ONC - NASDAQ

Good day, everyone. Welcome to BeiGene's Q4 and Full Year 2024 Earnings Call Webcast. All lines have been placed on mute to prevent any background noise. After the speakers' remarks, there will be a question-and-answer session. At this time, I would like to turn the call over to the company.

Good morning, and welcome. Thanks for joining us today. I'm Dan Maller, Head of Investor Relations at BeiGene. 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.beigene.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 on 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 this presentation, and we undertake no duty to update such information unless required by law. Now turning to today's call as outlined on Slide 3. John Oyler, our Co-Founder, Chairman and CEO, will provide opening remarks and an update on our hematology franchise. Matt Shaulis, our General Manager of North America, who'll provide an update on the U.S. commercial performance of BRUKINSA. Lai Wang, our Global Head of R&D, will discuss our R&D and pipeline progress. And Aaron Rosenberg, our CFO, will review the fourth quarter financial results and our 2025 financial guidance. We will then open the call to questions. I'll now pass the call over to John.

Thank you, Dan, and good morning, everyone. 2024 was a truly remarkable year in which we achieved $3.8 billion in revenue for the full year, $1.1 billion in Q4, positive quarterly cash flow from operations, BTKi leadership in new patient starts across all lines and all indications in the U.S. BRUKINSA U.S. revenue exceeded [indiscernible] for the first time in the fourth quarter. We introduced 13 new molecular entities into the clinic, and we matured as a global company with the completion of our $800 million U.S. flagship manufacturing facility, our ticker change to ONC, O-N-C, and our proposed name change to BeOne and redomiciliation to Switzerland. We believe that we've reached an inflection point, and we're truly excited for the future. Our company was purpose-built to address the long-lived challenges of return on investment in our industry. And as you know, it's not getting any easier to generate ROI on each R&D dollar. Clinical trials represent more than 75% of the total cost to develop and commercialize an oncology medicine, and they're now estimated to be $250,000 to $300,000 per patient still rising. It's increasingly challenging out there, but we built BeiGene from inception for a world that envisioned these challenges. Our truly global CRO-free clinical team of nearly 3,700 allows us to move at a greater speed and a lower cost than our industry peers. Paired with our internal research and internal manufacturing, we've enabled a fast-to-proof-of-concept approach that shaves meaningful time from early stage development. We're innovating with intentionality and we're building best-in-class franchises with better outcomes for patients that will provide superior returns in the increasingly competitive commercial landscape. In CLL, we believe we're in the middle of a once-in-a-lifetime opportunity, which is akin to that of Gilead and HIV and Vertex in cystic fibrosis. Our focus for 2025 is to deliver upon three strategic pillars: first, solidify and deepen our hematology franchise leadership. Second, advance our pipeline of internally developed assets. And third, drive superior financial performance. My section today will focus on our heme franchise. And of course, we can't talk about the franchise and our heme leadership without starting with BRUKINSA. BRUKINSA was designed from inception to provide 24/7 inhibition of BTK in all disease compartments and to address efficacy and tox challenges of ibrutinib. As you can see here, only BRUKINSA maintains serum exposures well above its IC50, whereas ibrutinib and exposures are well below their IC50 for the majority of the period. And you can't fight cancer part time or only in the blood. A recent peer-reviewed publication analyzed the differences in BTK occupancy between the three approved covalent BTK inhibitors. These results indicate to us that with regard to target engagement, only zanub provides complete and sustained inhibition of BTK across all relevant disease compartments. And that zanubis greater than ibrutinib, which is greater than acalab. These data and the clinical results shown here proved our hypothesis was correct. In the ALPINE trial, BRUKINSA demonstrated sustained superior PFS efficacy and lower cardiac tox head-to-head against ibrutinib. On the left, the ALPINE data in the high-risk deletion 17p, P53 subpopulation is shown. At 42 months, milestone PFS was 59% for zanub and only 32% for ibrutinib. On the right is the ELEVATE-RR study, also in the high-risk deletion 17p, P53 patients, which is said to have a hazard ratio of one, but please note the early separation is likely due to lack of tolerance to ibrutinib. But more importantly, that acalab crosses at just over 30 months, and actually becomes 8% worse than ibrutinib at 42 months. And at this time period, the milestone PFS is only 28%. Yes. I said 28%. And this compelling data has led to exponential growth in BRUKINSA global sales. Less than two years from our first approval in CLL and despite being the third to market, BRUKINSA has become the BTKi class leader for new patient starts. Perhaps the combination of the aforementioned data and real-world experience are leading to both patients and clinicians understanding that on efficacy

Thanks, John. Moving to BRUKINSA’s U.S. performance. BRUKINSA's commercial adoption has been remarkable and consistent with what you would expect to see with a clearly differentiated and best-in-class medicine. Within the BTK market, we continue to strengthen BRUKINSA's position as the BTK of choice, as demonstrated by its leadership in both frontline and relapsed/refractory CLL new patient starts. Overall CLL new patient share has grown to over 50%, and our strength and leadership extends beyond CLL. Our new patient share is even higher across our other approved indications. New patient shares leading indicator of value share, and we see the leadership in CLL and our other approved indications playing out on this slide. In Q4, we had $616 million of US sales, representing 97% growth compared to the prior year. This solid performance capped off a strong 2024, where we had $1.95 billion of revenue, representing growth of 106% versus 2023. We surpassed Calquence in US revenue in Q4, and we are close to overtaking IMBRUVICA, remarkably less than two years from BRUKINSA CLL approval. This is a testament to BRUKINSA's differentiated profile and our strong clinical development, medical and commercial execution. The CLL landscape remains competitive, but we are in an excellent position as we enter 2025. The overall global B-cell malignancy market opportunity and our approved indications is large and grown, totaling approximately $21 billion in 2024. The U.S. represents a significant portion of the global market, and CLL is over 50% of the market in the U.S. and similarly growing robustly. In terms of patient volumes, the BTK class represents about 50% of U.S. CLL patients. And as we've mentioned, BRUKINSA is the BTK leader in new patient starts in CLL. Given its differentiated profile, we believe BRUKINSA can further expand its lead in the BTK class. As we think about BRUKINSA as a continuous treatment, it's important to consider the stacking effect of patients that remain on therapy. In 2024, about one-third of BRUKINSA U.S. revenue came from new patients, and two-thirds came from patients that were already on therapy as we started 2024, which means we have several years of revenue growth from our increasing new patient share levels. As you can see on the chart, the remainder of patient volume beyond BTK is split between fixed duration regimens, BCL2 venetoclax, and chemo. Currently approved event-based fixed duration regimens are not for all patients, and over half of newly diagnosed patients have one or more high-risk features were event-based regimen treatment is associated with shorter PFS. AMPLIFY despite enrolling a fit non-representative patient population that excluded patients with these risk factors, nonetheless, confirm these shorter PFS endpoints, demonstrated low MRD rates that do not correlate durable remission and brought along safety challenges. Given the challenges with current fixed duration regimens and BRUKINSA's best-in-class profile, we see additional opportunity for BRUKINSA monotherapy to continue to take share from these treatment options. And beyond expansion of BTK monotherapy, we believe we have the opportunity for a franchise leadership strategy with [indiscernible] and our BTK Degrader that has the potential to far surpass the other existing treatment options and fulfill the needs of all patients with CLL regardless of risk profile. On that note, now over to you, Lai.

Thanks Matt, I would like to take a few minutes to highlight the rest of our portfolio. Back to 2022, BeiGene's growth was primarily driven by zanubrutinib and tislelizumab. Over the past three years, portfolio has ongoing significant transformation. For hematology, we now have three cornerstone assets, each with multibillion-dollar market potential. The solid tumor portfolio has transitioned from a broad immuno-oncology and pan-tumor strategy to a disease-focused approach. The pipeline targets lung, breast, and gastrointestinal cancers, focusing on critical segment pathways and TA-driven therapies supported by various technology platforms. Our R&D productivity has been remarkable and sets us apart from others in the industry. In 2024 alone, we put 13 new entities into the clinic, which is more than any of our peers above even the largest of pharma companies in the industry, and these assets are some of the most exciting ones in all of oncology. In addition to strengthening our drug discovery capability, we have assembled an internal global clinical development team with CIs in 37 countries, optimizing clinical process for superior execution. Our fast POC strategy consistently surpasses industry benchmarks. For instance, our CDK4 inhibitor trials achieved an average of just 6.4 weeks per dose level and they enrolled over 180 patients within 14 months, a remarkable feat mirrored across all early programs. In addition, we're enhancing late-stage trial efficiency as well. Recent today, we completed Phase 3 enrollment of the CELESTIAL-TNCLL study recording nearly 700 patients across 20 countries and 200-plus sites in just 14 months. It is worth noting that over 75% of our patients in these two studies were enrolled from United States, Europe, Latin America, Australia and Japan. Our speed and cost advantage have allowed us to advance one of the most promising pipelines in the industry. This slide highlights some of our scientifically exciting programs, many of which we believe have the best-in-class or first-in-class potential in significant markets. I will take you through each of these assets in a little bit more details in the following slides. Despite the success of CDK4/6 inhibitor, that dose-limiting toxicities highlight unmet macro need, a CDK4 specific inhibitor can border CDK6 related toxicities. BGB-43395 has the potential to be the best-in-class CDK4 inhibitor, due to its superior selectivity and potency compared to [indiscernible]. We are observing lower hematological toxicities aligned with its better selectivity and it might be dose higher to achieve better target inhibition, as shown in the graph, BGB-43395 achieved 80% TK1 inhibition at dose level 8, similar to a tislelizumab at RP2D and at dose level B-433955 further improved the TK1 inhibition to 95%. The proof concept data is expected in the first half of this year. KRAS mutations are funding almost one out of five cancer patients. Unlike pan-RAF inhibitors such as RMC-6236 from Revolution medicine, pan-KRAS inhibitors, spell, H-RAS and RAS possibly offering a better therapeutic window by not inhibiting the RAS pathway in normal tissues. This molecule began clinical trials in November 2024. B7H4 is expressed in several solid tumors, including breast, ovarian and endometrial cancers. Over 70 patients have enrolled across seven dose levels showing responses in various tumor types and at multiple dose levels. We believe we have a first-in-class opportunity here. EGFR CDAC, a first-in-class degraded with broader EGFR mutation coverage and sparing wide-type EGFR showed a strong efficacy in both osimertinib-sensitive and the resistant preclinical models. It entered the PINNACLE trial in December 2024. The demand pathway is quite straightforward, intent as add-on to the third-generation EGFR TKI for frontline adjuvant and locally advanced non-small cell lung cancer. MTAP deletions occurs in one of seven cancer patients, both PRMT5 and the MAT2A inhibitors called cells in MTAP-deleted tumors and show strong synergy in preclinical models. BeiGene is the only company with clinical stage assets for both. Our PRMT5 inhibitors stands out for its potency, selectivity and the brain penetration and our maturing inhibitor also penetrates the brain and demonstrates superior potency in preclinical models. [indiscernible] began the combination study of this two molecule in the second half of 2025. IRAK4 is essential for TLR and the interloping 1 receptor pathway. Sanofi KT-474 should near complete IRAK4 degradation in blood, but only 50% to 70% in skin. We developed BGB-45035 to fully degrade IRAK4 in target tissues and avoid cardiovascular risks and 45035 achieved a complete IRAK4 degradation blood. Phase I starts in late 2025, with tissue degradation data expected this year. And finally, I wanted to highlight a few of our key pipeline value inflection points. Our late-stage hematology assets have several significant milestones in 2025 including Phase 2 trial readouts that may support accelerated approval submissions as well as the initiation of Phase 3 pivotal trials for both zanu and our BTK degrader including the planned head-to-head versus product. Turning to our early stage pipeline. As you have heard, we have a number of proof-of-concept catalysts expected for our early-stage pipeline across multiple modalities and therapeutic areas. We look forward to sharing more data in future updates. With that, I'd like to pass it over to Aaron to review the financials.

Thanks, Lai. 2024 was a pivotal year of growth and an affirmation of our path to sustainability. We generated strong top line revenue growth with total sales of $3.8 billion for the year as compared to $2.5 billion in 2023. As revenue grew by 55% as compared to last year, with product revenues increasing by 73%, growth was seen across all key products and markets, which puts us in a position of strength as we enter 2025. Focusing on our fourth quarter results. Total revenue for the quarter was $1.1 billion with Q4 2021 product revenue growth of 77% compared to Q4 of last year. And consistent with recent trends, we see a broadening of our revenue base. The United States represented 55% of total revenues in the quarter, with Europe contributing another 10%. Sales of BRUKINSA totaled $828 million in Q4, representing 100% growth as compared to Q4 2023. In the United States, BRUKINSA growth was driven by demand given our expanding leadership in new patient shared CLL as well as other approved B-cell malignancies where BRUKINSA continues to have the broadest label in the BTK inhibitor class. Please note that this class does experience seasonality in the U.S. with Q4 and Q2 being quarters of seasonally high sales. In addition, the United States 2024 Q4 sales were also positively impacted by the timing of customer orders of approximately $30 million. In Europe, BRUKINSA continued its growth trajectory in Q4, culminating a full year where the business nearly tripled. We continue to grow share in Europe, where we are earlier in the product launch cycle as compared to the United States. BRUKINSA remains the leading BTKI in China. And as we've highlighted before, we are in the early stages of launch in key rest of world markets with large opportunities such as Brazil and Japan. We look forward to continuing to execute our plans to bring BRUKINSA to patients in these markets. TEVIMBRA revenue of $154 million resulted in 20% growth as compared to Q4 of 2023. We remain the market leader in China with the broadest NRDL label coverage in the class. Commercialization efforts for TEVIMBRA are ongoing in other markets, including the U.S. and Europe following recent regulatory approvals. We are launching in these markets in a targeted fashion and look forward to sharing updates over the course of 2025. Amgen in-license products were also strong key contributors to performance with $101 million of revenue in Q4, representing growth of 98% as compared to Q4 of 2023. Walking through our operating P&L and my comments will be on a GAAP basis. Product gross margin was 85.6% for Q4, an increase of 2.4 percentage points versus last year, largely due to favorable mix and cost of sales productivity for BRUKINSA and TEVIMBRA. Operating expenses totaled $1 billion and included $60 million in research and development expense associated with the in-license of our MAT2A inhibitor announced in December. The growth in OpEx supported capability built to deliver near and long-term revenue growth and to rapidly advance our robust and differentiated innovative pipeline. Our strong revenue growth and value-focused investment philosophy has resulted in significant operating leverage with product revenue growing more than 5x faster than expenses in the fourth quarter. This resulted in meaningful improvement in GAAP and non-GAAP operating results for Q4 2024, compared to Q4 of the prior year, and achievement of full year non-GAAP breakeven. Q4 delivered $79 million in adjusted income from operations, achieving our third consecutive quarter of non-GAAP operating income. And as mentioned, these results included the $60 million expense from the in-license of our MAT2A inhibit. And our focus on operating leverage has translated into a second consecutive quarter of positive operating cash flow generation, resulting in improved cash utilization on a full year basis. These are key metrics for the company as we transition to a self-sustaining enterprise. Now, turning capital allocation, where we follow a disciplined investment philosophy to support our dual mandate of both growth and sustainability. At the center, our conservative financial policies that serve as a balance to the inherent risk taking associated with being a leading high-growth innovative biopharmaceutical company. Having a strong balance sheet in our industry is a competitive advantage, and we are committed to continuing to prioritize its strength. And we are in an excellent position as we close 2024 with $2.6 billion in cash, while advancing towards sustained cash flow generation. We will continue to invest in our differentiated commercial assets and geographies to deliver profitable growth and bring our innovative medicines to more patients. At the same time, we will fuel our innovation engine with its unique and differentiated advantages in both time and cost, particularly through proof of concept. Value-creating business development plays an important role in our strategy by providing access to the best external science, particularly for assets that complement our internal portfolio. And consistent with previous collaborations, we will actively explore partnerships that strengthen our business. Now, turning to our 2025 guidance, which assumes late January exchange rates and no potential new business development activities. We expect another strong year of revenue growth given our leadership for BRUKINSA. We anticipate that the US will continue to gain new patient share and also benefit from year-over-year lapping of 2024 new patient starts. And we assume relatively stable net pricing for BRUKINSA in the US in 2025. This is supported by our specified small manufacturer designation which layers in the increases in manufacturer liabilities for Medicare Part D benefit redesign over a five-year period. Growth is also anticipated from continued global expansion in both Europe and other important rest of world markets. We project revenue to be between $4.9 billion to $5.3 billion. At these levels, foreign exchange represents an approximate 1% headwind for the year. And as you consider quarterly phasing in your models, please note the seasonal patterns and customer order timing that I previously mentioned. Our GAAP gross margin percentage is assumed to be in the mid-80% range, and it is anticipated to continue to benefit from improved mix and production efficiencies as compared to full year 2024. This guidance contemplates the potential impact in our understanding of current form from new U.S. tariffs on imports. Incremental costs from these tariffs are anticipated to be modest for us given our margin structure and the degree of manufacturing for BRUKINSA that is conducted in the United States. This does not contemplate unannounced additional measures, which may change this outlook. Operating expenses on a GAAP basis are forecast to be between $4.1 billion and $4.4 billion. Our investments support key growth in both commercial and research at a pace that continues to deliver meaningful operating leverage. This is demonstrated by significant reductions in expenses as a percentage of sales. Non-GAAP operating expenses are expected to track with our GAAP guidance with reconciling items remaining unchanged from existing practice. And finally, we are affirming our prior commitments to achieve full year GAAP operating breakeven in 2025 and generate positive cash flow from operations for the year. And with that, I will turn the call back to Dan.

Thanks, Aaron. We are now ready for Q&A. I kindly ask participants to limit themselves to one question to ensure we have time to hear from as many attendees as possible. Operator, we are ready for the first question.

[Operator Instructions] Our first question comes from Kelly Shi at Jefferies. Please unmute your line and ask your question.

Congrats on the impressive progress to the BeiGene team and thanks for taking our questions. For 2025, it is guided full year revenue guidance is of $4.9 billion to $5.3 billion. Could you please walk us through the key assumptions for the initial guidance? And what could be the key factors that determine where the final number lands in the range of this guidance? And very quickly, I just want to confirm, now we have B7-H4 ADC and CDK inhibitor moved up to first half of this year for data disclosure, just to confirm on that. Thank you very much.

Thanks Kelly, this is Aaron. I'll answer the first part of your question and then hand it over to Lai. So with respect to our 25% revenue guidance, we expect another strong year of revenue growth given our leadership for BRUKINSA. We're anticipating that in the U.S., we'll continue to gain share. And as I said in my prepared remarks, we also will benefit from the year-over-year lapping of 2024 new patient starts. This growth is against the backdrop, as I said, a fairly stable net pricing environment in the U.S. And we do expect strong growth to continue from our global expansion. I mentioned in Europe in 2024, we nearly tripled. And we have other important rest of world markets where we're really early. We're first launching in Japan in Q1 of this year as an example, and that's a meaningful market for BRUKINSA. We're not providing quarterly guidance, although I did provide some commentary on the seasonality of the BTKi class and with the second quarter and fourth quarter being typically strongest, but overall, we feel really confident about how we're entering the year following a really strong 2024. And with that, maybe I'll hand it over to Lai.

Thanks, Kelly, for the question. We plan to provide the first data disclosure for both the ADC as well as the CDK2 at ASCO. So this is for the first half of this year.

Thank you very much.

Our next question comes from Sean Laaman at Morgan Stanley & Co. Please unmute your line and ask your question.

Good morning everyone. Sorry about that, good afternoon everyone. Thanks for your presentation. I hope everyone is well. My question also relates to guidance. So, you're surpassing Calquence now in terms of share. You're growing a lot faster than them, but they are still going -- still growing. The cadence of their grower seems to be plating a little bit over the last few quarters. Sort of wondering in the context of guidance what the feedback is that you get from clinicians on the viability of that drug longer term? And maybe a bit longer dated, but any thoughts around what impact there might be from potential -- any approval of the doublet we be?

Yes. Sure. Happy to address that question. And yes, we definitely see that when we look at our overall growth, we've been very robust comparing fourth quarter of 2024 -- fourth quarter of 2023. And also, our full year growth is very robust comparing 2024 to 2023. To your question around the Calquence, we see that their growth rates are substantially less strong in that particular timeframe. And John, why don't you go ahead and make an additional comment.

Yes. In terms of the doublet, I think, look, we've shared a lot of data earlier in this call. The things you need for a fixed duration treatment are things that don't look very impressive in that study. And it is a successful study in terms of beating in an ultra-fit population that represents maybe the healthier quarter of patients in the real-world scenario and it's able to beat chemo on PFS at 36 months. That's what that study shows. The MRD negativity is statistically worse, as we showed earlier in the slides and much lower than any present data that's ever existed before despite being in this ultra fit, highly selected population. The safety data is not what you'd hope to see. And then you look at the PFS data straight out, again, it doesn't compare favorably to present data. It doesn't compare favorably to the and it certainly doesn't compare favorably to a continuous BRUKINSA therapy. So, I think from that perspective, look, it's a study which has met a primary endpoint that is not relevant. And I'm sure that they will market as much as they can about it and try to do their best to drive their commercial sales that are very powerful and successful marketing organization. But I think, ultimately, the data speaks for itself very clearly. And when people use that combination, their experience is highly likely to be in line with that data. So, I think this is more of the same as we looked at monotherapy, the story has been great around acala, but as we look at monotherapy and as people actually are using the medicines and as the data matures and they use it more and more, it's very clear to us. On the efficacy story we have a strong belief that we've laid out here,

And John, if I could just add a little bit of the color commentary around what we hear from physicians related to that part of the question. And here, I think, we continue to hear about safety and handling concerns related to venetoclax and the complexity and the burdens of nature of patient management on AV as well as on AVO, if you think about the triplet. And then when you look at the data that added acala to AVO, again, there, the outcomes don't suggest an overall favorable profile when you start to look at safety. So I think one of the things that we'll have to do, and we'll continue to hear from physicians just look at what labeling ends up looking like for that doublet. And that will be in the context of all those other factors.

Great. Thank you. Comprehensive. I will jump back in the queue. Appreciate it.

Our next question comes from Andrew Berens at Leerink Partners. Please unmute your line and ask your question.

Hi. Thanks. Nice job on your first slide earnings release. It's a big readout in gastric cancer for zani and tisle. Just wondering what you're looking for in ARM C [ph], what it could mean to the franchises? And also what's the company's commitment to breast cancer efforts that Jazz has embarked upon? And then based on John's squeeze a comments, I know you're not promoting fixed duration BRUKINSA yet, but are you seeing or expecting to see BRUKINSA or to use off-label and fixed-duration regimens? Is there a chance to get a – can be endorsement ahead of the several data? Thanks.

Thank you so much for the question. I will answer the first part of the question related to zani, and then I'll pass to my colleague, Matt to answer the second part of the question. In terms of zani, this is actually design as you pointed out, the third arm, which you mentioned is the combination of the tisle plus zanib plus the chemo. We believe this will further broaden the label for our tisle in the first-line gastric cancer. Right now, tisle labeled HER2 patient population. And if this trial is successful, will further broaden the label. As you are aware of, this trial now is the readout will be in the second half of 2025. I'd like to point out, this is the events-driven trial. So purely this is based on the event occurrence. With that, you'll have that question related to the breast cancer side of in discussion with our partner around the development of the zanib in breast cancer franchise.

Sure. And then maybe I can talk about spontaneous use on BRUKINSA. And I certainly understand the nature of the question given our best-in-class profile for BTKs. But I think it's also important to remember that we don't currently have a BTK plus been approved in the US. And also, when we look at things like NCCN guidelines and compendia, we don't yet have BRUKINSA listing in that setting. Now on the other hand, we did recently have data from the BOVIN study. And while that was MRD guided rather than purely fixed duration, there's certainly thought about what that could mean in the future.

Thank you.

Our next question comes from Jessica Fye at JPMorgan. Please unmute your lines and ask your question.

Great. Good morning and congrats on the strong guidance. Question about how you're thinking about the upcoming pirto readouts, both in frontline CLL and the data they're generating against IMBRUVICA? What are you going to be watching for there? And what will be the appropriate BRUKINSA cross trial to arise, i.e., should investors line those other ratios up with your trial? Or why or why not? I appreciate you guys are digging your degrader head-to-head against pirto, but thinking about potential near-term competitive dynamics? Thank you.

Yes. Thank you so much for the question. Pirto does have two Phase 3 trials ongoing in the frontline CLL, although the second trial is a mixed population, the first trial, I think that you're referring to is the 313 study, which is pirto being compared to chemoimmunotherapy. I do want to highlight chemoimmunotherapy is no longer really a standard care for the frontline treatment-naive CLL. This study, the readout does not necessarily mean will change the practice. So this what is study similar to what's [indiscernible], which is against another standard of care. The second study is an interesting design. This is a mixed population with up to 30% patient being the treatment-naive frontline cell patients and while the others will be relapsed refractory cell patients. This study is actually I want to point out is with ORR as a primary end point with [Indiscernible] study design. Even if this study has a positive readout, we don't believe this will be a practice changing. And also the competitor here is ibrutinib, not the best-in-class BTK inhibitor zanubrutinib. So I think we're eagerly to watching this data readout. And I think for pirto to take any significant share in the frontline that will require us really compared to true data standard care and then with a much longer follow-up. So we do not believe this short-term will change the dynamics in the adaptation of BTK inhibitor in the frontline. Pirto is probably more positioned as the BTK inhibitor after you finishing -- after the patients finishing treatment with covalent BTK inhibitor. We're very excited about our BTK degrader. From our data reported at ASH, we believe this molecule demonstrated better safety and better efficacy compared to pirto. This is why we're going ahead with head-to-head trial versus pirto. Excited to get this trial going and the potential it provide patients with a better treatment option after you finishing covalent BTK inhibitor.

Great. Thank you.

Our next question comes from Yigal Nochomovitz from Citigroup. Please unmute your line and ask your question. Thank you.

For the strong quarter. Hope you can hear me. I had a question regarding the comment on the patent settlement for BRUKINSA. First of all, was that in keeping with your expectations for 2037, but then more importantly, assuming you get combo data with zanro approved, is there any way that could protect you from a generic if you were to work on a fixed dose oral combo? And are you working on that strategy? Thank you.

Thanks for the question, Yigal. So certainly, we have publicly disclosed where we are with respect to our BRUKINSA patent protection. And as you said, 2037 is what we've talked about as a starting point. As it relates to our broader franchise, certainly, when you think about the combination of our assets, we're really seeking to fill all dimensions of the patient journey, and that is a long-lived franchise. Our assets beyond BRUKINSA, obviously being still in development have patent protection well beyond that point in time. So we see this as a franchise that's durable, sustainable. Most importantly, we'll fulfill significant unmet need in the market and physician best-in-class treatments for all patients with CLL. Thanks for the question.

Okay. Okay. Thank you.

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

Congratulations on -- great 2024. Can you guys hear me?

Yes.

Oh, got it. Thank you. Congratulations on amazing 2024 and even more amazing 2025 guidance. My question is on the completion of enrollment of the CELESTIAL study. Can you talk a little bit about how you're thinking about the event rates going forward? When we might expect top line data and a potential NDA submission? Thank you.

Yeah. Thank you very much for the question. Yeah, we're very excited about the study being able to finish enrollment in just about 14 months. This again demonstrates our ability to really execute clinical trials. In terms of the event side of it, we did not guide this study is event-driven PFS with endpoints. why eagerly as you are waiting for the study to read out. But as the control ARM the VO so it will take a little time to the readout.

Thank you.

Our next question comes from

Thank you very much for taking my question. Very great quarter in fourth quarter 2024. My question is really regarding the venetoclax because in the first line CLL, how do you see the potential patient preference? Are they going to prefer dose duration or it's going to be still more BTK monotherapies? The reason I'm asking this is because the slides that Matt was showing after about decade prescription of BTKI and the first line, we still see only about 50% of patients actually on BTKI while rest of the 50% is on other treatment. So I'm kind of wondering when the fixed duration come into market, what's going to be their patient and physician's preference? And also, what could potentially be the potential impact on the whole franchise sales given fixed duration definitely going to be triggering a shorter duration of treatment versus BRUKINSA itself. So I'm trying -- I'm wondering, what's going to be how you think about the overall franchise impact when fixed duration is going to come into the market? Or you're thinking about potentially we're going to start with fixed duration, then we're going to going to -- patients switch back to BRUKINSA therapy for longer-term maintenance therapy. Thank you.

Thanks for the great question. I think, first of all, fixed duration means lots of things, chemos fixed duration. I think you have venetoclax combinations. And then I think you have BI, which is not approved in the U.S., and you have AAV, which has a study that we'll seek approval and we'll see how that plays out. I think that what we've laid out for you is when you actually look at this data versus continuous BRUKINSA, BRUKINSA looks like a better option for most patients. I think also fixed duration should not be confused with intermittent therapy really what you're talking about in this study, highly selected ultra-fit population, only relevant for a-quarter of the patients, not deletion 17p patients, which have a worse outcome, not older patients, not less healthy patients. In that population, you're still seeing close to a-quarter of the patient's progress within three years. Remember, they were on treatment for 14 months, right? That's only 20 months of being off treatment, and they progressed 1/4 of the patients. And if you look at shape of that curve, you can jump back to it, look at it right after 36 months. And again, highly selective, this is like as good as it could ever possibly get. The real-world experience is going to be much less healthy patients with much worse outcome. And you just compare that to a continuous therapy it's just underwhelming. So I think if that's the hurdle you're looking at, you really have a choice between VO, which is a huge tox burden, a huge burden on patients. And even this VI, when you actually look at the patient journey on it, it's no better, it's probably worse than chemo in the burden to a patient of the hospitalization and the monitoring associated with venetoclax. So we don't anticipate that to dramatically change this percentage of fixed duration versus continuous therapy and actually we think there's an opportunity for continuous therapy to try to work its way more broadly into some of those patients. The 50% that aren't on continuous therapy today. And of course, we're the leader in that space. But more importantly, as we've laid out Sonro, plus BRUKINSA finally looks like it's a fixed duration where the squeeze and juice make sense together. And that would be a first. And I think we do believe that, if we can continue to mature that data and it looks the way it is that for the patients that are on fixed duration, which is roughly half the patients whether it's chemo, whether it's other venetoclax-based therapies, this will stand out as a much better option than all of that. And from that perspective, we should really be able to expand into that area. All of that said, still, BRUKINSA monotherapy, we believe has a strong role in this. And for patients that are hard to treat, you have to have a lot of confidence to take people off and stop therapy. Everyone likes it. The promise is good. But if you don't have MRD negativity, that's a bold thing to do. And if you don't have PFS that really does look better, it's a hard thing to do. And I think that with more and more experience, we are very comfortable with the role of continuous monotherapy moving on. We believe with the combinations, there's huge opportunity and half of the patients were really not reaching right now. And I think from the other perspective, just simply put, this is a franchise that will require combinations that will have for different types of patients, continuous therapy and fixed duration. And the three agents we have, I think as we've said, single-agent combinations, we can cover this entire space and we probably can cover it with better outcomes for patients in every setting and we're excited about that. And even fixed duration, even with zono plus BRUKINSA, it's not going to be fixed duration where you stop and there's never any progression. There will be progression and there will be retreatment a relapsed/refractory market, which will be substantial. It's not yet a cure as far from that. Thank you.

Got it. That’s very clear. Thank you, John.

Our next question comes from Michael Schmidt at Guggenheim Partners. Please unmute your line and ask your question.

Hi guys, [indiscernible] for Michael here. Congrats on the progress in 2024, and we're definitely looking forward to the year ahead. Just a follow-up on CDK4. You mentioned that the data will be at ASCO if I heard that correctly. I guess how are you setting expectations for that data disclosure? And what additional efficacy signals would you want to see to further support your planned Phase II development and also be differentiated from other programs? Thank you.

So can I ask you to repeat your question on which data you're referring to CDK4? CDK4, okay. Got it. Yes. Thank you so much for the question. The CDK4, we're already seeing very interesting data from our early dose escalation. We're really in the safety expansion cohort trying to determine what will be our dose taking forward. The set of data, as I mentioned today, we are very excited about, which is consistent with our hypothesis with better selectivity and a better potency. It seems like now this is translating into early in the clinical side of that, which is less heme toxicity, but we're also seeing a better targeting inhibition with the TK1 assay. So with that, and we are going to analyze our data as the data come in and really make a decision whether or not to starting the pivotal trial in the later part of this year or early next year.

All right. Thanks a lot guys.

Our next question comes from [indiscernible] at TD Cohen. Please unmute your line and ask your question. Thank you.

Hi. Thanks, it’s [indiscernible]. Thanks for taking my question. Congrats on a great quarter and 2025 guidance. Just a few quick ones from me. Number one, what are you expecting on TEVIMBRA in the US and EU for your 2025 guidance? And number two, on your degrader, I know you're evaluating some chemo free combinations, such as with BRUKINSA, sonro or CD20 bispecific. Of these, what are you most excited about? And how confident are you that you can maybe move your degrader up into earlier lines in CLL? Thanks so much.

Thanks so much.

There are no further questions. I will turn the call over to John Oyler for closing remarks. Thank you.