BeOne Medicines Ltd. Q3 FY2025 Earnings Call

Good day, everyone. Welcome to BeOne Medicine's Q3 2025 Earnings Call Webcast. After the speakers' remarks, there will be a question-and-answer session. At this time, I would like to turn the call over to the company.

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 3. John Oyler, our Co-Founder, Chairman and CEO, will provide a business update; Aaron Rosenberg, CFO, will provide an update on our third quarter financial results and financial guidance; and Lai Wang, our Global Head of R&D, will discuss our R&D and pipeline progress. We will then open the call to questions. And 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?

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. And 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 #1 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's going to discuss in more detail later. So 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 6 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 BTK inhibitors at 72 months. Interestingly, this level of sustained PFS at 6 years is in the same ballpark as other recent data from BTK van fixturation regimens at only 3 years. Long-term follow-up from years 3 through 6 when patients are not on active therapy will be critically important to inform the future relevance of these regimens within the CLL treatment paradigm. And 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 relevant CLL trials, such as AMPLIFY, with the last data cut off 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 van-based options fall far short of that promise. In our view, the current options fail to satisfy the 4 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 van-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. And 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 key opinion leaders that we meet. So 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 live 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 3 foundational MOAs in CLL: BRUKINSA, sonro, and our BTK CDAC. All 3 are anchored in differentiated design hypotheses and bolstered by an ever-growing body of evidence. All 3 have the potential for the broadest utility in the class. And all 3, whether as monotherapy or in combination, represent significant opportunities for patients, physicians, and for our shareholders. Together, BRUKINSA, sonro, and our BTK CDA are driving the future treatment paradigm and the $12 billion and growing global CLL market. Before I close, I'd like to introduce what we're calling our development global super highway. For those of you that are newer to our story, BeOne was built differently. Early on, we recognized that 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. So 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. And in today's hyper-competitive, costly, and complicated era of drug development we really believe that this global super highway 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 '26 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 III 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, 3 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.

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% versus Q3 2024, driven by the quality and differentiation of our long-term clinical data across all patient types. The pricing dynamics in the United States 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-licensed 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 market leadership and growth from our in-license assets. Europe contributed $167 million, with 71% year-over growth as we continue our launch trajectory of BRUKINSA with increased share across all major markets. Meanwhile, 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% and totaled $1.1 billion as we are investing with discipline to support our commercial growth and rapidly advance our innovative pipeline. I thought it's 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 a notable progress in our priority of balance sheet strength as a competitive advantage. In August, we entered into a transaction to monetize our global IMDELLTRA 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 IMDELLTRA royalty in other revenue as it is earned while simultaneously amortizing the financing liability and interest expense, please see our 10-Q for a full description of the accounting for this transaction. And 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 versus 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. And we are updating our operating expense guidance to be between $4.1 billion to $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 3 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 gains versus a typical 13-week quarter. This is simply the nature of the calendar, but it's something that should be considered in quarterly phasing. And 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. And with that, it seems like an excellent time to pass it over to Lai, who will share more progress about our pipeline.

Thank you, Aaron. Hi, everyone. Thanks for joining us today. Let me start with hematology. We have 50 abstracts, including 6 orals from our hematology portfolio that have been accepted for presentation at ASH this year. This is a tremendous validation of the strength and the depth of our science. I will highlight some of those key data later in my presentation. Importantly, sonro has now received FDA breakthrough therapy designation for mantle cell lymphoma. We're actively working on its first filing around the globe, and our BTK integrated program has just started the Phase III head-to-head trial versus pirtobrutinib in the last refractory cell patients, a major step towards transforming the 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 under GPC3x41BB bispecifics. To be noted, most of these assets have been in the clinic for less than 18 months and some less than 1 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 breast cancer in the first half of 2026. On the non-oncology side, our IRAK4 CDAC program achieved over 95% IRAK4 protein degradation in healthy volunteer 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, all molecules have already achieved clinical proof-of-concept, supporting pivotal study plans. This does not count our 4 degrade program, achieving tissue PD, proof-of-concept. Across the portfolio, our programs have completed R&D-enabling studies in the median of just 10 months, well 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 7 weeks. This level of speed and precision is what defines BeOne. Our ability to move fast, execute flawlessly turns innovation into impact. Moving on to our solid tumor portfolio. An area we are very excited about and where we feel increasingly confident in several programs advance towards 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 III 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 III 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 gynecological and endometrial 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 I data, we are now accelerating this program into frontline lung and frontline pancreatic cancer. And finally, our GPC3 x 4-1BB bispecific has delivered notable spikes, while seeing 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 x MET x MET trispecific, and the FGFR2b ADC programs are all showing encouraging early signals while continuing to advance the CDK2 inhibitor, EGFR CDAC, and the pan-KRAS inhibitor programs through Phase I dose escalation studies. At the same time, based on the current data and the broad competitive landscape, we have made the strategic decision to realign the B7-H3 ADC and Pro-IL15 programs within the portfolio. This really reflects BeOne's disciplined development strategy, focusing our resources on programs with clear differentiation and advancing them quickly to the most important value inflection point clinical proof-of-concept, where we can make data-based 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 greater efficacy, improved safety, and better convenience compared with the first-generation agents venetoclax. We're now in the process of filing for approval in relapsed/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 III trial comparing the ZS fixed duration regimen versus VO earlier this year. In addition, we plan to launch another global Phase III study in the first half of 2026, comparing ZS versus AV and aiming to establish ZS as the best oral fixed duration regimen in treatment-naive CLL. And finally, in 2026, we also plan to initiate a Phase III 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 2 selected abstracts published early this week on sonro monotherapy, starting with mantle cell lymphoma in 103 relapsed/refractory patients who had received prior BTK inhibitors and anti-CD20 therapy, which 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 advanced historical data in a similar population, even when van was used at 3 times its clinically proven dose. On the CRL side, the table on the right shows the data from a single-arm study of 100 patients who were post BTK factor 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 advanced previous published data in a similar population. Altogether, these results reinforce sonro's strong potential to be the best-in-class BCL2 inhibitor in hematological malignancies. In addition to the sonro monotherapy update, we are also presenting new data on the sonro combinations with Zanu and 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 months uMRD rate has reached 92%, and most impressively, with a median follow-up of 27 months to date, no patients have progressed in the 320-milligram 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. And 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 for monitoring. This is a meaningful improvement for both patients and the physicians. What's most exciting about this combination is the kinetics of the uMRD achievements, which John showed you earlier. As shown on the left, the median time to uMRD with the ZS combination was only around 4 months after starting the combo and importantly, this is independent of IGHV mutation status by about 1 year of combination therapy. That's the dashed line on the graph. In contrast, with the IV combination on the right, the median time to uMRD is 16 months for IGHV mutated and 10 months for unmutated patients. And at the 1-year mark of combo treatments, many still remain MRD positive. So overall, we believe that combining two potentially best-in-class agents, zanu and sonro, may provide the only true fixed-duration options that deliver optimal efficacy, safety, and convenience for patients with CLL in a reasonable time frame. Now for 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 a head-to-head Phase III trial against the pirtobrutinib in a potentially pivotal Phase II study. The readout is expected in the first half of 2026. We are also planning a fixed-duration combination Phase III study with sonro in relapsed/refractory CLL and potentially pivotal in Waldenström's Macroglobulinemia has been initiated. We will also show new BTK CDAC data at this year's ASH meeting. The table on that showed the CLL results published in the abstract. 16673 demonstrated an overall response rate of 86.4%, with a median 18 months follow-up, the 12-month progression-free survival is now mature at 79%, a very favorable profile compared with pirtobrutinib in the similar patient population. We also reported new data in Richter's transformation on Waldenström's Macroglobulinemia in Richter's. The OR was 52% with nearly 10% complete responses. In Waldenström's, we saw 83% ORR with a 26% VGPR risk. Altogether, this data further strengthens CDAC's position as a potentially best-in-class BTK degrader across multiple B-cell malignancies. The robust clinical activity we observed is consistent with the preclinical data package with regard to the potency as shown on the left. We observed similar DC50 and DC90 values for 16673 and the Nurex molecule in head-to-head BTK-degrader assays in both human whole blood cells and 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 observe the Nurex molecule to be resistant to 2 hotspot mutations at Methionine 477 and Glycerine 480. The broad mutation coverage of 16673 further reinforces its best-in-class potential and its ability to deliver potentially more durable responses for patients. Together, sonro and 16673 highlight the depths, quality, and momentum of our hematology portfolio advancing rapidly towards multiple late-stage milestones and the transformation opportunities in the years ahead. Finally, I'd like to share a few key milestones we are tracking for the remainder of this year and into 2026, focusing on the ones I have not mentioned earlier. First, for BRUKINSA, the Phase III interim analysis readout for the MAMRO study in treatment-naive mantle 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 are anticipating accelerated approval for sonrotoclax in relapse/refractory mantle cell lymphoma and 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 before the year-end and for other assets in 2026. We look forward to sharing more data in future updates. And with that, I will turn the call back to John.

Thanks, Lai. We'll now open the call to Q&A.

Our first question will come from Yaron Werber with Cowen and Company.

Hopefully, you can hear me.

Yes.

Congrats, really nice quarter. I'm going to violate the rule right away. Just 2 quick questions. Number one, BRUKINSA's the global leader. You're obviously a little bit behind in Europe in terms of when you launched any sense and when new territories are coming in to accelerate that? And then secondly, Life for the CDAC data in the first half next year in CLL for the potentially support accelerated approval, can you give us a sense of what to expect there? And sort of how mature is the PFS is going to be?

Right. So Xiaobin, do you want to start?

Yes. In Europe, we grow for BRUKINSA tremendously, so close to 70%. And we notified in Europe in some countries like Germany and Austria that AMPLIFY launched. We don't see much excitement among the market, and the company may actively switch the mono acala to AMPLIFY. But so far, we have not seen extremely a lot of prescriptions. Therefore, the total acala in Europe, if you see the number, is flattening.

So regarding to the CDAC data, this is a single-arm study, so likely to be based on the ORR as well as the DOL. So depending on the first discussion with the agency, as usually, it will probably be about 12 months after the last patient.

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? And should we be thinking that all these would likely progress to Phase III trials moving forward? And 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?

We wish that science worked in a way where everything worked. But Lai, why don't you answer that question?

I'll probably refer to Mark because he is on the frontline for all this data. Mark?

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 can think about that as some of those programs are meeting all of those criteria, the 4 of CDK4, PRMT5, B7-H4, GPC3, and therefore, we're actively planning acceleration to Phase III 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 both of the programs in the first half of '26.

Yes. Then in terms of the new molecular entities we are going to bring to clinic next year. I'm going to use the GPC3 4-1BB as an example. To be honest, among the program we took into the clinic last year, that 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. So 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. Just want to emphasize one more thing. What you have seen from BeOne is really just the beginning, what you can see from our really prolific discovery engine.

Let me give my congratulations on the progress and execution for the quarter. I think with Aaron's question, you answered one of the ones I had because Astra in their earnings release 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. So I just wanted to confirm that that's what you said. And then a question on the PRMT5 program. It's 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?

Yes, I confirm that the Ocala market share and revenue in the last three months are quite stable in Germany and not experiencing growth. With the approval of AMPLIFY and its fixed duration being incorporated into the respective guidelines, there may be some positive impact for Ocala. However, overall, the total data for Ocala in Europe and Germany is flattening.

Mark, do you want to take the second part?

So we, as you've 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 CNS penetration, we're now seeing objective responses across multiple tumor types, including both lung and pancreatic cancer as well as additional tumor types. And 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 frontline 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 frontline pancreatic cancer, and we'll look for similar development opportunities in early lines of other tumor types with frequent MTAP deletion.

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?

Please go ahead, Mark.

So at R&D Day, we talked about the 3 dose levels that are being explored in our expansion phase: 240, 400, and 600. We've completed enrollment of our frontline cohorts. And we're very excited with the data as they're coming in. We are seeing a high response rate that we think will justify as 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 III study start by the end of the first half of next year.

Okay. And then 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? So I'm just curious as to the rationale for that additional investment to further prove that point.

Please go ahead.

Yes. Thank you for the question, and we agree with your comments. But we felt this is important to establish ZS as really the best oral fixed-duration regimen. So we picked the one which likely will be approved soon by FDA, the AV regimen. We do have a lot of confidence in terms of this particular study.

Yes. 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, but still people will say, well, there's no head-to-head study against Ocala versus another BTK. And 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 key opinion leaders, at this point, with this long-term data, it's very clear. But nonetheless, there's always someone who says there's not a direct head-to-head. We just think it's important to do this so we can ensure that everyone is getting the best medicine and regimen. So we're committed to doing it.

Our next question comes from Leonid Timashev with RBC.

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 is how is BRUKINSA share holding up or growing there? And then ultimately, how do you expect the mix of a degrader, BRUKINSA, and covalent inhibitors to play in the future there?

Sure. Matt, please.

Sure, happy to address that. Yes, we continue to see strong new patient start share across the lines of therapy, including in that relapse setting. And then 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 plus 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. So, of course, we see the future opportunity for fixed duration with zanu plus sonro. But 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, and we have the confidence to do a head-to-head superiority study for the degrader versus pure dose. So we see a strong opportunity across patient types in the cross lines of therapy in CLL.

Our next question comes from Sean Laaman with Morgan Stanley.

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. And then also just to confirm, are we still going to see some data at San Antonio and what do you hope to present at that forum?

Thank you very much, Sean. Yes. So 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 in 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 frontline study. So, given this external dynamic and our strong internal data, we made the decision to deprioritize second-line and to accelerate frontline. Again, we're very much looking forward to that study. Currently, we subsequently made the decision that we would not share the second-line data this year at San Antonio. We think those data are relevant to our dose level selection for Phase III in the frontline and we, therefore, will not have data for this molecule at the San Antonio, but look forward to sharing data at a future venue that will substantiate our plans for the Phase III study in frontline.

Great. And one quick follow-up just on zani plus sonro versus V plus O. The Phase IIIs were recruited earlier this year. What is the pathway or the roadmap for future announcements regarding that trial?

Lai, do you want to answer that, please?

Yes. So to me, in that particular study is a PFS events-driven study, as you can imagine, with the control arm using the vial, it's really good therapy as well. So it would take a little bit of time to get to the PFS readout at the same time, we are also monitoring the uMRD rate; this will be something we can probably take an earlier look at.

Our next question comes from Jessica Fye with JPMorgan.

I have 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 segment those?

Sure, Mark. Please go ahead.

Sure. We have a number of different EGFR-targeted therapies that are moving forward. And 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. So 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 2 totally different mechanisms of action, and therefore, our expectations for what we would expect from each molecule are somewhat different.

Our next question comes from Clara Dong with Jefferies.

Can you hear me?

Yes.

Congrats on the quarter. So you talked about the seasonality for the entire BTKi class. So just wonder how the seasonality dynamics differ across key regions in the U.S., Europe, and the rest of the world as well. And then just looking at the time line for sonro and the BTK CDAC entering the market, sonro expected to file for MCL in the U.S. this year and BTK CDAC could have a pivotal readout next year in CLL. So is this the right understanding that potentially BTK CDAC could be approved first in CLL in the U.S.? And how do you anticipate this influencing physician sequencing strategy across B-cell malignancies, especially in CLL?

So Aaron, going to lock.

Great. Thanks for the questions, Clara. So 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. And then we did reference back to the same calendar issues that we experienced in '25 also in '26. Globally, you see that to a lesser effect in our business in China, Q4 is typically a relatively lighter quarter by comparison. But given the magnitude and import in terms of percentage 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 '25 to '26. So I can hand it over to Lai.

Aaron, you're correct. In terms of the U.S., as well as probably in the rest of the world, CDAC is likely to get the CLL approval probably ahead of sonro. But that's not the case in China. In China, we already filed the application for CLL, which we're also anticipating approval early next year. In terms of sequence of the therapy, we view that CDAC can provide a really broad coverage in terms of patients who had BTK inhibitors. As shown actually in one of the slides in today's presentation, this really covers pretty much everything except maybe one mutation. So we do believe this is probably, at this moment based on the level evidence, positioned very well in the later line therapies after the COVID and BTK inhibitors.

I just had another bigger picture question around the CLL market. As you noted in the slides, it sounds like the AMPLIFY regimen has moderate 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 in 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. So was just wondering if there's anything else going on in the 4Q that we should be aware of?

So maybe I'll start with a quick answer around that. As I laid out earlier in this long-term PFS really matters. You have 6 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 van-based fixturation treatments or other BTKs or pirtobrutinib, really all options beside chemo, they look pretty decent at 2 to 3 years. And there 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 6-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. It's 6 years follow-up, 74% PFS rate for BRUKINSA in first-line CLL. When you COVID-adjust this at 77%, our OS is 84%, 88% COVID-adjusted. In ELEVATE TN, Acalus PFS is 62%, and 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. In respect to pirtobrutinib, it's 18 months of follow-up in second-line CLL; it's not even close to being long enough. As we've mentioned, 2 to 3 years, you just can't differentiate yet. From that perspective, we're extremely confident in both the short-term. And 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, but the early data looks noticeably different than anything we've seen before. We're really, really excited about that. Now maybe I'll jump to Aaron to answer some of the other parts of that question.

Yes, 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 about our execution over the course of the year. As you referenced, we've taken up the bottom of our range from where we started the year at $4.9 billion to $5.3 billion, and now we're at $5.1 billion to $5.3 billion, showing increased confidence in really the great execution from our global 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 United States, and we want to make sure that that perspective is really incorporated. Thank you.

There are no further questions at this time. I will turn the call over to John Oyler for closing remarks.

All right. Thank you all. I would like to point out that a few weeks ago, BeOne 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. And on behalf of everyone here at BeOne, 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. So thank you again for your time today and your thoughtful questions. Have a great day.