BeOne Medicines - Q4 2025

Transcript

Operator (participant)

Good day, everyone. Welcome to BeOne Medicines Q4 and full year 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 (VP 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 on 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 our earnings release. All information in this presentation is as of the date of this presentation. 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, including commentary on our foundational CLL franchise. Aaron Rosenberg, our CFO, will provide an update on our fourth quarter financial results and 2026 financial guidance. Mai Wang, President and 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, General Manager of North America, Mark Lanasa, CMO for Solid Tumors, and Amit Aggarwal, CMO for Hematology. I'll now pass the call over to John. John?

John V. Oyler (Co-Founder, Chairman and CEO)

Thanks, Dan, thank you everyone for joining us today. Q4 marked another solid quarter of execution and a really strong finish to the year. What a year it was! 2025 certainly lived up to its promise as a year of inflection for BeOne. From a financial perspective, we delivered on our commitments, achieving significant product revenue growth, GAAP profitability, and meaningful cash flow generation. In 2025, our foundational BTK inhibitor, BRUKINSA, became number 1, both in the U.S. and globally. As you can see on this slide, the gap between BRUKINSA and the competition is widening. That's not just a commercial achievement, it's a scientific one. BRUKINSA's long-term data have consistently raised the bar in CLL, setting a new standard for efficacy and safety.

These results are reinforced by an expanding body of clinical and real-world evidence, all of which support the program's best-in-class hypothesis. CLL is a $12 billion and growing market due to remarkable therapeutic innovation and improvement in patient outcomes over the past 15 years. It wasn't always that way. As recently as the mid-2000s, patients with CLL received fixed-duration chemo, and outcomes were quite poor. In fact, the median progression-free survival for patients taking chlorambucil was less than 1 year. In 2008, bendamustine was approved and used in combination with rituximab, and the use became widespread, providing substantial benefit over the first chemo-based regimens. 6-year progression-free survival increased to 32%, which was better, but still not great. The FDA approval of ibrutinib in 2016 marked the first chemo-free option and a seminal innovation for patients.

Anchored by data that were superior to chemo, the field switched away from fixed-duration approaches to continuous BTK inhibition. Why? It provided the best long-term outcomes for patients. You can see ibrutinib's 6-year progression-free survival and overall survival of approximately 61% and 77%, respectively. At the same time, the field was developing new fixed-duration treatments that were enabled by the discovery of BCL2 inhibition and the approval of Venetoclax. These Ven-based approaches greatly improved upon historic chemo-based regimens. They began to approach the long-term benefits provided by the two continuous BTKi's, albeit with approximately 10% delta in 6-year progression-free survival. The VI regimen was not approved by the FDA. The addition of obinutuzumab to Ven has significant safety challenges, which I'm going to touch on later. As good as continuous use ibrutinib was, the molecule was not optimized for potency or selectivity.

The second approved BTK inhibitor, acalabrutinib, was designed to be more selective than ibrutinib and to have a very short half-life of roughly 1 hour. In that respect, Acala achieved its goal, demonstrating statistically significant improvement in AFib in the ELEVATE-RR study. However, in that same study, Acala demonstrated non-inferior PFS compared to ibrutinib. As shown on this scatter plot, Acala's 6-year progression-free survival and overall survival of 62% and 76% in treatment-naïve CLL is nearly superimposable on ibrutinib. Innovation never stops. The bar set by the first two continuous treatments would be raised yet again by a differentiated foundational medicine. Enter BRUKINSA. BRUKINSA was designed from inception to be both more potent and more selective than ibrutinib, with complete 24/7 target coverage.

We took that preclinical hypothesis into the clinic, where in head-to-head global Phase III trial, BRUKINSA demonstrated superior efficacy to ibrutinib and a more favorable safety profile. This includes statistically significant improvement in AFib. In ASH 2025, BRUKINSA set a new bar for long-term patient outcomes. Here we can see six-year progression-free survival and overall survival of 74% and 84%. Adjusting these for COVID, those are 77% and 87%, respectively. I really appreciate you bearing with me, as I know I've spent a lot of time on this slide, but the data, as you can see here, is really important. These data clearly establish BRUKINSA as a foundational standard against which all current and all future regimens must be compared, and the long-term outcomes that patients and physicians should expect and demand.

At BeOne, we believe that true innovation comes from improving upon the best. BRUKINSA did just that when it demonstrated superiority in terms of safety and efficacy over ibrutinib. No other BTK inhibitor can make that claim. Here we see the Kaplan-Meier curves from head-to-head trials of BRUKINSA and other BTK inhibitors versus ibrutinib in relapsed refractory BTK, naive CLL patients, and this is as assessed by Independent Review Committee, or IRC. In all of these studies, the IRC-assessed PFS is the predefined key secondary endpoint to demonstrate superiority over ibrutinib. In the ALPINE trial, BRUKINSA showed the greatest early separation from ibrutinib and remains separated with a hazard ratio of 0.69 and a P value of 0.001, demonstrating statistical superiority on PFS. We presented longer-term follow-up data from that study at ASH just a few months ago.

In the ELEVATE-RR study, Acala showed early PFS separation from Ibrutinib, albeit less than BRUKINSA, but that early separation was not sustained. As you can see in the middle chart, Acala crossed over and became numerically worse than Ibrutinib at roughly 33 months. ELEVATE-RR ultimately reported a hazard ratio of one. This brings me to pirtobrutinib, a non-covalent BTK inhibitor, which recently reported data from its head-to-head trial against Ibrutinib in CLL. On the right, we see the curves from relapsed refractory BTKi naive cohort of BRUIN CLL-314, which comprised two-thirds of the enrolled patients in that trial. You can see that Perto, with only 18 months of follow-up, shows the least early separation versus Ibrutinib, with a hazard ratio of 0.845 and a P value of 0.412.

We need to see much longer follow-up from BRUIN CLL-314 based on the minimal early separation in these short-term curves. Perto may face an uphill battle in showing statistical superiority to ibrutinib in PFS. If you've learned anything about BeOne Medicines over our 15 years of existence, it's that we're never satisfied with the status quo. Despite the incredible progress the industry has made, it's hard not to dream about the next chapter of CLL innovation. We think it's time to start talking about a cure. With that, we propose three aspirational goals for the next wave of innovation in CLL. The first one is an obvious one: life expectancy equal to that of the general population, matched for geography and age, for any patient diagnosed with CLL.

Second, for patients who prefer a time-limited therapy, any regimen must deliver long-term outcomes that are at least as good as the best continuous treatment available. Finally, any treatment designed to offer long-term life expectancy must also deliver quality of life, ease of use, and convenience. Applying these aspirations to the scatter plot clearly implies the need for further improvements on what's currently available. We do believe that BeOne is the only company with the foundational assets in our CLL portfolio and pipeline to take us there. The next chapter of CLL innovation is going to come from options that address the unmet needs and deliver the best long-term outcomes for patients. What about fixed duration? There's a clear desire from some patients and physicians for fixed duration options that provide a break from treatment.

For fixed duration to change the treatment paradigm, it must elicit a deep response, demonstrate sustained progression-free survival, be safe with only minimal infection risk over continuous BTKi, and be convenient to administer. We would argue it must be compared to the foundational CLL medicine, BRUKINSA. Naturally, patients want to be off treatment, but just as they want to know what they're gaining, every patient also wants to know what they're giving up. If that's overall survival, it's important that this is considered in the shared decision-making. How do current fixed duration options compare to BRUKINSA? In our opinion, not very well. Existing ven-based BTKi regimens have liabilities that have limited their uptake and approval.

These include underwhelming efficacy, as seen in the AMPLIFY trial, where the AV combination had an inferior depth of response compared to chemo, demonstrating an undetectable MRD of only 34%, despite AMPLIFY enrolling a young, fit, and low-risk frontline population. In fact, AV's PFS at 3 years follow-up was roughly the same as BRUKINSA's at 6 years. It's quite noteworthy that we haven't seen an updated cut from AMPLIFY for nearly 2 years. Similarly, with respect to safety, AV and VI have limitations due to venetoclax, a less potent and less selective first-generation BCL2 inhibitor. In terms of convenience, the low depth of response for AV may result in most patients having to be treated for far longer than 1 year to reach an undetectable MRD.

In addition, Ven requires cumbersome patient monitoring due to its long half-life and TLS risk, which calls into question the convenience benefit of this all-oral regimen. At the highest level, the primary benefit of fixed duration therapy is the treatment-free interval, during which patients are not exposed to the potential side effects of ongoing therapy. In CLL, this means avoiding the agents that suppress rapid B-cell expansion, which allow for immune recovery and a reduced risk of infection. Fixed duration therapies should lower infection risk over time, not raise it. The CLL17 trial studied fixed duration VO and VI versus continuous ibrutinib, and it was presented at ASH a few months ago. The chart on the left shows the CLL17 trial data, which tells a clear and quite concerning story.

First, after one year of VO, severe infections continued to climb for three years while the patient was off treatment, as seen in blue. These infections are serious, often requiring hospitalization and IV antibiotics. Second, even after four years, severe infections were still higher with VO than with continuous ibrutinib, despite the three-year treatment-free period. As a reminder, BRUKINSA demonstrated roughly one-third fewer grade 3, 4 infections versus ibrutinib in the ALPINE study. The VO arm also showed a 67% nominally increased risk of death versus ibrutinib. These findings are quite consistent with data from other recent studies, such as AMPLIFY, where the AVO regimen was not FDA-approved. In fact, the FDA specifically called out the higher death rate due to infections from the AVO arm. In our view, this profile stands in direct opposition to what patients want and deserve from a fixed duration treatment.

If you now look at the table on the right, for the highest-risk patients, roughly half of all CLL patients, VO shows notably lower PFS. This data shows that patients have an approximately 50% higher chance of progressing within 6 years. 50%! Look, there's a narrative that the current fixed duration options are good, and if someone I love was diagnosed with CLL, my first inclination might also be towards fixed duration. If I knew the disease had potentially 50% higher chance of progressing within 6 years, and if I knew that fixed duration wasn't reducing the risk of serious infection over 4 years, just accelerating it into the earlier years, I certainly would encourage them to think twice. The risk-benefit profile of current fixed duration regimens simply does not justify a shift away from established continuous BTKI therapy.

The evidence that existing time-limited therapies may not provide long-term outcomes comparable with BRUKINSA continues to build. Here we can see 3 recently published match-adjusted indirect comparisons of BRUKINSA versus AV, VI, and VO, which reach that conclusion. These reflect the early trends we're seeing in real-world data. Our goal for patients that prefer a fixed-duration treatment option is simple: we aim to develop a more efficacious, time-limited regimen that does not come with caveats or accommodations. We believe ZS is that therapy. The clinical data being generated by combining the best-in-class BTK inhibitor with a potentially best-in-class BCL2 inhibitor just looks different. With all the caveats of cross-trial comparison, ZS has demonstrated the highest undetectable MRD rate, the highest PFS for the respective follow-up when compared to other ven-based fixed-duration therapies. ZS shows a favorable safety profile with fewer high-grade adverse events and no deaths.

In terms of patient convenience, we've not yet observed any clinical or laboratory TLS, and we're very optimistic that for most patients, only one clinic visit during ramp-up will be required after zanu lead-in. Today, the CLL landscape is roughly split evenly into patients who receive continuous BTK inhibitors and those who receive some form of fixed-duration treatment. Currently, BRUKINSA captures approximately half of the continuous BTK segment of the market. ZS will enable BeOne to participate in the other half of the market, where today we have no presence. In summary, BeOne remains the only company with fully owned, potentially best-in-class assets across three foundational MOAs and CLL, BRUKINSA, sonrotoclax, and our BTK CDAC. As I said earlier, we think it is time to start talking about a cure.

All three of these foundational assets, whether as monotherapy or in combination, represent the next chapter in CLL innovation, raising the bar for patients everywhere. I'll pass it over to Aaron to provide the financial update.

Aaron Rosenberg (CFO)

Thanks, John. I'm pleased to share our fourth quarter and full-year results as we delivered against all of the financial commitments that we established in the beginning of 2025. Product revenue reached $1.5 billion in the fourth quarter, representing 32% year-over-year growth. BRUKINSA global revenues totaled $1.1 billion, growing 38% with strong performance across all geographies. For full year 2025, BRUKINSA global revenues were $3.9 billion, representing growth of 49%. As John shared earlier, BRUKINSA has established itself as the leading BTKi globally by an increasing margin as we closed 2025. In the U.S., BRUKINSA fourth quarter sales were $845 million, driven by volume growth of approximately 30% versus Q4 2024.

Our leadership is directly linked to the differentiated breadth, quality, and consistency of BRUKINSA's clinical data, including those shared at ASH 2025. 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. These results include the previously mentioned typical seasonality benefits seen in the fourth quarter of the year for both current year performance and the 2024 baseline. Meanwhile, TEVIMBRA reported an 18% increase, reflecting continued market leadership in China. This growth was supplemented by contributions from launch markets. Our in-licensed products also showed continued strength, growing 9% year-over-year. We continue to observe solid execution across geographies. The U.S. remains our largest market, generating $850 million, with year-over-year growth of 38%.

China revenue totaled $399 million, an 11% increase compared to the fourth quarter of 2024, supported by TEVIMBRA and BRUKINSA's market leadership and growth from our in-licensed assets. Europe contributed $174 million, with 53% year-over-year growth as we continue our launch trajectory with BRUKINSA, with increased share across all major markets. Rest of world markets grew 74%, driven by market expansion and new launches. Now, turning to the other components of our GAAP P&L, and my commentary will be on a full year basis, unless otherwise noted. Gross margin improved to 87% from approximately 84% in the prior year. This year-over-year improvement primarily reflects the benefits from favorable product mix, price, and product cost efficiencies.

Operating expenses grew by 12%, totaling $4.2 billion, as we are investing with discipline to support our commercial growth and rapidly advance our innovative pipeline. Income from operations totaled $447 million, showcasing the inflection in 2025 to a company that is at scale and profitable. Bridging from operating to net income, other income and expense included a non-recurring $40 million equity investment impairment in the fourth quarter. Income tax expense totaled $130 million for 2025, increasing from $112 million in 2024, including $25 million of non-recurring tax expenses and $20 million of timing-related tax expenses in certain geographies.

These effects, in part driven by our valuation allowance status, disproportionately impacted the fourth quarter. Altogether, and including these one-time items, net income reached $287 million in GAAP, with GAAP diluted earnings per ADS of $2.53. Our non-GAAP P&L includes adjustments for typical items with a full reconciliation provided in the appendix. Non-GAAP income from operations totaled $1.1 billion in fiscal 2025, up from $45 million in 2024. Non-GAAP net income came in at $918 million for full year 2025, which translates to diluted non-GAAP earnings per ADS of $8.09. We continued our strong trend of cash flow generation with free cash flow of $380 million in Q4. Full year 2025, free cash flow was over $940 million.

Turning to our 2026 financial guidance. We expect another strong year of revenue growth with continued global leadership for BRUKINSA. We anticipate that the U.S. will continue to see strong demand growth with relatively stable net pricing. Growth is anticipated in all markets and will benefit from continued global expansion in important rest-of-world markets. We anticipate modest initial contributions from our launches of sonrotoclax and zanidatamab as physicians begin to gain experience with these medicines ahead of launches in their respective larger market opportunities. We are pleased that these practice-changing medicines are becoming available to patients as they fulfill important unmet medical needs. In total, we project 2026 revenue to be between $6.2 billion-$6.4 billion.

As you model quarterly phasing for 2026, please recall that we expect similar seasonality and shipping weeks in Q1 2026, as we observed in Q1 2025. Therefore, we believe it is more useful to consider year-over-year growth rates in this upcoming period. Our GAAP gross margin percentage is expected to be in the high 80% range, with continued benefit from mix and a full year of productivity from improvements implemented last year. Operating expenses on a GAAP basis are anticipated to be between $4.7 billion and $4.9 billion. This level of investment ensures we are positioned to capture the full value of our commercial and late-stage pipeline opportunities. GAAP operating income is expected to be between $700 million and $800 million, and non-GAAP operating income is expected to be between $1.4 billion and $1.5 billion.

In terms of other income and expenses, we expect expenses to be between $25 million-$50 million. This includes interest expense associated with the Royalty Pharma arrangement. Turning to income taxes, where we have historically been an evaluation allowance, whereby our accumulated deferred tax assets have a reserve against them. Given our recent history of earnings, we believe that there may be sufficient positive evidence to recognize a portion of these assets in 2026. The exact timing and magnitude are uncertain, but we believe that a potential reversal would result in a material tax benefit to the income tax provision when recognized. When this reversal occurs, we will reflect deferred taxes in our financial statements, and our effective tax rate will become a more meaningful and predictable metric. We will provide additional updates on income taxes throughout the year.

In summary, we are pleased with our performance in 2025 and like our setup for continued growth and financial strengthening as reflected in our 2026 guidance. I would be remiss if I did not take this opportunity to thank our global teams across all parts of BeOne for their incredible dedication to our company's purpose, and the corresponding results that can be seen so clearly in our financial performance. With that, I'd like to pass the call over to Lai.

Lai Wang (President and Global Head of Research & Development)

Thank you, Aaron. Hi, everyone. Thanks for joining us today. 2025 has been a standout year for BeOne R&D. Most notably, it was a breakout year for Sonro. We achieved our first global approvals in China for relapsed refractory MCL and CLL. In addition, regulatory submissions for relapsed refractory MCL are under review in both the U.S. and the E.U., with FDA approval expected in the first half of this year. Our BTK degrader continues to advance steadily towards registration. In 2025, we initiated three Phase III studies, including a head-to-head trial versus CALQUENCE. In solid tumors, we also made strong progress. TEVIMBRA delivered a positive Phase III readout in HER2-positive gastric cancer in combination with zanidatamab and chemotherapy. The next wave of innovation is here.

In 2025 alone, 5 assets achieved the clinical POC, and over the past 2 years, we have advanced 17 new molecule entities into the clinic. BeOne has moved us through 2 defining chapters in our history. In the first 10 years, we built from the ground up. With limited capabilities, we delivered the 2 breakthrough medicines, BRUKINSA and TEVIMBRA, and a proof that BeOne could innovate at the highest level. The second chapter, over the past 5 years, was about scale and readiness. We invested heavily to build a powerful discovery engine and a truly differentiated global clinical development superhighway, transforming BeOne from a company with isolated wins into one capable of repeatable success. Today, we're positioned better than ever to deliver a continuous stream of innovation. 2026 marks the beginning of a new era for BeOne. Over the next 3 years, we are focused on 4 priorities....

First, we'll deepen our leadership in CLL, building on our three foundational medicines. Second, we'll expand across hematological malignancies, including indolent and aggressive lymphomas, as well as AML. Third, we'll establish BeOne as an oncology powerhouse in solid tumors, with leadership in three strategically chosen subtypes, driven by both internal innovation and external partnerships. Finally, we plan to advance one to two potential cornerstone immunology assets towards registration. It took us 15 years to build our foundational CLL franchise. We believe we can move faster and do even better across other diseases. With greater scale and a sense of urgency, we can reach far more patients than ever before. In CLL, today, BRUKINSA is approved for both treatment-naive and relapsed/refractory patients, giving us a strong foundation.

Looking ahead, in the frontline setting, BRUKINSA will serve as the foundational therapy, either as continued use for patients who prefer finer therapy as a potentially best-in-class fixed-duration regimen in combination with solo. In the relapsed/refractory setting, BeOne will offer BTK CDAC and other therapies. We see a potential accelerated approval opportunity for our BTK CDAC as a continuing use monotherapy as early as next year. There are three Phase III studies ongoing to establish strong evidence versus current standard cares. Beyond that, we believe the BTK CDAC and the solo combination has the potential to deliver best-in-class fixed-duration therapy for relapsed/refractory patients with strong efficacy, safety, and convenience. A Phase III study is being planned. We're also developing an alternative fixed-duration option, combining solo with anti-CD20 therapies, currently being tested head-to-head against venetoclax in a Phase III study.

We're also advancing our three foundational hematology assets across non-CLL indications. These molecules have demonstrated strong activity across multiple B-cell malignancies, including mantle cell lymphoma, Waldenström macroglobulinemia, follicular lymphoma, and marginal zone lymphoma. We're particularly excited about the Phase III interim analysis for zanu in combination with rituximab in treatment-naive mantle cell lymphoma, expected in the first half of this year. If successful, this would represent the first chemotherapy-free regimen in this setting. We're expanding Solo into multiple myeloma, with plans to initiate a pivotal Phase III study in combination with CD38 antibody and dexamethasone by the end of this year. 2026 will also be the year we expand beyond BTK and the BCL2 MOAs in the hematology oncology. A new wave of assets is entering the clinic, led by our proprietary off-the-shelf iPSC-derived gamma delta T-cell therapy, with 12 genetic engineering modifications.

This program is highly differentiated and designed to overcome many of the limitations of the existing off-the-shelf cell therapies. I'm very excited about its potential in the clinic. In parallel, we're advancing T-cell engagers and T-cell boosters for B-cell malignancies, particularly for aggressive lymphomas, to address challenges such as kill managing loss and inadequate or unsustained T-cell activation. For AML and MDS, we're building a focused portfolio to address the significant unmet medical needs. Beyond the SOLO, this includes a first-in-indication caspase inhibitor, supported by strong translational data, and a next-generation menin inhibitor designed to overcome all known resistance mutations. We also have additional undisclosed preclinical programs on the way that will continue to fuel our future pipeline. In summary, we have built a hematology portfolio defined by durability, differentiation, and depth, positioning BeOne for sustained impact well beyond our current leadership areas.

With that, let me turn to solid tumors. Previously, our solid tumor focus was largely on immuno-oncology. Over the last two years, we have fundamentally reengineered the portfolio, shifting towards critical oncogenical signaling pathways across breast, gynecological, lung, and gastrointestinal cancers, using multiple therapeutic modalities. As you can see on the slide, we now have more than 20 assets across these focus disease areas. Among them, 5 programs have achieved the proof of concept in 2025, and I will walk you through these key assets now. First, based on strong emerging efficacy and the safety data from Phase I expansion cohorts, we plan to initiate a Phase III trial in front-line hormone receptor-positive breast cancer in the first half of 2026. The safety profile suggests potentially best-in-class hematological safety with manageable gastrointestinal toxicity.

The Phase III study will compare BGB-43395 against the physician's choice of CDK4/6 inhibitor in combination with letrozole, with progression-free survival by central radiology review as the primary endpoint. Beyond the CDK4, we have 4 additional solid tumor programs advancing rapidly towards registration, all supported by compelling and evolving clinical data. B7-H4 ADC, encouraging activity in gynecological cancers and the triple-negative breast cancer. A Phase II study is expected to start within 1 year. GPC3x4-1BB bispecific. The strength of the positive data from this program has been a pleasant surprise, showing very exciting monotherapy signals in P1 pre-treated HCC patients in its first in-human study. A pivotal trial will be initiated before year-end. Beyond PI3K inhibitor, this asset stands out with potentially best-in-class potency, selectivity, and brain penetration.

Based on emerging Phase I data, we're accelerating this program into frontline non-small cell lung cancer. CDAC. We're seeing promising monotherapy activity in heavily pre-treated patients and are planning for the pivotal trials. It is important to note that all 4 assets have been in the clinic for less than 2 years, and the 3 for less than 18 months. This is a level of focus, efficiency, and execution we aim to deliver across the portfolio. Together, these 5 POC assets represent a step change in BeOne solid tumor impacts. With multiple modalities, rapid clinical execution, and a clear path to restoration, we're no longer building a pipeline, we're building a solid tumor franchise, and this is only the beginning. To complement our growing portfolio, we have also invested heavily in clinical execution capability.

We now call this our global clinical development superhighway, designed to deliver industry-leading speed, quality, and reliability. Let me give you a few examples. Over the past two years, we have completed around 200 dose escalation cohorts across multiple first in human studies, with a median of just 1.5 months per cohort. The industry norm is roughly three months. In late-stage development, last year, we completed enrollment of a select show PNCL study with around 700 CLL patients across 20 countries and more than 200 sites in just 14 months. As you know, CLL is not an easy indication to enroll. On the regulatory side, our most recent NDA filing, sonrotoclax's initial filing with FDA in mantle cell lymphoma, was completed within one month of top-line data. Industry standard are typically 4-6 months.

Finally, we're equipping the super highways with AI and automation. Today, we can already deliver near real-time data analysis and insights across all early-stage clinical trials. Over the next 2-3 years, we expect AI and automation to unlock even greater gains in speed, quality, and decision-making. This global clinical superhighway is a core competitive advantage for BeOne. We look forward to sharing continued progress in future updates. Very quickly, on 2026 catalysts, I have touched on most of them already, so let me highlight a few key ones I haven't mentioned yet. First, we just initiated a global Phase III study of ZS versus AV in human IVCLL, directly comparing two all-oral fixed duration regimens. Second, in the first half of this year, we expect to file tislelizumab for HER2-positive gastric cancer in combination with standard datmap and the chemo.

Finally, in immunology, we anticipate multiple proof of concept readouts this year, including BTK CDAC in CSU and IRF4 CDAC in OA. I will now turn it back to John.

John V. Oyler (Co-Founder, Chairman and CEO)

Thank you so much, Lai, for the comments. Really appreciate it. I think with that, we're gonna jump to Q&A. Operator, you know, please limit the number of questions to ensure we have time to hear from as many attendees as possible, but please go ahead.

Operator (participant)

Thank you. 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 upon, please unmute your line and ask your question. We will now take a minute for the queue to assemble. Our first question comes from Michael Schmidt at Guggenheim Securities. Please unmute your line and ask your question.

Michael Schmidt (Senior Managing Director and Senior Biotech Analyst)

Hey, guys. Good morning, and thanks for taking our questions. I had a commercial question around the BTK inhibitor market and BRUKINSA. Specifically, could you comment some more on how you think about potential net pricing development in the BTK inhibitor market longer term, especially as we see your competitor products enter the CMS Drug Price Negotiation Program this year and next? Thanks so much.

John V. Oyler (Co-Founder, Chairman and CEO)

Yeah, thank you. Nice to hear from you. I think from the perspective in this space, as we've tried to lay out, this is a very differentiated value proposition with BRUKINSA versus any of the current therapies that are on the market. You know, whether it's safety profile or whether it's just the long-term PFS and overall survival, this is, you know, in our mind, a best-in-class product that has demonstrated the translation of its mechanism of action into real clinical results. I think at this point, you know, certainly there are challenges for those other products, but you know, we're just standing by the value that the products are creating for patients, and it's there. That's why we're showing it to you.

Speaker 18

Can we jump to the next question, please?

Operator (participant)

Yes, of course. Our next question comes from Yaron Werber with TD Cowen. Please unmute your line and ask your question.

Yaron Werber (Managing Director and Senior Biotechnology Analyst)

Great, thanks so much, and congrats on really a lot of progress. I have a question I think a lot of us have been getting. In the guidance, what are you assuming in terms of competition from AV or Jaypirca is probably sort of late in the year. Then maybe secondly, in terms of Sonro for MCL, both in China and in the U.S., can you just help us think through a little bit, you know, kind of what's been the initial opportunity? Thank you.

Speaker 18

Matt, perhaps you can answer that a little bit, and then we can jump to Xiaobin.

Matt Shaulis (General Manager of North America)

Sure, yeah. I can provide some perspective on AMPLIFY and then Jaypirca as well. As you know, AVO was not approved. As we've discussed before, AV, while approved, was studied only in a very young and very fit patient population, which had a median age of around 61. We think those are some natural limitations there. Moreover, I think that we continue to be very confident in the clinical profile of BRUKINSA. You know, we've outlined, as you heard from John, the importance of meeting some criteria for treatment in CLL, deep and durable remissions, PFS, safety, and convenience. We see that AV doesn't live up to that standard. Certainly on MRD and PFS, it's very straightforward with safety and tolerability. I think that situation holds true.

The convenience is still tied to some of the cumbersome nature of vein utilization. Now, as for Jaypirca, we have seen some data back at ASH, and overall, that body of evidence doesn't yield the level of compelling data that we think is gonna really change the treatment paradigm in the earlier lines of therapy. Particularly, we continue to hear from clinicians that evidence does not rise to the level of burning a line of therapy with a continuous BTK, and that they will continue to position Jaypirca after the continuous BTKs. Obviously, in our case, that bodes really well for BRUKINSA.

Xiaobin Wu (President and COO)

China Sonrotoclax approved beginning of this year, 2026, we launched so quickly after that approval. Since launch, this is about six weeks, the reaction in the market has been very positive. We medicated, or doctor prescribed for over 300 patients, the approved indication is relapsed refractory mantle cell lymphoma and CLL. So far, the safety profile has been also very good. No major safety concern observed. There's a very positive experience from all the major China hematology centers. It looks like very positive, and we are aiming definitely to be a market leader for the BCL2 market going forward. There's 2 approved BCL2 in China.

One is, venetoclax, and another one is, China local lisaftoclax. Yeah.

Speaker 18

Thanks so much, Xiaobin. Can we jump to the next question, please?

Operator (participant)

Our next question comes from Zhi Chen with Goldman Sachs. Please unmute your line and ask your question.

Zhihong Chen (Managing Director)

Thank you so much, and congrats on the results. I got one question on the immunology pipeline you mentioned about. I think this is probably the first time during the earnings briefing, you mentioned about immunology is gonna be the next thing, you know, out of the four pillars you are gonna be working on. Lai mentioned about there are gonna be one or two cornerstone therapies that you could potentially pursue and move into pivotal studies for immunology. Could you elaborate a little bit more about what's gonna be the strategy for the immunology beyond hematology and solid tumor, that you are already being very strong at? What's gonna be over the next few years, what's gonna be the path and a journey towards becoming some meaningful player in immunology?

Speaker 18

Great. Please, Lai, thanks for the question.

Lai Wang (President and Global Head of Research & Development)

Yeah. Thanks for the question. In our preclinical pipeline, we have roughly about 20% of our assets are focused on immunology. With knowledge, we're still a young player in the immunology space. For us, we're gonna be optimistic, looking for potential opportunity to be the first in class or best in class. Our goal is, in the next about 2-3 years, to identify 1 or 2 molecules which we feel like can be cornerstone assets for distributor loans. We're looking forward to share with you the updates in the upcoming additional, you know, the earning calls. There are some very exciting molecules we are really developing at this moment. Some of that is already in the clinical stage.

Speaker 18

Thanks so much. Can we have another question, please?

Operator (participant)

Yes. The next question comes from Yigal Nochomovitz from Citi. Please unmute your line and ask your question.

Yigal Nochomovitz (Director and Senior Biotech Analyst)

Hi, great. Can you hear me? I just wanted to. Hi, John. You know, you made some excellent arguments regarding the fixed duration and the inferior options today versus continuous BTK, but I just wonder if you could just clarify, you know, if ZS does become the fixed duration regimen of choice and the standard of care in treatment naive, could you just clarify, you know, how you're not gonna sacrifice the long duration revenues with continuous BRUKINSA? I think that would be helpful to understand it a bit better, please. Thank you.

Aaron Rosenberg (CFO)

Sure. Sure.

Speaker 18

Aaron's gonna-

Aaron Rosenberg (CFO)

Thank you. Thanks for the question, Yigal. You've seen the, you know, different forms of the pie chart that John shared in his slides. You know, in the current dynamics, well, that's a view on the U.S. The dynamics aren't too dissimilar outside the U.S., although fixed-dose treatment for BTK, BCL-2 combinations are a bit more mature in Europe. You know, about half the market is receiving fixed-dose treatment, half's receiving continuous use, and as you saw in that view, you know, we're currently getting about 50% on a new patient basis for BRUKINSA. You know, what we're trying to state really clearly there is the combination of sonrotoclax plus zanubrutinib opens up 50% of the market where we don't play at all today.

From that dimension, and as we continue to mature candidly in our market share within the continuous use class alone with BRUKINSA, we view this as very market expanding.

Yigal Nochomovitz (Director and Senior Biotech Analyst)

Thanks.

Aaron Rosenberg (CFO)

Yeah, I think the promise is there, and we're hopeful that the data translates as positively as we've seen so far. You know, it really, you know, could fulfill the promise and, you know, the story that's being told now about, you know, fixed duration. You know, were that to happen, that would be a really wonderful thing, but it would place us in a truly unique position. I think regardless of that, for this 50% of the population that is already on fixed duration, if we're anywhere near the data we're showing at this moment, it's just on every one of those boxes, you know, checking on what would be required to, you know, be a best-in-class medicine. We're really excited about this opportunity.

We just need to wait a little bit for a little more data to mature from that perspective.

Yigal Nochomovitz (Director and Senior Biotech Analyst)

Thank you.

Operator (participant)

Thank you. Our next question comes from Reni Benjamin at Citizens JMP. Please unmute your line and ask your question.

Reni Benjamin (Managing Director and Senior Equity Research Analyst)

Hey, good morning, guys. Thanks for taking the questions and congratulations on a great year and the guidance that's provided. I guess, my question is regarding the BTK degrader. You had some, you know, pretty encouraging data that was presented at ASH. I thought that there was a potential for an accelerated approval in the first half of this year. I think it's been pushed out to the second half. Can you just kind of confirm that I'm reading that right, and can you provide some color as to what's causing the pushout and how we should be thinking about the first approval? Thank you.

John V. Oyler (Co-Founder, Chairman and CEO)

Great question. Amit, will you please respond?

Amit Aggarwal (Chief Medical Officer of Hematology)

Thank you for the question, Reni. I don't think there's been a change in terms of, you know, the timing and kind of how we're thinking about this. Obviously, this is a single-arm approach, and so in terms of what we're looking at there is based on a single-arm trial, and so we're following that data and look forward to having the interactions with the FDA midyear and file based on our interactions with the FDA. there's really no change in terms of the timing there.

Reni Benjamin (Managing Director and Senior Equity Research Analyst)

Got it. Thank you.

Speaker 18

Next question, please.

Operator (participant)

Our next question comes from Sean Laaman at Morgan Stanley. Please unmute your line and ask your question. Sean? Sean, can you please unmute your line and ask your question?

Sean Laaman (Executive Director)

Good morning, John and team. Sorry about that, thank you for taking my question. Just trying to understand a bit better, you know, the long runway of growth potential for BRUKINSA here. You did $3.9 billion at, I think for the year, at around 40% growth. CALQUENCE did, I think they did double-digit growth at, to get to three and a half billion, and Imbruvica is growing negative mid-teens, but still did $2 billion. That's about, you know, three and a half billion where BRUKINSA is not operating, if you like, and clearly winning the battle against Imbruvica. Given the compelling data that you have to show best-in-class, what's the tipping point or what's the wrestle here to really start eating into that CALQUENCE share?

John V. Oyler (Co-Founder, Chairman and CEO)

Aaron, would you like to answer that?

Aaron Rosenberg (CFO)

Thanks, Sean, and, you know, as we've been talking, you know, we certainly feel very confident in the totality of the evidence for BRUKINSA, and ultimately, the dynamics you're describing in terms of our performance in the marketplace, you know, is the data that's resonating and ultimately translating to the growth that you've described. You know, as you look at the market share slide that we showed in the deck, you know, on a new patient share, we're currently getting about 50% of the continuous use BTK market. We are the global market leader. We're not quite at 50% yet because we continue to mature into that profile.

As you think about the growth for our business, is the continued maturation into our growth profile, and certainly we believe, having the best-in-class medicine in the continuous use BTK space, there's more than ample opportunity to continue to grow share over time.

John V. Oyler (Co-Founder, Chairman and CEO)

I think our challenge is really just get people to look at the data. It speaks for itself. You know, that is a portion of the data that we're sharing on this call. Whether it's the long-term data, whether it's the head-to-head data, whether it's, you know, combination data versus their combination data, you know, every place you look, the story is the same. You know, there's, you know, work being done in real world data from that perspective, too. I just think it's this overwhelming body of evidence. You know, that's the challenge, you know. Of course, you know, we're the only person that wants to share that information.

The rest of the industry, it may not be in their best interest, but it's really, really important that we share it for patients so that they're getting the best medicine.

Sean Laaman (Executive Director)

Thank you.

John V. Oyler (Co-Founder, Chairman and CEO)

Can we jump to a new question?

Operator (participant)

Our next question comes from Chen Chen with UBS. Please unmute your line and ask your question.

Josh Chen (Research Analyst)

Thank you for taking my question. My question is on B7-H4 ADC, and actually, I think this is not in the model or in the valuation right now. I heard that you are going to initiate Phase III, like, within the next 12 months. May I know that in the clinical trial would be initiated in the first half or the second half? It has showed some promising efficacy and safety in gynecology and some breast cancers. May we know, like, in which indication are you going to initiate Phase III trial? I think the B7-H4 ADC is roughly like at least like 12 months, like, later than our, like, tiers B7-H4 ADC. What are the differentiation of this molecule? Thanks.

John V. Oyler (Co-Founder, Chairman and CEO)

Thanks for the question. Mark, could you address that, please?

Mark Lanasa (SVP and Chief Medical Officer)

Thank you very much for the question. We're really pleased with the progress that's been made with our B7-H4-targeting ADC. This has progressed swiftly through Phase I dose escalation, and as you heard from Ly, we are planning to disclose efficacy and safety data for the dose escalation in the 1st half of the year at a major medical congress. We recognize that the competitive landscape, that there are a number of competing molecules, both within B7H4 and more broadly within the Topo-1-conjugated ADC space, particularly in breast and gynecologic malignancies, which is why we're moving with urgency. I think that we will be able to speak in more detail regarding the differentiation of our compound once we disclose the data.

Suffice to say, we're very happy with the emerging efficacy data and think that we also have a nice safety profile with no target-mediated toxicities beyond what one would expect for a Topo-1-conjugated ADC, and a good hematologic safety profile. It's checking all the boxes to be on a path for a Phase III study start as soon as possible. Again, we'll be able to share more details about first indication for Phase III versus subsequent indications for Phase III as we disclose data throughout the year.

John V. Oyler (Co-Founder, Chairman and CEO)

Thanks, Mark. Could we take 2 more questions, please?

Operator (participant)

Yes. Our next question comes from Leonid Timashev with RBC Capital Markets. Please unmute your line and ask your question.

Leonid Timashev (Equity Analyst specializing in biotechnology)

Hi, guys. Thanks for taking my question. I wanted to ask on the BTK degrader development pathway, specifically on the Phase III. I guess, given you're gonna have a potential accelerated approval and you're running three Phase III studies, I guess, what's the incremental value of each of those studies? I guess, do you need ultimately all 3 to fully realize the opportunity? Or do you think you're still gonna have rapid uptake, you know, as the data starts to flow the way and over time? Thanks.

John V. Oyler (Co-Founder, Chairman and CEO)

Thank you. Amit, would you like to answer that question?

Amit Aggarwal (Chief Medical Officer of Hematology)

Yeah, thank you for that question. I think, you know, from a BTK degrader perspective, again, we're very encouraged by the data that we've seen so far. We do think that this is going to really be a foundational treatment as a BTK asset for the future. In terms of the Phase III, I think we're answering important questions with the Phase III studies that we have right now, particularly with the two global Phase III studies. I think, you know, one is in a slightly later line with the investigator's choice as a control arm, and then the other study is really a head-to-head study against bortezomib.

We do see incremental value, especially from that bortezomib study, to be able to show that as far as that population is concerned, the BTK degrader has a really sort of clear role in terms of the monotherapy. Beyond that, we're obviously, as Ly showed, working on a BTK degrader plus sonrotoclax combination as well, and so you'll continue to see us generate more data there.

John V. Oyler (Co-Founder, Chairman and CEO)

Thanks, Amit. Are there any more questions, or should we wrap up now?

Operator (participant)

We have one more question from Rebecca Liang, from Bernstein. Please unmute your line and ask your question.

Rebecca Liang (Senior Analyst)

Congratulations on the great results, thank you for taking my question. You showed a very interesting chart on the patient share between fixed duration and continuous therapies. I'm wondering how you see the future development between BRUKINSA and Sonro after Sonro plus BRUKINSA becomes a viable option. Given that now the fixed duration therapy has halved the patient share, but obviously much lower commercial sales. Venetoclax, for example, only selling around $2 billion-$3 billion versus the whole BTK market at around $10 billion because of the limitation of fixed duration in treatment duration. How do you see the future commercial, the sales split between the two products? Even if there's maybe no immediate guidance for the long-term peak sales, but qualitatively, the split between the two products. Thank you.

John V. Oyler (Co-Founder, Chairman and CEO)

First of all, I would clarify that although, you know, half the patients in CLL, in that pie chart are listed as fixed duration, they're not all getting that. There's all sorts of other things, even chemo, surprisingly, that is still being given to patients. First of all, as we move into that segment of the class, I think Ven has been very limited by its usability, especially in the community setting. I think that having a fixed duration treatment that can replace, you know, I don't know, I'd say some of these less evidence-based fixed duration treatments in that half that are being used broadly in the community center, I think, is a huge value to patients.

you know, we would expect with the quality of the early data from that this really could be a unique product combination within that 50% of the market for sure. To be clear, there's lots of patients that have different prognosis in CLL, and if we jump back to that, you have deletion 17p in unmutated patients. You also have mutated patients. About half of them are high-risk factor patients, and those patients are hard to handle for sure, and they're very hard for the current fixed duration therapies to address. I don't have the slide number. Maybe someone will flash it to me. you know, when you go back to the slide that showed on the left-hand side, the infection rates associated with VO. On the right-hand side, you could look at the numbers there.

When you look at unmutated patients and deletion 17p patients, really, the outcomes are not good at all. That's 'cause this is a harder disease to fight. Our hope is, you know, it would be great if, you know, our SZ doublet, which is all oral and easy to use and seems pretty safe, can treat all patients indefinitely, and that's truly a cure. You know, we don't have long-term follow-up yet on that. I think the early data makes it appear this is gonna be better than any fixed duration, you know, evidence-based therapy that you've seen to date. You know, we need time for that all to mature. Although it could be possible that this therapy, even in the highest-risk patients, is very compelling and can, you know, be as efficacious as continuous use or cannot.

It's a high bar. It's a really high bar. You know, you just go back and look on that scatter plot where VO is on the scatter plot versus, you know, continuous ibrutinib, which is the comparison that's made in CLL17. That's not the relevant comparison. The relevant comparison is continuous BRUKINSA, which of course, has much, you know, better-looking 6-year data, you know, from a patient and physician perspective. You know, we need to see how the thing evolves, but it will take time. It'll take more than 6 years to understand and establish for those high-risk patients, is this really something that's as good as and competitive with, you know, long-term continuous BRUKINSA use? Be great if it is, you know, nobody can be sure of that.

At any rate, thank you so much for the question, I'd like to, you know, thank everybody for, you know, today's discussion. It really marks the close of a strong fourth quarter, and it's a pivotal, you know, full year for BeOne. I think as you just heard, 2025 was defined by really flawless commercial execution and accelerated R&D momentum across our whole business. I do believe that our performance reflects what truly differentiates BeOne as a company. It's our commitment to scientific excellence, our exceptional speed, our relentless focus on developing the best long-term outcomes for all patients.

On behalf of everyone here, I really want to thank the broader oncology community, the patients and families who inspire our work, the clinicians who partner with us every day, and our almost 12,000 employees all around the world who continue to raise the bar. I truly believe that together we're how the world stops cancer. As we enter 2026, we're more confident than ever in the opportunity ahead of us. Thank you again, everyone, for your time today, and have a wonderful weekend.