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Pablo Cagnoni

Thank you, Herve, good morning. As we highlighted a year ago, and we summarized on this slide, we remain on track to deliver more than 10 high impact launches by 2030 from programs across the portfolio.
On slide 15, I would like to quickly highlight some of the key accomplishments during 2024, and I will then cover some of the milestones expected in 2025. We had a number of important regulatory achievements in 2024, including the approval of Niktimvo for third line plus chronic graft-versus-host disease, and three submissions to the FDA with expected approvals later this year, including Opzelura in pediatric atopic dermatitis, retifanlimab in SCAC, and tafasitamab in relapsed or refractory follicular lymphoma.
We disclosed data from our CDK2 inhibitor and BET inhibitor programs and provided pivotal study plans for both, which we anticipate initiating this year. We continue to evolve at R&D focus with the intent of increasing the rigor of our decision making, accelerating the progression of our pipeline, and optimizing our resource allocation.
Through the fourth quarter of 2024, we presented data at the American Society of Hematology annual meeting or ASH, from both our BET inhibitor program and Phase 3 results for tafasitamab in patients with relapsed or refractory follicular lymphoma. The Phase 3 results of tafasitamab in follicular lymphoma were presented at a late breaking session and showed that the study met its primary endpoint by demonstrating a statistically significant and clinically meaningful improvement in progression free survival.
This was to our knowledge, the first study to validate the combination of an anti-CD19 with an anti-CD20 monoclonal antibodies in patients with follicular lymphoma. tafasitamab was generally well tolerated, and safety was consistent with its known safety profile.
This data has been submitted to the FDA, and approval is expected in the second half of 2025. For our BET inhibitor, we shared additional data from the ongoing dose escalation study as both monotherapy and in combination with ruxolitinib. These results showed reductions in spleen volume as well as improvements in both symptoms and hemoglobin.
As highlighted on this slide, we plan to advance this program into Phase 3 development as a monotherapy in the post-JAK population, and we look forward to providing additional details later this year.
Moving to slide 18, we are continuing to execute a broad development plan for povorcitinib, our oral small molecule highly selective JAK1 inhibitor. Povorcitinib is currently being evaluated in Phase 3 studies in Hidradenitis Suppurativa, vitiligo, and Prurigo Nodularis, and in randomized Phase 2 proof of concept studies in chronic spontaneous urticaria and asthma, with data for both expected in 2025.
Povorcitinib has already shown encouraging efficacy and safety in a randomized Phase 2 study in patients with moderate to severe Hidradenitis Suppurativa, a highly painful inflammatory condition. As highlighted on the right side of the slide 19, but povorcitinib showed significant responses by week 12, including improvements in high score 50, 90, and 100. Additionally, povorcitinib demonstrated a rapid and significant reduction in pain, offering the potential to transform the current standard of care for this disease.
The two Phase 3 studies, STOP-HS1 and STOP-HS2, are fully enrolled, and we expect to have Phase 3 data in the first half of this year.
Turn to the mutant CALR antibody program on slide 20. The publication detailing our mutant CALR monoclonal antibody was recently featured on the cover of Blood, highlighting the importance of this innovative medicine. This antibody was developed entirely by Incyte, and unlike Jakafi, the mutant CALR antibody has the potential to eliminate the mutant clone and normalize hematopoiesis in patients with CALR mutated essential thrombocythemia and myelofibrosis, potentially leading to a functional cure. We look forward to sharing data from the ongoing proof of concept studies in both ET and MF later this year.
Turn to slide 21 on Ruxolitinib XR. We're pleased to announce that a bio-equivalency study of ruxolitinib 55 milligrams extended release demonstrated that once-a-day formulation to be bio-equivalent to twice-a-day ruxolitinib. Bio-equivalence was achieved for both AUC and C-min, and the geometric means ratios falling within the 80% to 125% bio-equivalence reference range. We have reviewed this data with the FDA, and with their agreement, plan to submit for approval by the end of the year once stability studies are completed.
As mentioned, 2025 will be an important year for Incyte, with over 18 key milestones, including 4 new product launches, 4 pivotal trial readouts, at least 3 Phase 3 study initiations, and 7 proof of concept study results. As you can see on slide 22, we have already achieved 2 of these milestones that we first highlighted just last month with the launch of Niktimvo and bio-equivalency data for ruxolitinib extended release.
We look forward to sharing additional updates on these milestones over the course of 2025, and with that, I would like to turn the call over to Christiana for the financial update.

Christiana Stamoulis

Thank you Pablo, and good morning everyone. Our fourth-quarter 2024 results reflect a strong commercial execution and continued growth with total revenues of $1.2 billion, up 16% versus the same period last year. Total product revenues of $1 billion in Q4 were driven by strong demand growth for Jakafi and Opzelura and increased revenue contribution from Monjuvi as a result of the acquisition of full rights to tafasitamab in 2024. Total royalty revenues were $159 million, up 6% compared to Q4 2023, driven by increased demand for Jakafi.
Turning to Jakafi on slide 26. Jakafi net products revenue was driven by strong patient demand growth across all indications. In the fourth quarter of 2024, net product revenue increased 11% year over year, driven by a 9% increase in total demand and a 14% increase in paid demand. For the full-year 2024, net product revenue increased 8% versus 2023, driven by a 7% increase in total demand and a 9% increase in paid demand.
Recall that in Q3 and Q4 2023, we saw a significant increase in the number of Medicare Part D patients receiving free product. As we anticipated, these patients returned to paid demand in 2024. As a result, year year-over-year paid demand growth exceeded total demand growth in both the fourth-quarter and full-year 2024.
Turning now to Opzelura on slide 27. Total net product revenue for the fourth quarter was $162 million, representing a 48% increase year over year, driven by growth in new patient starts and refills across both AD and vitiligo in the US, as well as continued contribution from the commercialization of Opzelura for vitiligo in Europe.
In the fourth quarter, ex-US Opzelura net product revenue was $24 million. For the full year, net product revenue was $508 million, representing a 50% increase year over year, and ex-US net product revenue was $61 million.
Moving on to slide 28 and our operating expenses, total GAAP R&D expenses for the fourth quarter were $466 million, an increase of 5% compared to the same period in '23, due to continued investment in our late-stage development assets and timing of certain expenses.
For the full-year 2024, ongoing R&D expenses, excluding the Escient acquisition upfront consideration and other one-time expenses, increased 14% year over year as a result of increased investment in our late-stage programs.
As we wrap up the clinical developments of certain of these programs as well as the development activities of discontinued programs, we anticipate the reduction in investment in those programs to partially offset the increased investment in other programs, which would allow us to control future R&D expense growth.
Moving to SG&A; total GAAP SG&A expenses were $327 million for the fourth quarter, representing an 11% year-over-year increase, primarily as a result of Incyte's now recording Monjuvi-related sales and marketing expenses in the US, following the acquisition of global rights to the program in 2024, as well as the timing of consumer marketing activities and certain other expenses.
For the full-year 2024, total GAAP SG&A expenses increased 7% year over year, as a result of us now recording Monjuvi-related sales and marketing expenses, and investment in the launch of Opzelura in Europe and the preparation for new product launches in the US.
Finally, total ongoing R&D and SG&A expense for the full year increased 10% versus a 15% increase in total revenues, leading to an increase in operating leverage and margins.
Moving on to 2025, I will now discuss the key components of our guidance on a GAAP basis. For Jakafi, we expect net products revenue to be in the range of $2.925 billion to $2.975 billion, well on track to achieve our long-term guidance of over $3 billion by 2028.
We expect net product revenue growth to be driven exclusively by continued demand growth, primarily in PB, and be partially offset by lower net pricing as a result of IRA-imposed price increase caps and continued growth in 340B volumes.
As in previous years, we expect the gross to net adjustment to be higher in the first quarter of the year, relative to the previous quarter and subsequent quarters, due to higher deductibles that are primarily impacting Q1.
For Opzelura, we expect total net product revenue to be in the range of $630 million to $670 million, driven by continued demand growth in AD and vitiligo in the US, initial contribution from the potential launch of Opzelura for pediatric AD, expected in the second half of the year, and increased contribution from Opzelura for vitiligo in Europe.
In the first quarter of the year, we expect to see again the effects of typical Q1 dynamics on nets sales, due to planned deductibles resetting at the beginning of the year and the impact of holidays, medical conferences, and other events on dermatology product sales. As a result, Q1 Opzelura net product revenue is expected to be below the previous quarter, consistent with what we saw in 2024.
For other oncology products, we expect total net product revenues to be in the range of $415 million to $455 million. These include contribution from both the current approved indications for our exclusive Niktimvo Monjuvi/Minjuvi, Pemazyre and Zynyz, as well as the launches of Monjuvi in SL and Zynyz in SCAC, anticipated in the second half of 2025.
Turning to operating expenses on a GAAP basis, we expect COGS to range from 8.5% to 9% of net product revenues. The increase in the COGS rate is driven by certain manufacturing related expenses and the impact of our profit share agreement with Syndax for Niktimvo in the US, as Syndax's portion of the profit share will be reflected in COGS.
R&D expenses are expected to be in the range of $1.93 billion to $1.96 billion, primarily driven by the progression of our pipeline. We expect SG&A expenses for the year to be in the range of $1.28 billion to $1.31 billion.
Operator, that concludes our preparing remarks. Please give your instructions and open the call for Q&A.

Question and Answer Session

Operator

(Operator Instructions)
Michael Schmidt, Guggenheim Partners.

Paul Jeng

Hey, good morning. Thanks for taking our question. This is Paul on for Michael. We have two on the pipeline. First on Opzelura. Can you set some expectations for the upcoming Phase 3 in prurigo nodularis? What's the clinical bar here given there's no (technical difficulty) therapies available? And then secondly, just on the CDK2 program. Are there any plans to provide another clinical update on the Phase 1 ovarian cancer study, perhaps with longer follow-up at the expansion dose levels? And what are the gating factors to formalizing a pivotal study dose selection?
Thank you.

Pablo Cagnoni

Certainly. Thank you for the questions. Let me take the second one real quick. For the CDK2 program, as we discussed earlier, this year, we plan to initiate pivotal trials this year. And as we discussed, that will be in platinum-resistant ovarian cancer. We've taken a dual approach there with a single-arm study for what we hope will be accelerated approval in the US as well as a randomized trial that we will provide more details over the course of the year. So that program is advancing rapidly, and we will provide an update later this year as you asked.
The second part of the question in terms of (technical difficulty) in prurigo nodularis. As you know, the Phase 3 data are coming in this half. And I think what -- in terms of setting the bar, when you look at the Phase 2 data and the improvement, both on the global assessment of itching as well as the WNRS end point, we think that if we are anywhere in the vicinity of what the Phase 2 trial showed, this is going to be a very important addition to the (inaudible) for patients with prurigo nodularis.
The availability of a topical for patients that have perhaps less severe disease than those that may require systemic medicines such as povorcitinib, we think it's going to be very important. So we want to be somewhere -- and as we all know, from the extensive safety track record of (technical difficulty) it's a very, very well-tolerated medicine. So if we're anywhere near what the Phase 2 results showed, I think we're going to be -- it's going to be a very important contribution for patients.

Operator

Tazeen Ahmad, Bank of America.

Tazeen Ahmad

Hi guys, good morning. Thanks for taking my questions. As it relates to Opzelura, can you give us a sense of how you got to guidance for this calendar year, specifically, how are you thinking about the number of tubes that are going to be used for the two approved indications? And then maybe one question on povo or for the HS data that's due in the first half of this year, what would you consider to be not only statistically significant but also clinically meaningful data? Thanks.

Christiana Stamoulis

This is Christiana. Regarding the Opzelura guidance. First of all, when you look at the guidance range that we provided to the $630 million to $670 million for the year, it represents 24% to 32% year-over-year growth.
As we indicated in our prepared remarks, this is driven by continued demand growth in AD and vitiligo and also reflects the potential launch of Opzelura in pediatric AD in the second half, the contribution from that indication and continued increased contribution from Europe.
The range that we provided primarily reflects variations in the patient mix as well as in the level of patient activation rate and adherence in vitiligo and the level of contribution from Europe.
In terms of the tube, the level of tubes, that especially around the vitiligo is reflected in the level of patient activation rate and adherence. We are seeing an increase in the average number of patients that are sticking with therapy, and therefore, refill their prescription, and also in the average number of prescriptions per patient.
But as we have commented in the past, this is an area that is evolving, and we expect to continue to evolve as we pursue additional initiatives to help patients, educate patients and help them appropriately use vitiligo -- Opzelura for vitiligo. And that is reflected in the guidance range that we have provided.
Finally, the other thing, again, to keep in mind, as you think about the guidance and how do you distribute it through the course of the year. Q1, as I mentioned in my prepared remarks, always tends to be lower than the previous quarter and the subsequent quarters. We saw that in '23, we saw it in '24 when we expect to see the same dynamics in '25.

Pablo Cagnoni

Let me take the second part of the question. So look, the first and most important thing is obviously to have a positive study or two positive studies, and that, as you know, means statistical significance for the primary endpoint, which, in this case, is HiSCR 50 at week 12 in the two hidradenitis suppurativa studies for povo.
Now beyond that, I think that when one looks at the Phase 2 results with the povorcitinib study and you look at the totality of the data, and that is effect on HiSCR50, 75, 90 and 100 as well has a strong effect on pain improvement that the study showed. Together with the safety profile, the Phase 2 was very clean in that study. There were no thrombotic events in the high-dose povo arm. There were no patients that discontinued due to (technical difficulty) well that we've seen in Phase 2. And we realize there's always a little bit of contraction in Phase 3,a little bit of -- the results can change a little bit. But we believe the overall profile that we saw in Phase 2, if we are somewhere in the vicinity of replicating those results in the Phase 3 studies, we think we have a very competitive profile with povorcitinib in hidradenitis suppurativa.

Operator

David Lebowitz, Citi.

David Lebowitz

Thank you very much for taking my question. Given the IRA out-of-pocket has moved to its go-forward levels, 1,000 per year, can you run us through what the processes that a patient must go through to actually ensure that the cap is put in place. What steps do they need to take? And how long do you think it might be until the benefit of that starts showing up in sales?

Christiana Stamoulis

So the cap for the out-of-pocket this year is reduced to 2,000 a year. Patients do have an option to have this spread through the course of the year in equal payments. There is a process that they would have to go through. We expect that it would take some time for them to figure out that process. So we may not see the immediate benefit right away, although we expect to see a continued benefit from the lower out-of-pocket as we saw in 2024.

David Lebowitz

Thanks for taking the question.

Operator

Jessica Fye, JPMorgan.

Jessica Fye

Hey guys, good morning. Thanks for taking my questions. A couple on povo in HS. So I think north of 60% of the patients in your Phase 3 trials are biologic-naive. Are you going to seek a label that includes biologic-naive patients? Or do you expect it will be labeled for post biologic patients? And then within the trials, are you powered for both the biologic naive and experienced subgroups? And is there anything you can say about the powering assumptions there?

Pablo Cagnoni

Yeah, Jess. So as you point out, we haven't disclosed a specific percentage, but it's roughly -- directionally, that's correct in terms of biologics naive biologically exposed patients. Our products supports the biologics as a stratification criteria in the Phase 3 trials. We expect to analyze the data based on prior exposure to biologics. I'm not going to comment on the full powering. Obviously, the studies are powered on the basis of assumptions around the primary endpoint and the key secondary endpoints for the study. So we'll discuss the results in more detail. And obviously, in terms of labeling discussions, we'll see what the data looks like, and we'll discuss with FDA at the right time.

Jessica Fye

Pablo, can I follow up on one of the responses to, I think it was Tazeen's question. When you said, if you show something that's close to what you showed in Phase 2, that would be super competitive. Because I think the Phase 2 deltas on HiSCR50 differed a little bit, if you look at the 16-week versus the 12-week time point. And I think in Phase 3, it's a 12-week. So when you say close to Phase 2, do you mean close to the 12-week cut of Phase 2 or close to the 16-week?

Pablo Cagnoni

Yeah, you're correct. So if you remember, the placebo subtracted HiSCR50 at week 12 is 28% and at week 16, it's 17% in the Phase 2 studies. That's, I think, what you're referring to.
Look, we selected week 12. It's a key, one of the key difference, I think, when you look at the public data, and not just in HS, but also in PN, for example, is how quickly it works. And that is very important for patients with painful or intensely pruriginous diseases like HS and PN. So that's the importance of the week 12.
My comment was referring roughly to replicate the profile that we saw in Phase 2. I don't want to set a number. We're running the Phase 3 studies to have clarity on what the actual benefit of povorcitinib is in large Phase 3 studies, Jess. So any -- the number, the specific percentage that we see is not something we're going to comment on right now, but a profile that is consistent with the Phase 2 is what we expect to see in the Phase 3.

Operator

Salveen Richter, Goldman Sachs.

Salveen Richter

Good morning. Thanks for taking my question. Just a follow-up here on povo. With regard to the Phase 2 data, and we saw this drop from week 12 to week 16. Could you just speak about the read-through to this trial and the risk that may play out there? And then also in your 2025 guidance, just speak to us about how you model for Part D redesign for Jakafi? Thank you.

Pablo Cagnoni

Certainly, I think, look, clinical trials, particularly in diseases like HS, where they have a placebo effect, as you know, you're going to see some movement on the efficacy endpoints, in the efficacy curve over time.
What we saw in the Phase 2, as both you and the previous caller, Jess, pointed out, was that from week 12 to week 16, there was a drop in the placebo-subtracted response within povo, in the povo arms. It's probably variability and noise related to clinical trials. We are not concerned about that. The studies are well powered to demonstrate what we believe is a statistically significant difference between povo and placebo. And we think we'll see not only statistically significant, but clinically meaningful impact of povo and the primary endpoint, which is HiSCR50 at week 12 as well as the key secondary endpoints, which include obviously other levels of clinical benefit and other time points in the study.

Christiana Stamoulis

Regarding your second question, Salveen, on the impact of the Medicare Part D redesign on gross to net for Jakafi. We do expect to see some savings in Medicare Part D since our contribution to the donut hole will now be replaced by a 1% participation to the catastrophic coverage, given that we have the small biotech exception. However, these savings would be offset by continued increase that we see in 340B.

Operator

James Shin, Deutsche Bank.

James Shin

Hey, good morning, guys. I just wanted to follow up on povo STOP-HS1 and 2 Phase 3 trials. How will you disclose this data? Will we get a press release with HiSCR top line followed by full data at the (technical difficulty) conference? And then any update on the X2 program for CSU? Thank you.

Pablo Cagnoni

So on povo for HS, our plan is once we have the data is to disclose in a press release. And almost certainly, we have a call to discuss our results with the investment community. On 262, I don't have an update at this point. We are still completing the valuation of the events that we described late last year in the preclinical financing, the toxicology, and we'll provide an update later this year.

Operator

Vikram Purohit, Morgan Stanley.

Vikram Purohit

Hi, good morning. Thanks for taking our questions. We had just one on the proof-of-concept data sets expected for [you and keller] then also for JAK2V617Fi for later this year. Could you just help us kind of frame what we can expect to learn and what you're setting at the bar for success for these data sets and what the hurdle is going to be for moving these programs forward?. Thank you.

Pablo Cagnoni

So let me start with mutant-CALR. So as you point out, we'll have proof-of-concept data this year for both patients with ET and MF. That will come over the course of the year. What we expect to see and just to -- first of all, let me tell you a little bit about what you're going to see, and it's going to be a substantive amount of data. We expect to have data at different dose levels with some amount of follow-up in order to have clarity on some of the important measures of success for those programs.
Obviously, we discussed over the past few months the importance for this program, not only to show an impact on the traditional endpoints in patients with myeloproliferative neoplasms such as blood counts, symptoms, spleen, et cetera. But also to see some early evidence of (technical difficulty) reduction, which we think it's an important measure of success. This is not going to be obviously a definitive data, but we want to have some evidence that a mutant-CALR antibody in patients with ET and MF can show some evidence of our reduction. So that will all be part of the update.
617F, if you recall, started in the clinic later. We started dosing patients with MF in the third quarter of 2024. So it's a little bit behind. We intend to have an update this year. And the same point supply basically to that program. We would like to see impact, not only a traditional endpoint but some early evidence of a lead reduction in that program as well.

Operator

Marc Frahm, TD Cowen.

Marc Frahm

Hey, thanks for taking my questions. Maybe just a one nuance question on Stop-HS. Just Pablo, you mentioned earlier often these trials do have a little bit of a decline in treatment effect from Phase 2 to Phase 3. In HS specifically, we've seen kind of changes in antibiotic use and how that's treated with an SAP to maybe drive some of that effect. Can you remind us just how antibiotic use is being treated, what's treated in Phase 2 and how that may or may not differ in the Phase 3 trial?
And then for Christiana, on the absolute guidance, can you break down some of the assumptions there on US versus ex US growth, just given the kind of label changes that are happening, but also increasing reimbursement outside the US?

Pablo Cagnoni

So let me take the first part of the question. So first of all, the use of antibiotics in the Phase 3 was treated the same way that it was in the Phase 2. So let me just remind you what that is. Patients are not allowed to be on systemic antibiotics at study entry. Over the course of the study, if patients have started on systemic antibiotics or a flare, that's treated as a non-responder. Now if patients have started in the systemic antibiotic for a completely unrelated reason, that is not treated as a non-responder, and that's consistent with the Phase 2.

Christiana Stamoulis

In terms of the Opzelura guidance, the guidance that we have provided global, and it does reflect increased contribution from Europe. In 2024, the contribution was primarily driven by Germany and France. And in '25, we expect continued contribution from those two countries, but also now increased contribution from Italy and Spain. We are not going to be breaking down the guidance between the two regions.

Operator

Kelly Shi, Jefferies.

Kelly Shi

Thank you for taking my questions. I have two. Firstly, can you share a little bit more color on [KRASG21D] program. In terms of POC data, what kind of like sample size and also tumor indications could we expect? And also based on the preclinical data achieved so far, do you think it hints any potential differentiation from other competitive G12D programs? And for Pablo, just quickly, I want to confirm, for the HiSCR75, 90 and 100, do you plan to show at a 12-week follow-up only or actually both 12 and 16 weeks follow-up?

Pablo Cagnoni

Let me thank you, Kelly. So let me -- thank you, Kelly. So in terms of KRAS. The indications here as -- that have been the focus for us are pancreatic cancer and colorectal cancer. And specifically in pancreatic cancer, we're trying to accelerate enrollment because obviously, it has become a very competitive space. We're fully aware of what our competitors are doing. We believe, based on the profile here, that we have preclinically, which is a highly selective and potent G12D inhibitor, that if we accelerate this program, we can still compete in this space.
Now it will come down, obviously, to the efficacy and safety that we see. But when we look at the data from our competitors, we think that particularly as you move to early lines of therapy in combination with chemotherapy, there's still space for a highly selective, well-tolerated G12D inhibitor. So we look forward to discussing data later this year, but that continues to be our view.
In terms of what we're going to disclose for the povo HS studies in terms of other endpoints, that's not a decision that we've made at this point. Obviously, we'll have to communicate the overall results of the study, as I answered a little bit earlier here. But whether we add a number of other endpoints or other release, we haven't decided.

Operator

Brian Abrahams, RBC Capital Markets.

Brian Abrahams

Hey, good morning. Thanks for taking my question. Maybe on the BET inhibitor, can you talk about the role you foresee for that in a post-Jakafi amount of therapy setting? And then what's your latest thinking on the frontline development path? What are you looking for out of the treatment that you've combo data to move forward? And are we still looking for results from that this year? Thanks.

Pablo Cagnoni

Certainly. So on the second line, look, I think that today, as we know, eventually, as good as Jakafi is for patients with myelofibrosis, eventually all patients progress and they need better treatment options when they progress. Obviously, in addition to the BET inhibitor, we're developing the mutant-CALR antibody in the V617F inhibitor.
But in the relatively near term, we think that the BET inhibitor can provide a very good treatment options for patients with MF to progress after Jakafi. That's why we are accelerating that second line program as much as we can. And we disclosed the basic design at ASH, and you'll hear more of an update there this year.
In terms of first-line indication for the BET inhibitor, what we need are more data. We need more clarity on the safety profile and the impact on endpoints that has a combination with Jakafi in previously untreated patients. We showed an update at ASH, which we think is very encouraging in terms of the ability to combine our BET inhibitor with Jakafi and the impact on spleen, symptoms and importantly, the impact that we saw in hemoglobin in the presentation that we gave at ASH. So we're still encouraged by the data. I think we need additional data to make that decision and to have another conversation with FDA on a potential first study.

Operator

Jay Olson, Oppenheimer.

Jay Olson

Hey congrats on the quarter. For ruxolitinib XR -- also congrats on achieving bioequivalence. Can you just talk about your plans to commercialize rux XR and also the timeline for a fixed-dose combination with your BET inhibitor? Thank you.

Herve Hoppenot

So maybe on the commercialization, I mean, the timeline is basically, we are now waiting for the end of the stability study to submit to FDA by the end of this year. So that will -- it's a response to a CRL. So it's a slightly different timelines, and we should be commercializing in 2026, which if you look at the window it gives us versus the 2029 first generic of twice a day is around 2.5 years. And obviously, the goal of that during that period is to have as many patients as possible being treated with once a day as a single agent as Jakafi is used today in most indications, in most patients.
Now related to the first-line study and the BET combination, obviously, the whole program depends on what Pablo was just speaking about, which is a profile of the first-line combination. And also, if you think about it, of how the rest of our portfolio in MPN is evolving with the CALR and the 617F. So none of that has been firmly decided yet, but that's probably going to be happening over the next year also on how we can put it in combination with our BET inhibitor.

Operator

Eric Schmidt, Cantor Fitzgerald.

Great, thanks. Great. Two questions here. This is [Emma] on for Eric. The first one on povo and HS, you shared about the HiSCR50, 12 and 16 weeks. I guess in terms of HiSCR75 as well, could you share any ranges of what you think would be meaningful and competitive data there in the evolving landscape? And then the second question is on the tafasitamab first-line and DLBCL study? What do you see as meaningful data there over the (inaudible) arm?

Pablo Cagnoni

Okay. So on the first one, on povo and HS, I'm going to have to give a similar answer to what I've given earlier, which is, obviously, you want to see statistical significance for the primary endpoint. The key secondary endpoint, obviously, are not similarly powered, but there are important endpoints to show a clear difference with placebo.
I don't think it's productive to really set a bar for what we have to clear. If you look at the data from the Phase 2 study with the 20% at week 12 and 13% placebo subtracted at week 16 for povo, I think those are really strong results in the context of prior data releases in patients with HS. So if we are in the vicinity of those results, I think that's going to be a very important contribution.
There's a top line first line, the first-line DLBCL study, as you know, this is a curative setting. So even a small impact on the primary endpoint of the study, I think, could be really, really important. And if you look at recent benchmarks such as the Polivy data, which showed a modest impact on PFS, it still has led to a substantial adoption of that in frontline patients. So I think it's a very clear indication where modest improvements could lead to a potentially wide adoption because you're talking about potential (inaudible) therapy.

Operator

Matt Phipps, William Blair.

Matt Phipps

Yeah, thanks. Two for me. One, can you maybe just remind us on the learnings from the robust trial that were incorporated into front line where you think you can succeed when that trial fails? And then for the mutant-CALR program, is that just going to be monotherapy this year? Or could we also get some Jakafi combo? And can you remind us preclinically, if you saw any differential activity between type 1 versus type 2 mutations in CALR. Thank you.

Pablo Cagnoni

So in terms of the mutant-CALR antibody, we haven't really decided -- we have initiated a combination with Jakafi. The specific details are what we're going to disclose. We haven't really decided. But it's possible that we'll disclose some Jakafi combination data. It's an important part of the development plan.
As we've discussed previously, we don't necessarily commit to a combination development for the mutant-CALR antibody. But it's possible that because of the really rapid and strong impact of Jakafi in patient symptoms, particularly as you know, as well as other end points, a short induction with Jakafi combined with mutant-CALR and then a long-term maintenance therapy with mutant-CALR antibody could be a treatment paradigm, but none of that has been decided. We'll discuss the development plan, the future development plans for the mutant-CALR antibody when we do we disclose the data.
What we have disclosed into the type 1, type 2 is that these are -- these two types of mutations are very different in the structure in the gene. And what we've discussed previously was that the affinity for the antibody for type 1, the type 2 is pretty different. In terms of what we expect to see in the clinic, we'll discuss that when we have the data results, but it's possible that we have a different level of activity in patients with different types of mutations.

Operator

Andrew Berens, Leerink Partners.

Andrew Berens

Hey, thanks. Congrats on the good quarter in 2024. A couple more on Jakafi XR. I don't think you commented on the Cmax. Just wondering how that would (technical difficulty) increase the dose to Cmin. And is there anything else that's gating approval either in the stability studies?

Pablo Cagnoni

So in terms of XR, so look, you cannot replicate the Cmax with a once-a-day formulation compared with twice-a-day formulation. The FDA understands that. And that was not the purpose of the study. So that, what you have -- what you have to meet is obviously the (technical difficulty) you see at steady state and the Cmin at steady state. As we disclosed in the slide deck, both of those endpoints were met. They're only gating factors is the stability studies. As I mentioned in my prepared remarks, we have discussed the results of the study with FDA, and we have an agreement with them on the stability studies necessary for the resubmission for the response to the CRL, and we expect that, that will be done before the end of the year.

Operator

Andy Chen, Wolf Research.

Andy Chen

Hey, thank you for taking the question. So on povo HS again, can you talk about specific protocol differences between your trial and other trials, especially from IL-17 antibodies? What have you learned from the trials? And what might you be doing differently to amplify your efficacy here? And then also in your base case scenario, are you expecting only the high dose to be approved or both doses?
Thank you.

Pablo Cagnoni

So Andy, it's difficult to get into specific difference between studies because we don't have all the details of every protocol that's out there. We think that the design of the Phase 3 studies is consistent with the way our competitors are studying patients with hidradenitis suppurativa. We designed a Phase 3 to have a slightly high percentage of patients with as opposed to (technical difficulty). That was an important point that we wanted to emphasize in order to reduce the placebo effect since it's harder in patients with more advanced disease. And that was an important point that we wanted to emphasize.
I think that there were a couple of things that we did as well as we were careful in selecting sites. We run a series of trainings with the sites, which was consistent with what we did in the Phase 2 to make sure that the way these patients are assessed by the investigators is consistent with what we did in Phase 2. So we try to replicate in Phase 3 as much as we did in Phase 2. And obviously, as I mentioned earlier, the primary endpoint we selected based on the Phase 2 data, I think that was an important lesson in order to really see how quickly we can provide benefit to patients with a week 12 improvement, which also was the best endpoint for us in our Phase 2 study.
In terms of the dose, when we have the data, we'll discuss with FDA, obviously. Yes, it's possible that both doses are positive. We will lead to a broader label with different rates of doses, but we'll discuss that when we have the data with FDA.

Operator

Salim Syed, Mizuho.

Hi, thanks for taking our question. This is Eric on for Salim. So just looking at modeling Jakafi through 2025. Just wondering how we should think about the change, the growth versus 2024? And how we should think about that through the year? It's more loaded in first half, second half, anything like that?
Thank you.

Christiana Stamoulis

So the guidance range that we provided implies a year-over-year growth of 5% to 7%. In terms of how to model it through the year, remember that Q1 always is the lowest quarter and lower than the prior quarter. And this is because of the reset of the deductibles at the beginning of the year, which on the commercial side, you would expect to continue to see this year. And even on the Medicare Part D, unless patients get to spread it through the course of the year, it will continue to have more of an impact in the first quarter of the year. So expect Q1 to be the lowest quarter and lower relative to Q4 of '24.

Operator

Evan Seigerman, BMO Capital Markets.

Evan Seigerman

Hi guys, thank you so much for taking my questions. Two for me. Just walk me through some of the initial assumptions for the pediatric Opzelura launch? What does this initial uptake curve look like? And how much is factored into your guidance? And second, kind of a hypothetical here. Would you ever consider an adalimumab head-to-head trial in HS versus povo, given that you want to establish yourself as a systemic standard of care in this market. I'm just thinking if this is a biosimilar market, you're coming in as a branded, and it could help you kind of getting a leg up here.

Matteo Trotta

Yeah, I'll take the ADP launch. We're very excited about the opportunity that we have there. to help these patients between 2 and 11 years old, also because the very vast majority of them are still uncontrolled and pretty much on steroidal therapies. Obviously, in the second half of the year, we will see the initial uptake from the indication contributed to our net sales. But overall, in terms of sizing at peak, we think that, that opportunity will represent anywhere around 10% or 15% of the total atopic dermatitis Opzelura business.

Pablo Cagnoni

Let me take the second one. We have not discussed in the past whether to conduct a head-to-head study with adalimumab. There's a couple of points there. First of all, we -- let's wait to see the data for the HS-1 -- for the HS studies that are coming. Once we have the data in hand, we'll make decisions about future development. The challenge with the data that has been reported in the past with Humira and when you discuss this between physicians, is that while the response that has been reported was high and which has not been replicated since the original study, the drug failure on Humira is relatively fast. Patients seem to progress. presents with HS seem to progress relatively quickly.
So this is one of the reasons why HS has become such an important market, such important indications for a number of companies because there's a fair amount of dissatisfaction with the data, with the results in the real world with Humira. So at this point, we haven't made a decision to go ahead to study future development in HS. We'll discuss it after we have the data.

Operator

Ash Verma, UBS.

Ash Verma

Great, thanks for taking my question. Just one. So on povo and HS, I wanted to understand what is your view of the potential upcoming readouts from competitors? You have [LIMBER]. How would that impact your value proposition for povo in this market? Thanks.

Pablo Cagnoni

So at risk of being repetitive. So if we look at the Phase 2 data that we've reported in a number of places, both week 12, week 16, and the totality of the data across all the endpoints HiSCR50, 75, 90, 100 and pain response, we think we have a very competitive profile with povo. Assuming everybody has a certain level of correction from Phase 2 to Phase 3, we believe that when you put together all the efficacy data, together with the safety profile we saw in the Phase 2, that we have a very competitive profile with biologics and certainly with LIMBER.

Operator

Kripa Devarakonda, Truist Securities.

Kripa Devarakonda

Hey guys, thank you so much for taking my question. On Jakafi, it think like PV is primarily driving growth. Can you talk about the patient population where you're getting uptake? And what the expectations are in terms of growth? Is it primarily through new patient adds or duration on therapy as well? And beyond rux XR and the V617F inhibitor, any additional life cycle management plans for your footprint in PV, which seems to be growing?

Herve Hoppenot

Yes, I can speak. I mean as you see, I mean, PV is (technical difficulty) indication is the one that is growing the fastest. And it is driven by earlier treatment, and that's based on the data we have shown that by treating early, you can basically reduce the incidence of thrombosis.
So basically, help patients have a longer thrombosis-free survival. And that was the MAGIC study that we have been sharing with physicians over the past year, and it has been driving this adoption that we are seeing in PV as well as the change in the Medicare co-pay for the Medicare patient, which is also helping in PV.
So we, as we said in the prepared remarks, we think PV will become the largest of the three indications over time, driven by this new patient -- this new earlier patient flow and the duration of treatment we are observing in PV.
Regarding the overall portfolio, obviously, the V617F, mutation is the course of 90% -- 80% to 90% of PV cases in the US. So that will be the key driver of the next generation of products for Incyte.

Operator

Thank you. We reached the end of our question-and-answer session. I'd like to turn the floor back over for any further or closing comments.

Ben Strain

Thank you all for participating in the call today and for your questions, the IR team will be available for the rest of the day for any follow-up. Thank you, and goodbye.

Operator

Thank you. That does conclude today's teleconference and webcast. You may disconnect your line at this time, and have a wonderful day. We thank you for your participation today.