BeOne Medicines - Earnings Call - Q3 2025
November 6, 2025
Transcript
Operator (participant)
Good day, everyone. Welcome to BeOne Medicines' Q3 2025 earnings call webcast. All lines have been placed on mute to prevent any background noise. After the speaker's remarks, there will be a question-and-answer session. At this time, I would like to turn the call over to the company.
Dan Maller (Head of Investor Relations)
Hello and welcome. Thanks for joining us today. I'm Dan Maller, Head of Investor Relations at BeOne Medicines. Before we begin, please note that you can find additional materials, including a replay of today's webcast and presentation, on the Investor Relations section of our website, ir.beonemedicines.com. I would like to remind all participants that during this call, we may make forward-looking statements regarding, among other things, the company's future prospects and business strategy. Actual results may differ materially from those indicated in the forward-looking statements as a result of various factors, including those risks discussed in our most recent periodic report filed with the SEC. Please also carefully review the forward-looking statements disclaimer in the slide deck that accompanies this presentation.
Reconciliations between GAAP and non-GAAP financial measures discussed on this call are provided in the appendix to our presentation, which is posted to our Investor Relations website along with the earnings release. All information in this presentation is as of the date of this presentation, and we undertake no duty to update such information unless required by law. Now turning to today's call, as outlined on slide three, John Oyler, our Co-founder, Chairman, and CEO, will provide a business update. Aaron Rosenberg, our CFO, will provide an update on our third-quarter financial results and financial guidance. Lai Wang, our Global Head of R&D, will discuss our R&D and pipeline progress. We will then open the call to questions.
Joining the team for the Q&A portion of the call will be Xiaobin Wu, President and Chief Operating Officer, Matt Shaulis, our General Manager of North America, and Mark Lanasa, our Chief Medical Officer for solid tumors. I'll now pass the call over to John. John?
John Oyler (CEO)
Thanks, Dan, and thank you, everyone, for joining us today. The third quarter marked another strong quarter of execution. From a financial perspective, revenue reached $1.4 billion, which represents 41% year-on-year growth. GAAP earnings per ADS were $1.09, which represents growth of more than $2 over Q3 of last year. We generated over $350 million of free cash flow during the quarter. As Aaron will touch on, we strengthened our balance sheet and ended the quarter with over $4 billion in cash. BRUKINSA® has continued its momentum with sustained U.S. leadership, and it's now the number one BTK inhibitor globally. Sonro, our next-generation BCL2 inhibitor, recently received FDA breakthrough designation in relapsed refractory mantle cell lymphoma, and we're really excited about the totality of data emerging from that molecule, some of which we're going to highlight today.
BRUKINSA®, Sonro, and our BTK-CDAC are the core elements of our leadership in B cell malignancies, and they'll be on display next month at ASH, where we'll present 47 abstracts from across our Heme Portfolio. The quarter also yielded multiple developments across our growing Solid Tumor Pipeline, including clinical proof of concept for multiple early-stage assets, which Lai is going to discuss in more detail later. Let me start with BRUKINSA®, the backbone of our Heme franchise. BRUKINSA® continued to perform exceptionally well in the third quarter, growing 51% and exceeding $1 billion in quarterly global revenue for the first time. As a result, and also for the first time, BRUKINSA® is now the global value share leader amongst the growing BTK market. This, of course, is a major milestone for BRUKINSA® and for our company.
As I discussed in detail on our Q2 earnings call, the commercial success of BRUKINSA® is not by chance. It's the direct result of an overwhelming body of evidence that has accumulated over more than a decade. It's evidence that spans preclinical, human pharmacokinetics, head-to-head clinical trials, real-world data sets, and patient-physician preference in the market. The evidence is remarkable for both its strength as well as its consistency, and this evidence continues to build, with each new piece of data both reconfirming and further strengthening our initial therapeutic hypothesis that BRUKINSA® is the best BTK inhibitor. At BeOne, we're relentlessly focused on our goal of discovering and developing innovative medicines that deliver long-term outcomes for patients. At ASH, we're presenting a 74% landmark PFS at six years for BRUKINSA® in first-line CLL. This is from our phase III Sequoia trial.
We believe that these data have set the bar for what monotherapy BTK can and should be, what they should achieve in CLL. With all the caveats of cross-trial comparisons, this is double-digit better than what has been reported for other single-agent BTKIs at 72 months. Interestingly, this level of sustained PFS at six years is in the same ballpark as other recent data from BTK ven fixed-duration regimens at only three years. Long-term follow-up from years three through six, when patients are not on active therapy, will be critically important to inform the future relevance of these regimens within the CLL treatment paradigm. I think along those lines, what's also relevant about this year's ASH is what you're not seeing.
Given what I've just said about the importance of our long-term BRUKINSA® data in CLL, the absence of other long-term follow-up data from many other relevant CLL trials, such as Amplify, with the last data cutoff April 30, 2024. Captivate and Elevate, where data hasn't been reported for a couple of years. Long-term data are the gold standard in CLL for a reason, because CLL is an indolent disease, and it takes time to fully and truly understand how these regimens perform. BRUKINSA® delivers the level of progression-free survival that patients and physicians should expect and should demand. We believe in the promise of fixed duration, but we also feel that the current ven-based options fall far short of that promise. In our view, the current options fail to satisfy the four key criteria that you see on this slide: depth of response, sustained PFS, safety, and convenience.
Specifically, we have concerns related to the low MRD negativity rates and sustained PFS for AV combinations, the cardiac safety, uveitis, and general tolerability for IV combinations. The long-term effects on the immune system and the related additional hospitalizations due to infections of obinutuzumab use, and the overall treatment burden and feasibility of use with all of the ven-based regimens. Our goal in fixed duration is simple. We aim to develop a more efficacious, time-limited regimen that does not come with caveats or accommodations. Based on the data we've generated to date, we believe that the combination of Zanu and Sonro is well on its way to achieving just that. Our confidence in ZS is based on the totality of clinical data to date, but there are a couple of key aspects in the data that we find exceptionally compelling.
Here you can see the UMRD rates and the time-to-blood MRD from our phase I trial. This was presented at our R&D day in June, and we'll provide a further update on these curves at ASH. Of all the data our Heme Franchise is generating, these might be the most compelling to the KOLs that we meet. Let me explain. First, the combination of Zanu and Sonro can drive very high rates of deep response. Secondly, and perhaps more impressively, it does so exceptionally quickly, with kinetics previously unseen in other trials of drugs targeting similar mechanisms. This slide is so important that we're going to show it to you twice today, once now and once in Lai's section.
This is the type of deep response that we're looking for in a fixed-duration regimen to give physicians and patients the confidence to stop therapy and to achieve positive long-term outcomes. BeOne stands out as the only company with fully owned, potentially best-in-class assets across the three foundational MOAs in CLL: BRUKINSA®, Sonro, and our BTK-CDAC. All three are anchored in differentiated design hypotheses and bolstered by an ever-growing body of evidence. All three have the potential for the broadest utility in the class, and all three, whether as monotherapy or in combination, represent significant opportunities for patients, physicians, and for our shareholders. Together, BRUKINSA®, Sonro, and our BTK-CDAC are driving the future treatment paradigm in the $12 billion and growing global CLL market. Before I close, I'd like to introduce what we're calling our development global superhighway.
For those of you that are newer to our story, BeOne was built different. Early on, we recognized the vast majority of the time and cost to develop and deliver a medicine was in clinical trials. We felt that such a critical component of the biopharma supply chain should be a core competency rather than something that is outsourced to a CRO. We saw the synergies that were possible by vertically integrating manufacturing with an industry-leading clinical organization, and we know from experience how hard this can be for a small company. Fast forward 15 years, and we're proud to have built a global organization of nearly 6,000 colleagues across these two areas: clinical development and manufacturing. In today's hyper-competitive, costly, and complicated era of drug development, we really believe that this global superhighway is unique to BeOne, and it's critical to generating superior returns on R&D investment.
To close, we're in the midst of an exciting milestone-rich period for both our heme franchise and our solid tumor pipeline. By the end of 2026, we expect the initial global approval and launch of Sonro and potentially pivotal data for our BTK-CDAC. Our internal clinical team will be running more than 20 phase three trials. We anticipate more than 10 proof of concept data readouts, and our research organization will advance around 10 new molecular entities into the clinic, three of which will be in heme and not just in CLL, but broadening our portfolio to help patients in other areas. Now I'll pass it over to Aaron to provide the financial update.
Aaron Rosenberg (CFO)
Thanks, John. In the third quarter, we sustained business momentum across our product portfolio with another quarter of solid execution by our global commercial teams. Product revenue reached $1.4 billion in the second quarter, representing 40% year-over-year growth. BRUKINSA® global revenues eclipsed $1 billion for the first time in a quarter, growing 51%, driven by strong performance across all geographies. As John mentioned, BRUKINSA® is now the leading BTK globally. In the U.S., we grew BRUKINSA® volume by approximately 40% vs Q3 2024, driven by the quality and differentiation of our long-term clinical data across all patient types. The pricing dynamics in the U.S. were consistent with commentary provided last quarter, with a mid-single-digit pricing benefit on a year-over-year basis. Meanwhile, TEVIMBRA reported a 17% increase, reflecting continued market leadership in China, albeit in an increasingly competitive market environment. This growth was supplemented by early contributions from launch markets.
Our in-license products also showed continued strength, growing 17% year-over-year, driven by growth of 31% from the Amgen In-Licensed Asset Portfolio. We continue to see solid execution as we look at revenue from a geographic dimension. The U.S. remains our largest market, generating $743 million with year-over-year growth of 47%. China revenue totaled $435 million, a 17% increase supported by TEVIMBRA and BRUKINSA®'s market leadership and growth from our in-license assets. Europe contributed $167 million, with 71% year-over-year growth. As we continue our launch trajectory, BRUKINSA® with increased share across all major markets. Rest of world markets grew 133%, driven by market expansions and new launches. Now turning to the other components of our GAAP P&L. Gross margin improved to 86% from approximately 83% in the prior year.
This improvement reflects the benefit from favorable product mix, price, and product cost efficiencies, offset by period costs related to repositioning of our manufacturing capacity. Operating expenses grew by 11%, totaling $1.1 billion, as we are investing with discipline to support our commercial growth and rapidly advance our innovative pipeline. I thought it worth noting that the Q3 2024 base for R&D has higher expenses for both business development milestones, plus approximately $25 million in accelerated depreciation charges. Together, this has the effect of depressing the year-over-year growth rates in our Q3 2025 R&D expense, which you can observe to a degree on the non-GAAP P&L slide, which excludes depreciation. We continue to invest assertively to advance our most promising development candidates. Income tax expense totaled $22 million for the quarter, and altogether, net income reached $125 million, representing diluted earnings per ADS of $1.09.
Our non-GAAP P&L includes adjustments for typical items with a full reconciliation provided in the appendix. Non-GAAP net income reached $304 million, reflecting an increase of $252 million compared to the previous year. This performance translates to diluted non-GAAP earnings per ADS of $2.65 for the third quarter. The third quarter saw notable progress in our priority of balance sheet strength as a competitive advantage. In August, we entered into a transaction to monetize our global indulger royalty rights, generating $885 million in cash in the quarter while allowing us to participate in the potential upside with the asset. The Royalty Pharma agreement is accounted for as a liability, and therefore, we will continue to recognize the full indulger royalty in other revenue as it is earned while simultaneously amortizing the financing liability in interest expense. Please see our 10-Q for a full description of the accounting for this transaction.
With our meaningful top-line growth with margin expansion, we've seen a notable increase in free cash flow generation to $354 million in this quarter. Cash generation is the key metric of business sustainability, and we are very pleased with our progress on this dimension. All in, Q3 ending cash and cash equivalents totaled $4.1 billion, an increase of $1.3 billion vs Q2. Moving to our 2025 financial guidance. Given our continued execution, we are updating our full-year revenue guidance to be between $5.1 billion and $5.3 billion. Our gross margin guidance is unchanged, remaining in the mid to high 80% range. We are updating our operating expense guidance to be between $4.1 billion-$4.3 billion. We remain committed to achieving positive GAAP operating income, and we expect to generate positive free cash flow for the year.
Overall, we are pleased with our execution through the first three quarters of 2025, and we remain focused on full-year delivery across all financial performance measures. Now, while early and staying away from providing detailed guidance, I'd like to provide some perspectives on 2026. As you consider your models for the fourth quarter of 2025 and into the first quarter of 2026, I thought it would be useful to remind you of the seasonality patterns in the U.S. of the BTK class. This includes factors such as typical inventory increases at the end of the year, followed by normal drawdowns in January. Also, just like this year, Q1 2026 will have fewer shipment days versus a typical 13-week quarter. This is simply the nature of the calendar, but it is something that should be considered in quarterly phasing.
While we remain committed to margin expansion across our planning horizon, the pace of improvement will be measured in the near term to ensure we are investing to maximize the value of our late-stage pipeline opportunities. We look forward to providing our detailed 2026 guidance on our Q4 earnings call in February. With that, it seems like an excellent time to pass it over to Lai, who will share more progress about our pipeline.
Lai Wang (Global Head of Research and Development)
Thank you, Aaron. Hi, everyone. Thanks for joining us today. Let me start with Hematology. Nearly 50 abstracts, including six OROs from our Hematology Portfolio, have been accepted for presentation at ASH this year. This is a tremendous validation of the strengths and the depths of our science. I will highlight some of those key data later in my presentation. Importantly, Sonro has now received the FDA breakthrough CRP designation for mantle cell lymphoma. We're actively working on its first filing around the globe, and our BTK degrader program has just started the phase III head-to-head trial vs zanubrutinib in the last refractory CLL patients. A major step toward transforming this space. On the solid tumor side, our momentum continues to build. We have achieved proof of concept for several innovative programs, including our CDK4 inhibitor, B7-H4 ADC, PRMT5 inhibitor, and the GPC3-41BB bispecific.
To be noted, most of these assets have been in the clinic for less than 18 months and some less than one year. This is the level of efficiency and the focus we aim to deliver across the portfolio. For CDK4, we aim to initiate a phase III trial in first-line BC in the first half of 2026. On the non-oncology side, our IRAC4 CDAC program achieved over 95% IRAC4 protein degradation in healthy volunteers' skin tissue, a clear PD proof of concept. We have already initiated a phase II trial in Rheumatoid Arthritis. Over the past few years, especially in the last 24 months, we have dramatically increased our output from the discovery engine. In that time, we have advanced 16 new molecular entities into the clinic, including 13 from our internal research team.
Among them, four molecules have already achieved a clinical proof of concept supporting peptide study plan. This does not count our IRAC4 Degrader Program achieving tissue PD PoC. Across the portfolio, our programs have completed R&D enabling studies in a median of just 10 months. We are ahead of industry benchmarks. Even more impressively, in 2024 and 2025, we have completed over 170 dose escalation cohorts with a median time of only seven weeks. This level of speed and precision is what defines BeOne, our ability to move fast, execute flawlessly, and turn innovation into impact. Moving on to our Solid Tumor Portfolio, an area we're very excited about and where we feel increasingly confident as several programs advance toward registration. This confidence is built on strong, evolving clinical data. First, our CDK4 inhibitor program is moving forward quickly.
We plan to initiate a phase three trial in first-line hormone-receptor-positive breast cancer in the first half of 2026, driven by emerging strong efficacy and the safety data from our expansion cohorts. In addition, we deprioritized the phase three development in the second-line post-CDK4/6 setting due to the evolving competitive landscape. In that context, we decided for competitive reasons to delay the disclosure of our late-line data since it is also relevant to our dose selection in frontline. Second, our B7-H4 ADC program has completed dose escalation, and we are now conducting dose optimization studies with particularly encouraging responses seen in the gynecological and the triple-negative breast cancers. Third, our PRMT5 inhibitor stands out with potentially best-in-class features, including potency, selectivity, and most importantly, brain penetration. Based on the emerging phase one data, we are now accelerating this program into frontline lung and the frontline pancreatic cancer.
Our GPC341BB bispecific has delivered a pleasant surprise. We're seeing very exciting signals as monotherapy in its first in-human study in heavily pretreated HCC tumors. Altogether, this is a portfolio that is maturing quickly and backed by early clinical momentum, and we are incredibly energized by what's ahead. For our other solid tumor assets, we'll continue to execute and prioritize programs with the strongest potential. Our CEA ADC, EGFR MET MET trispecific, and the FGFR2B ADC programs are all showing encouraging early signals. We're continuing advancing the CDK2 inhibitor, EGFR CDAC, and the pancreas inhibitor programs through phase one dose escalation studies. At the same time, based on the current data and the broader competitive landscape, we have made the strategic decision to realign the BCMH3 ADC and the PROR15 programs within the portfolio.
This really reflects BeOne Medicines' disciplined development strategy, focusing our resources on programs with clear differentiation and advancing them quickly to the most important value inflection points, clinical PoC, where we can make database decisions. This is how we continue to build a high-quality, high-velocity portfolio in solid tumors. Moving on to our Hematology Portfolio, our Sonro program is shaping up to be a potential best-in-class BCL2 inhibitor, offering great efficacy, improved safety, and better convenience compared with the first-generation agent and FCLACS. We're now in the process of filing for approval in the last refractory mantle cell lymphoma globally, and then we look forward to sharing good news very soon in this space. The most critical indication for Sonro is CLL. We have completed enrollment in our phase three trial comparing the Zanu fixed duration regimen vs VO earlier this year.
In addition, we plan to launch another global phase three study in the first half of 2026, comparing ZS vs AV, aiming to establish ZS as the best oral fixed duration regimen in treatment line CLL. Finally, in 2026, we also plan to initiate a phase three in second-line plus multiple myeloma, exploring Sonro-based triplet combination. Next, a quick update on the ASH presentation for Sonro. What you see on this slide are two selected abstracts published early this week on Sonro monotherapy, starting with mantle cell lymphoma in 103 relapsed refractory patients who had a PAL BTK inhibitor and anti-CD20 therapy. Sonro achieved an overall response rate of 53%, with a median progression-free survival of 6.5 months and a median duration of response of 15.8 months.
These results look favorable compared to VEN's historical data in a similar population, even when VEN was used at 3x its clinically proven dose. On the CLL side, the table on the right shows the data from a single-arm study of 100 patients who were post-BTK inhibitor and post-chemoimmunotherapy. Here, Sonro achieved a 76% overall response rate with 19% complete responses. Both the efficacy and the safety profile look quite favorable relative to VEN's previously published data in a similar population. Altogether, this result reinforces Sonro's strong potential to be the best-in-class BCL2 inhibitor in hematological malignancies. In addition to the Sonro monotherapy update, we're also presenting new data on the Sonro combinations, with Zanu and the OR with obinutuzumab in CLL at this year's ASH. For the ZS combination, we have more mature data as additional patients have gone through treatment.
The 12-month UMRD rate has reached 92%. Most impressively, with a median follow-up of 27 months to date, no patients have progressed in the 320 mg cohort, which is truly remarkable. For the ASH presentation, we have another data cut with additional months of follow-up showing consistent results. In terms of the safety, the profile continues to show a clear advantage compared to other fixed duration regimens. In terms of convenience, we're very optimistic that for the vast majority of patients, only one clinical visit during the ramp-up will be required after Zanu leading. This is a meaningful improvement for both patients and the physicians. What's most exciting about this combination is the kinetics of the UMRD achievement, which John showed you earlier. As shown on the left, the median time to UMRD with the Zanu combination was only around four months after starting the combo.
Importantly, this is independent of IgHB mutation status. By about one year of combination therapy, that is the dashed line on the graph, the vast majority of patients achieved UMRD. In contrast, with the IV combination on the right, the median time to UMRD is 16 months for IgHB mutated and 10 months for unmutated patients. After the one-year mark of combo treatment, many still remain MRD positive. Overall, we believe that combining two potentially best-in-class agents, Zanu and Sonro, may provide the only two fixed duration options that deliver optimal efficacy, safety, and convenience for patients with CLL in a reasonable timeframe. Now, the update on our BTK CDAC, BGB-16673. 16673 is the most advanced program of its kind in the clinic with clear best-in-class potential.
We have initiated the head-to-head phase three trial against beta-glutinib and the potentially pivotal phase two study in relapsed refractory CLL is expected to have a data readout in the first half of 2026. We're also planning a fixed duration combination phase III study with Sonro in relapsed refractory CLL, and the potentially pivotal two. In Waldenström macroglobulinemia has been initiated. We will also share new BTK CDAC data at this year's ASH meeting. The table on the left shows the CLL results published in the abstract. BGB-16673 demonstrated an overall response rate of 86.4%. With median 18 months follow-up, the 12-month progression-free survival is now mature at 79%, a very favorable profile compared with beta-glutinib in the similar patient population. We also reported new data in Richter transformation and in Waldenström macroglobulinemia. In Richter's, the OR was 52% with nearly 10% complete responses.
In water-strums, we saw an 83% OR with a 26% VGPR rate. Altogether, this data further strengthens CDAC's position as a potentially best-in-class BTK degrader across multiple BCL malignancies. The robust clinical activity we observed is consistent with the pre-clinical data package. With regard to the potency, as shown on the left, we observed similar DC50 and DC90 values for 16673 and the nuvex molecule in head-to-head BTK degrader assays in both human whole blood cells and the B cells. We believe 16673 holds a clear mechanistic advantage in terms of BTK mutation coverage, as shown on the right. Except for the A42AD mutation, 16673 can cover all other BTK mutants. Whereas we observed the nuvex molecule showed two resistant hotspots at methionine 477 and glycine 480 residues.
The broad mutation coverage of 1673 further reinforces its best-in-class potential and its ability to deliver potentially more durable responses for patients. Together, Sonro and the 1673 highlighted the depth, quality, and the momentum of our hematology portfolio, advancing rapidly toward multiple late-stage milestones and the transformational opportunities in the years ahead. Finally, I'd like to share a few key milestones we're tracking for the remainder of this year and into 2026, focusing on the ones I have not mentioned earlier. First, for Bakensa, the phase III interim analysis readout for the Mangrove study in treatment line evidential cell lymphoma has been delayed from the second half of this year to the first half of next year due to the slower-than-anticipated event rate. In addition.
We're anticipating accelerated approval for Xylantho CLACS in relapsed refractory mantle cell lymphoma and the CLL in China early next year, important milestones as we continue to broaden access for patients globally. Turning to our early-stage pipeline, we're anticipating PoCs for CEA ADC before the year end and the other assets in 2026. We look forward to sharing more data in future updates. With that, I will turn the call back to John.
John Oyler (CEO)
Thanks, Lai. We'll now open the call to Q&A. Please limit the number of questions to ensure we have time to hear from as many attendees as possible. Operator, please go ahead.
Operator (participant)
If you would like to ask a question, please use the raise hand icon, which can be found at the bottom of the webinar application. When you are called on, please unmute your line and ask your question. We will now take a minute for the queue to assemble. Our first question will come from Yaron Werber with Cohen and Company. You may now unmute your audio and ask your question.
Yaron Werber (Managing Director and Senior Biotechnology Analyst)
All right. Terrific. Hopefully, you can hear me.
John Oyler (CEO)
Yes.
Yaron Werber (Managing Director and Senior Biotechnology Analyst)
Excellent. Congrats. Really nice quarter. I'm going to violate the rule right away. Just two quick questions. Number one, Bakensa is the global leader. You're obviously a little bit behind in Europe in terms of when you launched NESENSE and when. New territories are coming in to accelerate that. Secondly, Lai, for the CDAC data in the first half next year in CLL for the potential support accelerated approval, can you give us a sense of what to expect there and sort of how mature is the PFS going to be? Thank you.
John Oyler (CEO)
All right. Xiaobin, do you want to start? Yeah.
Xiaobin Wu (President and COO)
In Europe, we grow for Bakensa tremendously, so close to 70%. We notified in Europe, in some countries like Germany, Austria, Amplify launched, and we do not see much excitement among the HCTs. The company may actively switch the mono-ACALA to Amplify, but so far, we have not seen, we see some prescription, but not extremely a large prescription. Therefore, the total ACALA in Europe, if you see the number, is flattening.
Lai Wang (Global Head of Research and Development)
Regarding the CDAC data, this is a single-arm study, so likely to be based on the OR as well as the DOR. Depending on the further discussion with the agency, as usually, it will be probably about 12 months after the last patient year.
John Oyler (CEO)
Great. Next question.
Operator (participant)
Our next question comes from Reni Benjamin with Citizens Bank. You may now unmute and ask your question. Hey, good morning, guys.
Reni Benjamin (Managing Director and Senior Equity Research Analyst)
Thanks for taking the questions, and congratulations on another amazing quarter. Would love to just focus on the earlier stage pipeline a little bit. You had mentioned proof of concept data. Can you maybe provide a little bit more color as to what you're seeing with some of these other assets? Should we be thinking that all these would likely progress to phase three trials moving forward? If I can sneak one in, is there a teaser you could provide regarding the 10 new molecular entities that you're filing next year? Is there a novel target that you're most excited about? Thanks.
John Oyler (CEO)
God, we wish that science worked in a way where everything worked, but Lai, why don't you answer that question?
Lai Wang (Global Head of Research and Development)
I'll probably refer to Mark because he's in the front line for this data, Mark?
Mark Lanasa (Chief Medical Officer of Solid Tumors)
Thank you, Lai. Thank you, Reni. What I would say is that for all of our early programs, we established very clear criteria of what success looks like based upon the preclinical data. What are we looking for in terms of PK, PD, safety, and ultimately efficacy? If you think back to the slide that Lai showed where he talked about where the different programs stand, I think you could think about that as some of those programs are meeting all of those criteria, the four of CDK4, PRMT5, B7-H4, GPC3, and therefore, we're actively planning acceleration to phase three studies and program growth. Others, we continue to wait for data, and we believe that we'll have the data to make the final determination for most of the programs in the first half of 2026.
Lai Wang (Global Head of Research and Development)
Yeah. In terms of the new molecular entities we're going to bring to the clinic next year, I'm going to use the GPC3 for one baby as an example. To be honest, among the programs we took into clinic last year, this certainly was not the most exciting one for us based on the preclinical data, but certainly, we are very pleased with what we have seen in the clinic today. I'm not going to say which one is the most exciting one for us in the next year, but we're certainly looking forward to bringing more. I just want to emphasize one more thing. What you have seen from BeOne Medicines is really just the beginning, what you can see from our really prolific discovery engine.
John Oyler (CEO)
All right. Next question, please.
Operator (participant)
Next question comes from Andrew Berens with Leerink Partners. Please unmute your line and ask your question.
Andrew Berens (Managing Director and Senior Research Analyst)
Hi. Thanks. I want to give my congratulations on the progress and execution for the quarter. I think with Yaron's question, you answered one of the ones I had because Astra and their earnings released today did highlight the fixed duration Amplify regimen getting traction in Europe, but it sounds like you guys have not seen a lot of that yet. I just wanted to confirm that that is what you said. A question on the PRMT5 program. It is still expected by year-end. Just wondering, I know you mentioned the first-line PDAC and non-small cell lung cancer opportunity. Just wondering how you think of combination partners for those settings. Thanks.
Lai Wang (Global Head of Research and Development)
Yeah. I confirm. ACALA market share and also the revenue in the last three months are pretty stable in Germany and not increasing. Of course, with Amplify approval and the fixed duration of Amplify will be added to the respective guideline. This may give some, yeah, some surplus for ACALA, but overall, in Europe and also in Germany, the ACALA total data are flattening.
John Oyler (CEO)
Mark, do you want to take the second question?
Mark Lanasa (Chief Medical Officer of Solid Tumors)
Sure. We, as you heard, are very excited about our PRMT5 molecule. That's only been in the clinic since January of this year, but given its high potency and CLS penetration, we're now seeing objective responses across multiple tumor types, including both lung and pancreatic cancer, as well as additional tumor types. Critically, given its high selectivity, we're also seeing a very favorable safety profile that we think will enable combinations, which will be key to unlocking the potential of this mechanism. Therefore, we're advancing into front line to combine with current standards of care.
We do not yet have the data, but it is our expectation that we'll be able to combine with chemotherapy and PD-1 in non-small cell lung cancer and standard of care chemotherapy in front line pancreatic cancer. It will look for similar development opportunities in early lines of other tumor types with frequent MTAP deletion.
Andrew Berens (Managing Director and Senior Research Analyst)
Okay. Thanks. Any belief that maybe combining with some of the selective agents might work in certain mutations, like the RAS mutations?
Mark Lanasa (Chief Medical Officer of Solid Tumors)
We are very interested in RAS biology. Our PNK RAS molecule is advancing through phase one. We discussed at R&D day a commitment to bring multiple additional RAS-targeting molecules into the clinic. Certainly, in pancreatic cancer, for example, we will ultimately look to combine PRMT5 with KRAS.
Again, the aspiration, given potency and selectivity, is that we should be able to combine with whatever is the appropriate additional therapies for that patient, given the disease state and any other concurrent mutations.
Andrew Berens (Managing Director and Senior Research Analyst)
Okay. Thank you. Congrats again.
John Oyler (CEO)
Thanks.
Operator (participant)
Our next question comes from Yigal Nochomovitz with Citigroup. Please go ahead with your question.
Yigal Nochomovitz (Director of Biotech Equity Research)
Hi. Can you hear me?
John Oyler (CEO)
Yes.
Yigal Nochomovitz (Director of Biotech Equity Research)
Okay. Great. This one is for Lai or Mark, maybe. Could you give a little more detail on the design of the CDK4 phase III in terms of what you can say at this point about the control arm, the size of the study, anything on the powering, and also what are the doses that are the final contenders for that study?
John Oyler (CEO)
Please go ahead, Mark.
Mark Lanasa (Chief Medical Officer of Solid Tumors)
Yeah. Thank you, Yigal. At R&D day, we talked about the three dose levels that are being explored in our expansion phase: 240, 400, and 600. We've completed enrollment of our front line cohorts. We're very excited with the data as they're coming in. We are seeing a high response rate that we think well justifies initiation of a phase III study. The core hypothesis with the molecule is that having a more selective CDK4 inhibitor will be superior to currently available CDK4/6 inhibitors. Therefore, we're intending a head-to-head study. We're still waiting for data to make final decisions around study size and powering, but we certainly should be able to share those details in the near future as we move towards a phase three study start by the end of the first half of next year.
Yigal Nochomovitz (Director of Biotech Equity Research)
Okay. Thanks. I think Lai mentioned the new phase III, ZS versus AV. I was just wondering regarding the rationale around that. I was under the impression you kind of already knew the conclusion there that ZS was better. I'm just curious as to the rationale for that additional investment to further prove that point.
John Oyler (CEO)
Please go ahead, Lai.
Lai Wang (Global Head of Research and Development)
Yeah. Thank you for the question. We agree with your comments. We felt this is important to establish ZS as really the best oral fixed duration regimen. We picked the one which likely will be approved soon by FDA, the AV regimen. We do have a lot of confidence in terms for this particular study.
Mark Lanasa (Chief Medical Officer of Solid Tumors)
Yeah. I think if I just elaborate a little bit on that. We encourage everyone to look frequently at the CLL data, especially the long-term data that we've presented. Still, people will say, "Well, there's no head-to-head study against. ACALA vs Xanet. Still, people will discount the body and wealth of information that's there. I think when you look at the data and you talk to the top KOLs, I think at this point, with this long-term data, it's very clear. Nonetheless, there's always someone who says there's not direct head-to-head. I think this commercially is helpful. It's helpful to bridge that information gap, help educate people more quickly. I mean, just when we're looking at that space, the long-term data, it's meaningfully different with all the cross-trial comparisons. As we said, it's double-digit different. Look at the PFS, look at the OS data. It's impressive. We still get that comment in a small portion of the population around the globe.
We just think it's important to do this so we can ensure that everyone is getting the best medicine and the best regimen. We're committed to doing it.
Yigal Nochomovitz (Director of Biotech Equity Research)
Great. Thank you.
Operator (participant)
Our next question comes from Leonid Timashev with RBC. Please go ahead with your question.
Leonid Timashev (Biotech Analyst)
Hey, guys. Thanks for taking my question. I just want to ask maybe on some of the commercial dynamics you're seeing outside of the early line setting in CLL and maybe more in the relapsed refractory setting. How's BRUKINSA®'s share holding up or growing there? Ultimately, how would you expect the mix of a degrader, BRUKINSA®, and covalent inhibitors to play in the future there? Thanks.
John Oyler (CEO)
Sure. Matt, please.
Matt Shaulis (General Manager of North America)
Sure. Happy to address that. Yeah, we continue to see strong new patient start share across the lines of therapy, including in that relapse setting.
As we've discussed in the past, we're really confident in our overall CLL franchise leadership strategy. You made reference to the multiple mechanisms that are in our portfolio. As you've heard from John, we continue to have confidence in our BTK mono due to our head-to-head superiority with another BTK and our best-in-class profile, including PFS, safety, and tolerability in the long-term setting that John mentioned. We also see an opportunity for therapy that will include Zanu+Sonro. We've spoken before about the requirements for therapy there. We're confident in a really strong MRD, PFS, safety, and tolerability profile, but also in the convenience that Sonro can bring to that regimen. Of course, we see the future opportunity for fixed duration with Zanu+Sonro. Right now, we're confident in monotherapy.
Of course, when it comes to the degrader, we see a clear opportunity there in later lines of therapy. I'm sure you're familiar with resistance mutations that can happen in those earlier lines. We have the confidence to do a head-to-head superiority study for the degrader versus pure dope. We see a strong opportunity across patient types and across lines of therapy in CLL.
John Oyler (CEO)
Next question, please.
Operator (participant)
Our next question comes from Sean Laaman with Morgan Stanley. Please go ahead with your question.
Sean Laaman (Executive Director and Lead US SMID Cap Biotechnology Equity Research)
Good morning, everyone, and hope you're all well. Just to go back on the CDK4 inhibitor, just to maybe throw some meat on the bones around the decision not to pursue later lines and to go for first line. Also, just to confirm, are we still going to see some data at San Antonio? What do you hope to present at that forum? Thank you.
John Oyler (CEO)
Go ahead, Mark.
Mark Lanasa (Chief Medical Officer of Solid Tumors)
Yeah. Thank you. Thank you very much, Sean. Yeah. Again, what we're seeing in our expansion cohorts is a very strong emerging response rate. We are waiting for data maturity. Now, in the context of the strength of that data, and also importantly, the context of emerging data externally. There are a number of new agents that are leading to both fragmentation of the second line as well as an increasing bar for success in second line. We always view the second line opportunity as a transitional opportunity for this molecule and the key study as the front line study. Given this external dynamic and our strong internal data, we made the decision to deprioritize second line and to accelerate front line. Again, we're very much looking forward to that study.
Concurrently, we then subsequently made the decision that we would not share the second line data at this year's San Antonio. We think those data are relevant to our dose level selection for phase three in front line. We, therefore, will not have data for this molecule at this San Antonio, but look forward to sharing data at a future venue that will, shall we say, substantiate our plans for the phase III study in front line.
Sean Laaman (Executive Director and Lead US SMID Cap Biotechnology Equity Research)
Great. Thank you. One quick follow-up just on the Zanu plus Sonro vs V+O. Phase threes are recruited earlier this year. What is sort of the signpost pathway or the map going forward in terms of future announcements around that trial?
John Oyler (CEO)
Lai, do you want to answer that, please?
Lai Wang (Global Head of Research and Development)
Yes. Certainly, in that particular study, it is a PFS, advanced-driven studies. As you can imagine, with the control arm using the VO, it's really good therapy as well. It will take a little bit of time to get into the PFS readout. At the same time, we're also monitoring the UMRD rate. This will be something we can probably take an earlier look at.
Sean Laaman (Executive Director and Lead US SMID Cap Biotechnology Equity Research)
Wonderful. Thank you.
Operator (participant)
Our next question comes from Jess Fye with JP Morgan. Please go ahead with your question.
Jess Fye (Sell-side Equity Research Analyst)
Hey, guys. Good morning. Thanks for taking my question. I had one on the EGFR targeted assets. I guess, what in particular makes you say that the EGFR CMET product goes in the promising bucket, whereas the EGFR CDAC is in the still exploring bucket? Is that based on clinical data? Or if not, can you just elaborate on kind of how you segmented those? Thank you.
John Oyler (CEO)
Sure, Mark. Please go ahead.
Mark Lanasa (Chief Medical Officer of Solid Tumors)
Sure. Thank you, Jess. We have a number of different EGFR targeted therapies that are moving forward. As I mentioned earlier, for each program, based upon the preclinical evidence, we have expectations of what we would like to see for the molecule. Initially in terms of PK and safety, but ultimately in terms of efficacy. What we're seeing from the EGFR MET/MET trispecific, though it's very early days in dose escalation, is that we are seeing clinically meaningful responses with that agent. With the EGFR degrader, we continue through dose escalation. We've had some tumor regressions. We're happy with the PK and the safety profile. We simply need more data maturity. It's important to highlight that these are two totally different mechanisms of action, and therefore our expectations for what we would expect from each molecule are somewhat different.
Jess Fye (Sell-side Equity Research Analyst)
Thank you.
Operator (participant)
Our next question comes from Clara Dong with Jefferies. Please go ahead with your question.
Clara Dong (VP of Biotechnology Equity Research)
Hi. Good morning. Can you guys hear me?
John Oyler (CEO)
Yes. Yes, we can hear you. Now we can't hear you.
Clara Dong (VP of Biotechnology Equity Research)
Can you still hear me?
John Oyler (CEO)
Yes.
Clara Dong (VP of Biotechnology Equity Research)
Okay. Great. Congrats on the quarter, and thanks for taking our questions. You talked about the seasonality for the entire BTKI class. I just wonder how the seasonality dynamics differ across key regions in the U.S., Europe, and the rest of the world as well. Just looking at the timeline for Sonro and the BTK CDAC entering the market, Sonro is expected to file for MCL in the U.S. this year, and BTK CDAC could have a pivotal readout next year in CLL. Is this the right understanding that potentially BTK CDAC can be approved first in CLL in the U.S.? How do you anticipate this influencing physician sequencing strategy. Across B-cell malignancies, especially in CLL? Thank you.
John Oyler (CEO)
Great. So Aaron, go into Lai.
Aaron Rosenberg (CFO)
Great. Thanks for the questions, Clara. As I said in my prepared remarks, I just wanted to reinforce, as you think about your models, the seasonality patterns. This is really a focus in the U.S. where we typically do see inventory builds across the sector in the fourth quarter, and then that unwinds to a degree in the first quarter. We did reference back to the same calendar issues that we experienced in 2025, also in 2026. Globally, you see that to a lesser effect. In our business in China, Q4 is typically a relatively lighter quarter by comparison.
Given the magnitude and import in terms of % of revenue for BRUKINSA® in the U.S., we thought it was really important to highlight as you think about rolling over your models from 2025 to 2026. I can hand it over to Lai.
Lai Wang (Global Head of Research and Development)
Yeah. You're correct. In terms for in the U.S., as far as probably you said, CDAC is likely to get the CLL approval probably ahead of the Sonro. That is not the case in China. In China, we already found the Sonro for the CLL, which we're also anticipating approval early next year. In terms of sequence of the therapy, we view the CDAC can provide a really broad coverage in terms of patients who had a BTK inhibitor. As Shu actually involved the slide in today's presentation, this really covers pretty much everything except maybe one mutation.
We do believe this is probably at this moment, based on the level of evidence, is positioned very well in the later line therapies after the covalent BTK inhibitor.
Clara Dong (VP of Biotechnology Equity Research)
Great. Thank you.
Operator (participant)
Our next question comes from Michael Schmidt with Guggenheim Partners. Please go ahead with your question.
Michael Schmidt (Senior Managing Director and Biotech Analyst)
Oh, hey. Thanks for taking my question. I just had another bigger picture question around the CLL market. As you noted in the slides, I mean, it sounds like the amplifier regimen has modest uptake, but fixed duration treatment will clearly be part of the CLL treatment landscape longer term, including your own combination. I was just wondering how you think about how that might impact the overall size of the CLL market, the BTK inhibitor market. Longer term. And then just a clarification on seasonality.
Aaron, I know you made some comments around inventory and stocking at the end of the year, but then when I look at guidance, it seems like the top line, the higher end, the top end of the range for revenue could be achieved with almost only flat Q on Q growth. I was just wondering if there's anything else going on in 4Q that we should be aware of.
Mark Lanasa (Chief Medical Officer of Solid Tumors)
Maybe I'll start with a quick answer around that. As I laid out earlier in this, long-term PFS really matters. Six years of follow-up for data matters. These are cancer patients, and you don't want progression. There's no area outside of CLL I've seen where people talk about, "Let's take a regimen where you give up years of milestone PFS." You just don't see that.
Whether it's current ven-based fixed duration treatments or other BTKs or PRTO, really all options beside chemo, they look pretty decent at two to three years. This just isn't enough time to understand the durability and the outcome for patients. BRUKINSA® consistently shows best long-term patient outcomes in CLL. It's why it's the standard of care, and it's why it's the global leader. The more follow-up we show as we're doing at ASH, the more differentiated it looks. The six-year data in CLL in first line and second line, and in all high-risk subgroups, the story is the same. The best long-term outcomes for patients. At six years follow-up, 74% PFS rate for BRUKINSA® in first line CLL. When you COVID adjust this, it's 77%. Our OS is 84%. 88% COVID adjusted. In Elevate TN, acalabrutinib PFS is 62%. Their OS is 76%.
At the same time period. In second line and deletion 17P, it's the same story. Unparalleled median PFS from Alpine, and our Sequoia deletion 17P data shows that BRUKINSA® works very well in high-risk patients. It's just not the case with the other options. We're still reporting our follow-up data because it tells the story. Where is the other data? Where is the long-term data from Elevate? Where is it from Captivate? Where is it from Amplify? It's very noticeable it's not being reported. With respect to PRTO, it's 18 months of follow-up in second line CLL. It's not even close to being long enough. As we've mentioned, two to three years, you just can't differentiate yet. I think from that perspective, we're extremely confident in both the short term.
When we talk about long term, the really exciting thing is this desire to have fixed duration treatments. It's a great thing if you can get there. So far, it does look like SC is going to be unlike anything we've seen yet. It's too early to be sure. There's not enough long-term follow-up data for that either. The early data looks noticeably different than anything we've seen before. We're really, really excited about that.
Maybe I'll jump to Aaron to answer some of the other parts of that question.
Aaron Rosenberg (CFO)
Yeah. Thanks. Obviously, there's tremendous opportunity across the franchise as we think about where we're participating today in a $12 billion and growing market, whether you look at it from either a BTK space or an overall CLL space.
To your question on the guidance, we did reinforce the seasonality really to make sure we support dialing in your modeling. In that regard, given the history, we feel really confident on our execution over the course of the year. As you referenced, we've taken up the bottom of our range from where we started. We started the year at $4.9 billion-$5.3 billion, and now we're at $5.1 billion-$5.3 billion, showing increased confidence and really the great execution from our local teams. As you said, if you annualize the current quarter run rate and you think about the next quarter, we feel that the range that we provided is certainly within our expectations. The import of the seasonality comment is really specific to the U.S., and we want to make sure that that perspective is really incorporated. Thank you.
Operator (participant)
There are no further questions at this time. I will turn the call over to John Oyler for closing remarks.
John Oyler (CEO)
All right. Thank you all. I would like to point out that a few weeks ago, BeOne Medicines celebrated our 15th anniversary as a company. It's very hard to believe that in this relatively short period of time, we've been able to become one of the leading oncology companies in the world. I'd really like to think that this is because, as you heard today, we're driven by scientific excellence, exceptional speed, and a relentless drive to provide the best long-term outcomes for patients. On behalf of everyone here at BeOne Medicines, I'd really like to thank the broader oncology community, including the patients, their families, the clinicians, our employees, and all of you who have been with us for the journey. We truly believe that together, we are how the world stops cancer, and we're just getting started.
Thank you again for your time today and your thoughtful questions. Have a great day.