BeOne Medicines Ltd.

Good day, everyone. Welcome to B1 Medicine's Q3 2025 earnings call webcast. All lines have been placed on mute to prevent any background noise. After the speaker's remarks, there will be a question and answer session. At this time, I would like to turn the call over to the company.

Hello and welcome. Thanks for joining us today. I'm Dan Maller, head of investor relations at B1 Medicines. Before we begin, please note that you can find additional materials, including a replay of today's webcast and presentations, on the investor relations section of our website, ir.b1medicines.com. I would like to remind all participants that during this call, we may make forward-looking statements regarding, among other things, the company's future prospects and business strategy. Actual results may differ materially from those indicated in the forward-looking statements as a result of various factors, including those risks discussed in our most recent periodic report filed with the SEC. Please also carefully review the forward-looking statements disclaimer in the slide deck that accompanies this presentation. Reconciliations between GAAP and non-GAAP financial measures discussed on this call are provided in the appendix to our presentation, which is posted to our investor relations website, along with the earnings release. All information in this presentation is as of the date of this presentation, and we undertake no duty to update such information unless required by law. Now turning to today's call as outlined on slide three. John Euler, our co-founder, chairman, and CEO, will provide a business update. Aaron Rosenberg, our CFO, will provide an update on our third quarter financial results and financial guidance. 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 Chalas, 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. Gap 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 Erin will touch on, we strengthened our balance sheet and ended the quarter with over 4 billion in cash. Rukinza has continued its momentum with sustained US leadership, and it's now the number one BTK inhibitor globally. Sonro, our next-generation BCL2 inhibitor, recently received FDA breakthrough designation in relapsed refractory mantle cell lymphoma, and we're really excited about the totality of data emerging from that molecule, some of which we're going to highlight today. Rukinza, 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 ASHE. where we'll present 47 abstracts from across our heme portfolio. The quarter also yielded multiple developments across our growing solid tumor pipeline, including clinical proof of concept for multiple early stage assets, which Lai is going to discuss in more detail later. So let me start with Brukinza, the backbone of our heme franchise. Brukinza 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, Brukenza is now the global value share leader amongst the growing BTK market. This, of course, is a major milestone for Brukenza and for our company. As I discussed in detail on our Q2 earnings call, the commercial success of Brukenza 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 Brukinza is the best BTK inhibitor. At B1, 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 at six years for Brukinza in first line CLL. This is from our phase three Sequoia trial. We believe that these data have set the bar for what monotherapy PTK can and should be, what they should achieve in CLL. With all the caveats of cross trial comparisons, this is double digit better than what has been reported. for other single agent BTKIs at 72 months. Interestingly, this level of sustained PFS at six years is in the same ballpark as other recent data from BTK ven fixed duration regimens at only three years. Long-term follow-up from years three through six when patients are not on active therapy will be critically important to inform the future relevance of these relevant 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 Brukinza data in CLL, the absence of other long-term follow-up data from many other relevant CLL trials, such as Amplify with the last data cut off April 30th, 2024, captivate, and elevate where data hasn't been reported for a couple 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. Brukenza 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 Venn-based options fall far short of that promise. In our view, the current options fail to satisfy the four key criteria that you see on this slide, depth of response, sustained PFS, safety, and convenience. Specifically, we have concerns related to the low MRD negativity rates and sustained PFS for AV combinations. the cardiac safety, uveitis, and general tolerability for IV combinations, the long-term effects on the immune system, and the related additional hospitalizations due to infections of ovenituzumab use, and the overall treatment burden and feasibility of use with all of the Venn-based regimens. Our goal in fixed duration is simple. We aim to develop a more efficacious, time-limited regiment 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 CS 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 one trial. This was presented at our R&D day in June, and we'll provide a further update on these curves at ASH. Of all the data our heme franchise is generating, these might be the most compelling to the KOLs that we meet. So let me explain. First, the combination of ZANU and SONRO can drive very high rates of deep response. Secondly, and perhaps more impressingly, 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. B1 stands out as the only company with fully owned, potentially best-in-class assets across the three foundational MOAs in CLL, Rukinza, Sonro, and our BTK SEDA. All three are anchored in differentiated design hypotheses and bolstered by an ever-growing body of evidence. All three have the potential for the broadest utility in the class. And all three, whether as monotherapy or in combination, represent significant opportunities for patients, physicians, and for our shareholders. Together, Brickenza-Sonroe and our BTK CDAC are driving the future treatment paradigm in the $12 billion and growing global CLL market. Before I close, I'd like to introduce what we're calling our Development Global Superhighway. For those of you that are newer to our story, B1 was built different. Early on, we recognized the vast majority of the time and cost to develop and deliver a medicine was in clinical trials. We felt that such a critical component of the biopharma supply chain should be a core competency rather than something that is outsourced to a CRO. We saw the synergies that were possible by vertically integrating manufacturing with an industry-leading clinical organization. And we know from experience how hard this can be for a small company. 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 superhighway is unique to be one. 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 three trials We anticipate more than 10 proof of concept data readouts and our research organization will advance around 10 new molecular entities into the clinic, three of which will be in heme and not just in CLL, but broadening our portfolio to help patients in other areas. Now I'll pass it over to Aaron to provide the financial update.

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. Rukinza global revenues eclipsed $1 billion for the first time in a quarter, growing 51% driven by strong performance across all geographies. As John mentioned, Rukinza is now the leading BTK globally. In the U.S., we grew bookings of 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-license products also showed continued strength, growing 17% year-over-year, driven by growth of 31% from the Amgen in-license 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 Brukinza's market leadership and growth from our in-license assets. Europe contributed $167 million with 71% year-over-growth. as we continue our launch trajectory at Brukinza with increased share across all major markets. And rest of world markets grew 133%, driven by market expansions and new launches. Now turning to the other components of our GAAP P&L. Gross margin improved to 86% from approximately 83% in the prior year. This improvement reflects the benefit from favorable product mix, price and product cost efficiencies, offset by period costs related to repositioning of our manufacturing capacity. Operating expenses grew by 11%, totaling 1.1 billion as we are investing with discipline to support our commercial growth and rapidly advance our innovative pipeline. I thought it worth noting that the Q3 2024 base for R&D has higher expenses for both business development milestones, plus approximately 25 million in accelerated depreciation charges. Together, this has the effect of depressing the year-over-year growth rates in our Q3 2025 R&D expense, which you can observe to a degree on the non-GAAP P&L slide, which excludes depreciation. We continue to invest assertively to advance our most promising development candidates. Income tax expense totaled $22 million for the quarter, and altogether, net income reached $125 million, representing diluted earnings per ADS of $1.09. Our non-GAAP P&L includes adjustments for typical items with a full reconciliation provided in the appendix. Non-GAAP net income reached $304 million, reflecting an increase of $252 million compared to the previous year. This performance translates to diluted non-GAAP earnings per ADS of $2.65 for the third quarter. The third quarter saw notable progress in our priority of balance sheet strength as a competitive advantage. In August, we entered into a transaction to monetize our global Indelta 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 Indelta royalty in other revenue as it is earned, while simultaneously amortizing the financing liability and interest expense. Please see our 10Q 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 three quarters of 2025, and we remain focused on full-year delivery across all financial performance measures. Now, while early and staying away from providing detailed guidance, I'd like to provide some perspectives on 2026. As you consider your models for the fourth quarter of 2025 and into the first quarter of 2026, I thought it would be useful to remind you of the seasonality patterns in the U.S. of the BTK class. This includes factors such as typical inventory increases at the end of the year, followed by normal drawdowns in January. Also, just like this year, Q1 2026 will have fewer shipment days versus a typical 13-week quarter. This is simply the nature of the calendar. but it is something that should be considered in quarterly phasing. 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. Nearly 50 abstracts, including six orals from our hematology portfolio, have been accepted for presentation at ASH this year. This is a tremendous validation of the strengths and the depths of our science. I will highlight some of those key data later in my presentation. Importantly, Solon has now received the FDA Breakthrough CRP designation for mental cell lymphoma. We're actively working on its first filing around the globe. And our BTK degrader program has just started the phase three head-to-head trial versus predabutinib in the last refractory cell patients. A major step toward transforming the space. On the solitum side, our momentum continues to build. We have achieved proof of concept for several innovative programs, including our CDK4 inhibitor, B7H4 ADC, PMD5 inhibitor, and the GPC341BB bicycle space. To be noted, most of these assets have been in the clinic for less than 18 months and some less than one year. This is the level of efficiency and the focus we aim to deliver across the portfolio. For CDK4, We aim to initiate a phase three trial in first line BC in the first half of 2026. On the non-oncologic side, our IROC4 CDAC program achieved over 95% IROC4 protein degradation in healthy volunteer skin tissue, a clear PD approval concept. We have already initiated a phase two 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 molecule entities into the clinic, including 13 from our internal research team. Among them, four molecules have already achieved the clinical proof concept, supporting capital study plan. This does not count our R4 degraded program achieving tissue PD POC. Across the portfolio, Our programs have completed R&D enabling studies in a medium of just 10 months. We are ahead of industry benchmarks. Even more impressively, in 2024 and 2025, we have completed over 170 dose escalation cohorts with a median time of only seven weeks. This level of speed and precision is what defines B1. Our ability to move fast, execute flawlessly, and turn innovation into impact. Moving on to our solid tumor portfolio, an area we're very excited about and where we feel increasingly confident as several programs advance toward the registration. This confidence is built on strong, evolving clinical data. First, our CDK4 encrypted program is moving forward quickly. We plan to initiate a phase three trial in first-line hormone receptor positive breast cancer in the first half of 2026, driven by emerging strong efficacy and the safety data from our expansion cohorts. In addition, we de-prioritized the phase three development in the second line post-CDK46 setting due to the evolving compatible 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 B-SAMH-4 ADC program has completed dose escalation, and we are now conducting dose optimization studies with particularly encouraging responses seen in gynecological and triple negative breast cancers. So, our PNG-5 inhibitor stands out with potentially advancing class features, including potency, selectivity, and most importantly, brain penetration. Based on the emerging phase one data, we're now accelerating this program into frontline lung and the frontline pancreatic cancer. And finally, our GPC341BB bispecific has delivered a pleasant surprise. We're seeing very exciting signals as mono-SAP in its first in-human study in heavily pre-treated 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, MAT-MAT tri-specific, and the FGFR2B ADC programs are all showing encouraging early signals. We're continuing advancing the CDK2 inhibitor EGFR, SEDEC, and the pan-KVS inhibitor programs through phase one of those escalation studies. At the same time, based on the current data and the broader competitive landscape, we have made the strategic decision to realign the B7H3 EDC and the ProR15 programs within the portfolio. This really reflects B1's disciplined development strategy, focusing our resources on programs with clear differentiation, and then advancing them quickly to the most important value inflection point, clinical POC, where we can make database decisions. This is how we continue to build a high-quality, high-velocity portfolio in solid tumors. Moving on to our hematology portfolio, our Solon program is shaping up to be a potential best-in-class PCL2 inhibitor, offering great efficacy improved safety, and better convenience compared with the first-generation agents, and that's correct. We're now in the process of filing for approval in RAS, Reflection Mentors, and Informa globally. And then we look forward to sharing good news very soon in this space. The most critical indication for Solon is CLL. We have completed enrollment in our phase three 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 CES versus AV, aiming to establish CES 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 class multiple myeloma, exploring soron-based triplet combination. Next, a quick update. on the S-personation for SOMO. What you see on this slide are two selected abstracts published earlier this week on SOMO monotherapy, starting with mental cell lymphoma in 103 relaxed refractory patients who had a PAL-BTK inhibitor and anti-CD20 therapy. SOMO 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 Venn's historical data in a similar population, even when Venn was used as three times of its clinical proven dose. On the CLR side, the table on the right shows the data from a single-arm study of 100 patients who were post-BTK inhibitor and post-chemoimmunotherapy. Here, SORN achieved a 76% over-response rate with 19% compute responses. Both the efficacy and the safety profile look quite favorable relative to Ben's previous published data in a similar population. Altogether, this results reinforce SORN's strong potential to be the best-in-class Bcl-2 inhibitor in hematological malignancies. In addition to the SORN monocyte B update, We're also presenting new data on the sonal combinations with ZANU and O with obinutuzumab in CLL at this year's ASH. For the ZS combination, we have more mature data as additional patients have gone through treatment. The 12-month UMRD rate has reached 92%, 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 amounts 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 ZANU leading. This is a meaningful improvement for both patients and the physicians. What's most exciting about this combination is the kinetics of the UMRD achievements, which John showed you earlier. As shown on the left, the median time to UMRD with the ZS combination was only around four months after starting the combo. And importantly, this is independent of IgHV mutation status. By about one year of combination therapy, that's the dashed line on the graph, the vast majority of patients achieved UMRD. In contrast, with the IV combination on the right, the medium time to UMRD is 16 months for IgHV mutated and 10 months for unmutated patients. And at the one year mark of combo treatment, many still remain MRD positive. So overall, we believe that combining two potentially best-in-class agents, ZANU and SORO, may provide the only two fixation options that delivers optimal efficacy, safety, and convenience for patients with CLL in a reasonable timeframe. Now, the updates on our BTK-CDAC, BGB16673. 16673 is the most advanced program of its kind in the clinic with clear best-in-class potential. We have initiated the head-to-head phase 3 trial against the predobutinin. The potentially pivotal phase 2 study in relapsed refractory CLL is expected to have a data readout in the first half of 2026. We're also planning a fixation combination phase 3 study with SONO in relapsed refractory cell, and potentially pivotal two in water-strewn macroglobulinemia has been initiated. We will also share new BDK-C-DAC data at this year's ASHME. The table on the left shows the cell results published in the abstract. 16673 demonstrated an over-response rate of 86.4% with medium 18-month follow-up. the 12-month progression-free survival is now mature at a 79%, a very favorable profile compared with perturbutin in the similar patient population. We also reported new data in rictor transformation on the water storm microglobulinemia. In rictors, the OR was 52%, with nearly 10% complete responses. In water storms, we saw 82% OR, with a 26% VGPR rate. Altogether, this data further strengthens CDAX position as a potentially best-in-class BTK-degrader across multiple B-cell microorganisms. The robust clinical activity we observed is consistent with the per-clinical data package with regard to the potency as shown on the left. We observed similar DC50 and DC90 values for 1673 and the Nurex molecule in head-to-head BTK-degraded assays in both human whole blood cells and the B cells. And then we believe 1673 holds the clear mechanism advantage in terms of BTK mutation coverage, as shown on the right. Except for the A42AD mutation, 1673 can cover all other BTK mutants, whereas we observed the new risk molecule showed two resistant hotspot, etamycin 477 and glycine 480 residues. The broad mutation coverage of 1673 further reinforces its passing cost potential and its ability to deliver potentially more durable responses for patients. Together, Sonro and the 1673 highlighted the depth, quality, and the momentum of our hematology portfolio, advancing rapidly toward multiple late-stage milestones and the transformation opportunities in the years ahead. Finally, I'd like to share a few key milestones we're tracking for the remainder of this year and into 2026, focusing on the ones I have not mentioned earlier. First, for Purpinza. The phase three in-term analysis readout for the mangrove study in tumor-naive mental cell lymphoma has been delayed from the second half of this year to the first half of next year due to the slower than anticipated event rate. In addition, we're anticipating accelerated approval for sorentoclax in respiratory mental cell lymphoma and the CLL in China early next year. Important milestones as we continue to broaden access for patients globally. Turning to our early stage pipeline, we're anticipating POCs for CEADC before the year ends and the 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. Please limit the number of questions to ensure we have time to hear from as many attendees as possible. Operator, please go ahead.

If you would like to ask a question, please use the raise hand icon, which can be found at the bottom of the webinar application. When you are called on, please unmute your line and ask your question. We will now take a minute for the cue to assemble. Our first question will come from your own Werber with Cohen and Company. You may now unmute your audio and ask your question.

All right. Well, terrific. Hopefully you can hear me. Yes. Excellent. Congrats. A really nice quarter. I'm going to violate the rule right away. Just two quick questions. Number one, Brookings is the global leader. You're obviously a little bit behind in Europe in terms of when you launched AnySense and when new territories are coming in to accelerate that. And then secondly, live for the CDEC data in the first half next year in CLL for the potential support accelerated approval. Can you give us a sense what to expect there and sort of how mature is the PFS going to be? Thank you.

Right, so Xiaobeng, do you want to start?

Yeah. In Europe, we grow for Brookings have tremendous, so close to 70%. And we notified in Europe, in some country like Germany, Austria, Amplify launched. And we don't see much excitement among the HCPs. The company may actively switch the mono-ACALA to Amplify, but so far we have not seen. We see some prescription, but not extremely a lot of prescription. Therefore, the total ACALA in Europe, if you see the number, is flattening.

So regarding to the CEDAX, data. And this is a single arm study. So likely to be based on the OR as well as the DOR. So depending on the further discussion with the agency, as usually, it will be probably about 12 months after the last patient.

Great. Next question.

Our next question comes from Wendy Benjamin with Citizens Bank. You may now unmute and ask your question.

Hey, good morning, guys. Thanks for taking the questions and congratulations on another amazing quarter. Would love to just focus on the earlier stage pipeline a little bit. You had mentioned proof of concept data. Can you maybe provide a little bit more color as to you know, what you're seeing with some of these other assets? And should we be thinking that all these would likely progress to phase three 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? Thanks.

God, we wish that science worked in a way where everything worked, but I'd love to answer that question.

I'll probably refer to Mark because he's in the front line for this data. Mark?

Thank you, Lai. Thank you, Renny. What I would say is that for all of our early programs, we established very clear criteria of what success looks like based upon the preclinical data. What are we looking for in terms of PK, PD, safety, and ultimately efficacy? If you think back to the slide that Lai showed where he talked about where the different programs stand, I think you could think about that as Some of those programs are meeting all of those criteria, the four of CDK4, PRMT5, B7H4, GPC3, and therefore we're actively planning acceleration to phase three studies and program growth. Others, we continue to wait for data, and we believe that we'll have the data to make the final determination for most of the programs in the first half of 26th.

Yeah, then in terms of the numeric entities we're going to bring to the clinic next year, I'm going to use the GPC-3 form BB as an example. To be honest, among the programs we took into clinic last year, this certainly was not the most exciting one for us based on the clinical data, but it's 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 bring more. Just want to emphasize one more thing. What you have seen from B1 is really just the beginning, what you can see from our really prolific discovery engine.

All right. Next question, please.

Next question comes from Andrew Behrens with Lorinc Partners. Please unmute your line and ask your question.

Hi, thanks, and let me give my congratulations on the progress and execution for the quarter. I think with Jeroen's question, you answered one of the ones I had, because Astra and their earnings release today did highlight the fixed-duration Amplify regiment 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 had said. And then a question on the PRMT-5 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. Thanks.

Yeah, I confirm. So Akala, market share, and also the Revenue in the last three months are pretty stable in Germany and not increasing. Of course, with Amplify approval and a fixed duration of Amplify will be added to the respective guideline. This may give some plus for Acala, but overall in Europe and also in Germany, the Acala total data flattened.

Mark, do you want to take the second part?

So we, as you heard, are very excited about our PRMT5 molecule. That's only been in the clinic since January of this year, but given its high potency and 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 and non-small cell lung cancer and standard of care chemotherapy and frontline pancreatic cancer. It will look for similar development opportunities in early lines of other tumor types with frequent MTAP deletion.

Okay, thanks. Any belief that maybe combining with some of the selective agents might work in certain mutations like RAS mutations? Yes.

So we are very interested in RAS biology. Our PADK RAS molecule is advancing through phase one. We discussed at R&D Day a commitment to bring multiple additional RAS-targeting molecules into the clinic. So certainly in pancreatic cancer, for example, we will ultimately look to combine PRNT5 with KRAS. So, again, the aspiration, given potency and selectivity, is that we should be able to combine with whatever is the appropriate additional therapies for that patient, given the disease state and any other concurrent mutations.

Okay. Thank you. Congrats again.

Our next question comes from Jaigo Nochomevitz with Citigroup. Please go ahead with your question.

Hi. Can you hear me? Yes. Okay, great. This one is for Lai or Mark, maybe. Could you give a little more detail on the design of the CDK4 phase three 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.

Yeah, thank you, Yigal. So at R&D Day, we talked about the three dose levels that are being explored in our expansion phase, 240, 400, and 600. We've completed enrollment of our 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 well justifies initiation of a phase three study. The core hypothesis with the molecule is that having a more selective CDK4 inhibitor will be superior to currently available CDK4-6 inhibitors. Therefore, we're intending a head-to-head study. We're still waiting for data to make final decisions around study size and powering, but we certainly should be able to share those details in the near future as we move towards a phase three study start by the end of the first half of next year.

Okay, thanks. And then I think Lai mentioned the new Phase 3 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, Lai. Yeah, thank you for that. And we agree with your comments, but we felt this is important to establish ZS as really the best oral fixation regimen. So, you know, 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.

Yeah, I think if I just elaborate a little bit on that, you know, 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 Acala versus Xanax. And still people will discount, you know, the body and wealth of information that's there. And I think when you look at the data and you talk to the top K wells, I think at this point with this long-term data, it's very clear, but nonetheless, there's always someone who says there's not direct head to head. And I think this commercially is helpful and it's helpful to, you know, bridge that, you know, information gap, help educate people more quickly. I mean, just, you know, when we're looking at, you know, that space, you know, the long-term data, it's meaningfully different. with all the cross-trial comparison, as we said, it's double digit different. Look at the PFS, look at the OS data. It's impressive, but we still get that comment, you know, in a small portion of the population around the globe. So we just think it's important to do this so we can ensure that everyone is getting the best medicine and the best regimen. So, you know, we're committed to doing it.

Great. Thank you.

Our next question comes from Leonard Timoshev with RBC. Please go ahead with your question.

Hey, guys. Thanks for taking my question. I just want to ask maybe on some of the commercial dynamics you're seeing outside of the early line setting in CLL and maybe more in the relapsed refractory setting. How's Brukinza's share holding up or growing there? And then ultimately, how would you expect the mix of a degrader, Brukinza, and covalent inhibitors to play in the future there? Thanks.

Sure. Matt, please. Sure.

Happy to address that. Yeah, we continue to see strong new patients start share, you know, 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. And as you've heard from John, you know, 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 Sanro. We've spoken before about the requirements for therapy there, and we're confident in a really strong MRD, PFS safety and tolerability profile, but also in the convenience that Sanro can bring to that regimen. So, of course, we see the future opportunity for fixed duration with Xanu plus Sanro, 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 dope. So, we see a strong opportunity across patient types and across lines of therapy and CLL.

Next question, please.

Our next question comes from Sean Lehman with Morgan Stanley. Please go ahead with your question.

Good morning, everyone, and hope you're all well. Just to go back on the CDK4 inhibitor, you know, just to maybe throw some meat on the bones around, you know, the decision not to pursue late lines and to go for first line. And then also just to confirm, you know, are we still going to see some data at San Antonio and what do you hope to present at that forum?

Please go ahead, Mark. Yeah, thank you. Thank you very much, Sean. Yeah, 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. So there are a number of new agents that are leading to both fragmentation of the second line, as well as an increasing bar for success in second line. We always view the second line opportunity as a transitional opportunity for this molecule and the key study as the 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. Concurrently, we then subsequently made the decision that we would not share the second line data at this year's San Antonio. We think those data are relevant to our dose level selection for phase three in frontline. And we therefore will not have data for this molecule at this San Antonio, but look forward to sharing data at a future venue that will, shall we say, substantiate our plans for the phase three study in frontline.

Great, thank you. And one quick follow-up, just on Vizani plus Sonro versus V plus O. So phase threes are recruited earlier this year. What's sort of the signpost pathway or the map going forward in terms of future announcements around that trial?

Lai, do you want to answer that, please? Yes. So to me, in that particular study, it's a PF. as events-driven studies. As you can imagine, with the control arm using the VO, it's really good therapy as well. So it will take a little bit of time to get into the PFS readout. At the same time, we're also monitoring the UMRD rate. This will be something we can probably take an earlier look at.

Wonderful. Thank you.

Our next question comes from Jess Phi with JP Morgan. Please go ahead with your question.

Hey guys, good morning. Thanks for taking my question. I had one on the EGFR targeted assets. I guess what in particular makes you say that the EGFR CMET product goes in the promising bucket, whereas the EGFR CDAC is in the still exploring bucket? Is that based on clinical data or if not, can you just elaborate on kind of how you segmented those? Thank you.

Sure, Mark, please go ahead. Sure. Thank you, Jess. So 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 tri-specific, though it's very early days in dose escalation, is that we are seeing clinically meaningful responses with that agent. With the EGFR degrader, we continue through dose escalation. We've had some tumor regressions. We're happy with the PK and the safety profile. We simply need more data maturity. It's important to highlight that these are two totally different mechanisms of action, and therefore our expectations for what we would expect from each molecule are somewhat different.

Thank you. Our next question comes from Clara Dong with Jefferies. Please go ahead with your question.

Hi, good morning. Can you guys hear me?

Yes.

Yes, we can hear you. Now we can't hear you.

Can you still hear me?

Yes.

Okay, great. Congrats on the quarter and thanks for taking our questions. So you talked about the seasonality for the entire BTKI class. So just wondering how the seasonality dynamics differ across key regions in the US, Europe, and the rest of the world as well. And then just looking at the timeline for Solo and the BTK CDAC entering, the market is expected to file for MCL in the US this year and BTK-CDAC could have a pivotal readout next year in CLL. So is this the right understanding that potentially BTK-C that can 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? Thank you.

So Aaron, go into line. Great. Thanks for the questions, Claire. 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. You know, 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 Brookings 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 Lyle.

Yeah, you're correct. In terms of in the U.S., as far as public use out of it, CDAP is likely to get the CRL approval probably ahead of the SORO. But that's not the case in China. In China, we already filed the SORO for the CRL, which we're also anticipating approval early next year. In terms of sequence of the therapy, you know, we view the CDAP can provide a really broad coverage in terms of patients who had a BDK inhibitor. As she actually involved the slide 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 is positioned very well in the later line therapies after the COVID and BDK inhibitor.

Great. Thank you. Our next question comes from Michael Schmidt with Guggenheim Partners. Please go ahead with your question.

Oh, hey, thanks for taking my question. I just had another bigger picture question around the CLL market. As you noted in the slides, it sounds like the amplifier regimen has modest uptake, but Fixed duration treatment will clearly be part of the CLL treatment landscape longer term, including your own combination. And so 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 and Q growth. And so I was just wondering if there's anything else going on in 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. Six years of follow-up for data matters. These are cancer patients, and you don't want progression. There's no area outside of CLL I've seen where people talk about, let's take regimens. where you give up years of milestone PFS. You just don't see that. Whether it's current VEN-based fixed duration treatments or other BTKs or PERTO, really all options beside chemo, they look pretty decent at two to three years. And this just isn't enough time to understand the durability and the outcome for patients. Brukenza, 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 it at ASH, the more differentiated it looks. The six-year data in CLL in first line and second line and in all high-risk subgroups, the story is the same. The best long-term outcomes for patients. It's six years follow-up. 74% PFS rate for Brickenza in first line CLL. When you COVID adjust this, it's 77. Our OS is 84%, 88% COVID adjusted. In Elevate TN, Acala's 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 Brukenza works very well in high-risk patients. It's just not the case with the other options. And 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. And, you know, with respect to Berto, it's 18 months of follow-up in second-line CLL. It's not even close to being long enough. And as we've mentioned, you know, two to three years, you just can't differentiate yet. And I think 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. And 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. So 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 growing market, whether you look at it from either a BTK space or overall CLL space. To your question on the guidance, we did reinforce the seasonality really to make sure we support dialing in your modeling in that regard, given the history. We feel really confident on our execution over the course of the year. As you referenced, we've taken up the bottom of our range from where we started. We started the year at 4.9 to 5.3, and now we're at 5.1 to 5.3, showing increased confidence and really the great execution from our low-win teams. You know, as you said, if you annualize the current quarter runway and you think about the next quarter, we feel that the range that we provided is certainly within our expectations. You know, the import of the seasonality comment is really specific to the United States, and we want to make sure that that perspective is really important. Thank you.

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

All right, thank you all. I would like to point out that a few weeks ago, V1 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 B1, 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.