making?
We really don't -- to be honest with you, we report both 25 and 35 as it has been done in other trials in the past. Some of these patients have relatively short follow-up. We have patients enrolled at a range of doses. As you know, these are dose escalation trials.
So we think it's important to have directional data where the spleen shrinkage is going. But the key element here is SVR35, make no mistake about that. We report 25 as well, but SVR35 is what we really care about.
Our final question today is coming from Kripa Devarakonda from Truist Securities.
Another one on 989. So when it comes to a rux combo, is there a rationale to develop both in suboptimal responders as well as in rux naive patients? Or do you see it as a better strategy to focus on one versus the other for the longer term? And secondly, what's the FDA guidance for the endpoints? Now I know you said you need to show both SVR35 and TSS50, but would they be co-primary endpoints?
And do you have to hit on both?
So let me take the second part of the question first. Look, we'll have discussions with FDA on the appropriate regulatory endpoints for what is a novel treatment paradigm for patients with MF, which we think 989 represents. We think it's going to be based on clinical endpoints predominantly, what those specific clinical endpoints will be, we'll discuss it with FDA. We think there's an argument to be made about modifying some of what has been done previously in terms of co-primaries for SVR35 and TSS50. The impact on anemia, for example, we think could be very important and very interesting for FDA to contemplate.
In terms of VAF pivotal trials we will do in MF, those decisions are in the process of being made, and we'll update you over time probably in early 2026. But we intend to develop 99 to try to address the needs of all patients with MF that are mutant CALR positive. That includes patients that are naive or patients that were treated with Jakafi initially and did not respond or were intolerant. And in those 2 contexts, monotherapy and in combination with ruxolitinib potentially can have a role. We'll give you more details over time as we disclose the data.
Thank you. We reached the end of our question-and-answer session, and that does conclude today's teleconference and webcast. You may disconnect your lines at this time, and have a wonderful day. We thank you for your participation today.