Earnings Call Transcript - ONC Q1 2025

Operator, Operator

Our Investor Relations website, along with our earnings release, contains all information as of the date of this presentation. We do not have any obligation to update this information unless required by law. Now turning to today's call as outlined on Slide 3. John Oyler, our Co-Founder, Chairman, and CEO, will provide a business update; Xiaobin Wu, our President and Chief Operating Officer, will provide an update on our global commercial progress; Matt Shaulis, our General Manager of North America, will update us 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 first-quarter financial results and financial guidance. We will then open the call to your questions. I will now pass the call over to John. John?

John Oyler, CEO

Thank you, Dan, and welcome, everyone, to our Q1 earnings call. Last quarter's call, I spoke about three priorities for 2025. The first was solidifying and deepening our hematology franchise leadership. The second was advancing our prolific pipeline of internally developed assets. And the third was driving superior financial performance. I'm excited to share with you how we delivered on these priorities through the first quarter. BeiGene is the only company with an internally discovered and wholly owned portfolio of potentially in-class molecules across all three foundational mechanisms in CLL. We believe our relentless focus on serial innovation and CLL uniquely positions us to address the full scope of unmet patient needs across all lines of therapy in subpopulations. BRUKINSA is the best-in-class BTK inhibitor that serves as the backbone of our franchise. In the U.S., BRUKINSA is the leader in new patient starts for both frontline and relapsed refractory CLL and across all of its approved indications. BRUKINSA possesses the broadest label of any BTKi and for the first time, BRUKINSA has surpassed both ibrutinib and acalabrutinib in overall U.S. quarterly revenue and continues to outpace its BTKi competitors in year-over-year growth. This leadership follows science and the data and reflects BRUKINSA's clear clinical differentiation. BRUKINSA is the only BTKi to exhibit complete and sustained inhibition, and it's the only BTKi to demonstrate superior efficacy and safety in a head-to-head trial against ibrutinib. And anchored by its best-in-class clinical data, BRUKINSA has now treated over 200,000 patients globally. Sonro, our potentially best-in-class BCL-2 inhibitor, continues to advance rapidly through late-stage clinical development. We've completed enrollment in our Phase III CELESTIAL trial of sonro plus zanu in treatment-naive CLL and we've progressed two additional Phase III trials as Lai will review. Importantly, we've reached our first registrational milestone for sonro, with a regulatory filing submitted in China and we plan to submit our first global filing in the second half of this year. These filings mark the beginning of sonro's evolution as a potential game-changing therapy across multiple B-cell malignancies. We're the leading next generation of innovation in CLL with our first-in-class BTK CDAC program, which is now dosed over 600 patients and continues to progress rapidly. We've reached an agreement with the FDA on a Phase III dose, and we've already initiated our first Phase III trial with plans to initiate another Phase III trial against pirtobrutinib in the second half of the year. We continue to expect data from our potentially pivotal Phase II trial next year and pending positive results intend to complete global regulatory submissions. Outside of heme, we continue to advance one of the broadest solid tumor pipelines in the industry. Our CDK4 inhibitor continues to advance rapidly, with over 300 patients enrolled, including over 100 in just the past two months. Our B7H4 program, a key area of enthusiasm, has completed seven monotherapy cohorts with promising signs of clinical activity. We enrolled the first patients in both of our claudin-6 CD3 bispecific program for gynecological and other solid tumors and our second-generation BCL-2 for metastatic breast cancer. Our PRMT5 inhibitor also entered the clinic in early Q1, marking another milestone in our targeted lung cancer therapy portfolio. This year, we anticipate more than ten proof-of-concept readouts across our solid tumor pipeline, each representing a potential near-term value inflection point. These assets feature differentiated, potentially first and/or best-in-class profiles and have the potential to deliver transformational impacts for both patients and shareholders. Our internal clinical development team of over 3,700 continues to demonstrate time, cost, and quality advantages that are driving higher ROI for each R&D dollar spent. And we're routinely seeing proof of these advantages and programs in competitive settings like our BTK CDAC, our BCL-2, and our CDK4 inhibitor, just to name a few. Moving to financial performance. We achieved a major milestone in Q1: GAAP profitability for the first time. Aaron will provide more detail later in the call, but these strong quarterly results pace us on solid footing to deliver on our full-year financial guidance. I'd like to close by sharing a few reflections on the external landscape as our industry continues to navigate an increasingly challenging and complex global environment. I believe our unique model positions us exceptionally well to succeed in spite of today's challenges. Over the past fifteen years, we've built an organization from scratch that is technology-enabled, time and cost advantaged and now vertically integrated. It was built not only to survive but to thrive in a world with pricing pressure. In today's macro environment, a global manufacturing footprint and regional resilient supply chain are essential to ensuring product availability and operational continuity. This has been a foundational principle of our operations across the U.S., Europe, China, and other key markets. We've realized this vision with action, including most recently an $800 million investment in our Hopewell, New Jersey manufacturing facility, which opened in 2024. Given the landscape around trade policies and tariffs will continue to evolve, our commitment to regional manufacturing helps us mitigate potential risks and maintain reliable supply. Finally, I'm pleased to announce that the shareholders have approved our redomiciling to Switzerland from the Cayman Islands as well as our name change to BeOne Medicines, reflecting our continued evolution into a globally diversified oncology leader and our deepening ties to the world-class Swiss biotech ecosystem. And with that, I'll pass it over to Xiaobin to provide a global commercial update.

Xiaobin Wu, President and COO

Thank you, John. Our global development strategy and the Board trial design have resulted in the broadest label and widespread coverage for BRUKINSA and TEVIMBRA. We have achieved significant global reach in a short period of time and have now treated over 1.7 million cancer patients with our therapies. These foundational assets are well positioned to deliver meaningful benefits to patients worldwide. We have built a commercial infrastructure to successfully launch and scale across more than 80 markets. This strong foundation also positions us to fully leverage our global network to support internal clinical development and drive the successful commercialization of our pipeline. In the first quarter, global sales were $1.1 billion, growing 49% from Q1 2024. The U.S., our largest market, grew 60%, which reflects our strong BRUKINSA demand growth, as Matt will discuss later. In addition, TEVIMBRA was approved for frontline ESCC in the U.S. during the quarter. China sales grew by 26% compared to the prior year period, with TEVIMBRA and BRUKINSA sustaining their market leadership positions. TEVIMBRA expanded NRDL coverage in frontline gastric and frontline small cell lung cancer, and Amgen collaboration products also continued their strong momentum in the first quarter. Europe experienced 75% growth as we continue our launch for BRUKINSA and TEVIMBRA. We received reimbursement for our TEVIMBRA in Spain and early this week, European Union approval for TEVIMBRA in frontline extensive stage small cell lung cancer. We’re encouraged by the growth perspective of the region for 2025. Rest of the world sales totaled $32 million in the first quarter, growing 146% compared to the prior year. This was primarily driven by expansion and new launches in Asia-Pac, LATAM, and MENA regions, including notable progress in South Korea, Japan, Mexico, and Brazil. While we’re still in the early stage of commercialization in our rest of the world market, we expect them to be strong, consistent contributors to future revenue growth and help us realize our mission to reach many more patients with improved access and affordability. I will now pass the presentation over to Matt to provide the U.S. commercial update.

Matt Shaulis, General Manager of North America

Thanks, Dr. Wu. Moving to BRUKINSA's U.S. performance. Q1 U.S. BRUKINSA sales reached $563 million, representing growth of 60% versus the prior year, establishing BRUKINSA as the market leader by revenue in the large and growing U.S. BTK market, which grew 11% year-over-year. This is an important milestone that was reached just two years after our CLL launch. And while this strong performance underscores BRUKINSA's continued momentum, the Q1 revenue reflects the typical seasonality seen across all products in the BTK class, as previously discussed on the Q4 update. BRUKINSA's Q1 net revenue and net revenue growth were driven primarily by strong underlying demand, as you can see on this slide. Year-over-year demand growth was 54% when compared to the first quarter of 2024 and 6% sequentially when compared to the fourth quarter. This steady trend of demand growth reflects our leadership in terms of new patient starts, where we lead across all lines of therapy and indications, including both frontline and relapsed/refractory CLL. This momentum, combined with the growing base of existing patients, underscores a solid foundation for ongoing growth. We're confident in the underlying business fundamentals and well positioned for strong performance in the second quarter and the rest of 2025. Significant growth opportunities remain within the frontline CLL market, where treatment success requires deep responses, impressive and sustained PFS, and a strong safety profile—all areas in which BRUKINSA has consistently demonstrated proven advantages. Nearly half of all newly diagnosed CLL patients have one or more high-risk features, including unmutated IGHV, deletion 11q, and TP53 deletion 17p, and even more have high-risk comorbidities such as AFib. In the ALPINE trial, BRUKINSA became the only BTK to demonstrate superiority over ibrutinib in a head-to-head trial. And in the high-risk TP53 deletion 17p population subset of ALPINE, BRUKINSA's PFS at 42.5 months median follow-up was 59% versus ibrutinib's PFS of 32%, an impressive 27% higher. BRUKINSA is the best-in-class option for all patients regardless of mutation or significant comorbidities. Given the challenges with current fixed duration regimens, and BRUKINSA's best-in-class profile, we see additional opportunities for BRUKINSA monotherapy to continue to take market share from these treatment options. And beyond the expansion of BTK monotherapy, we believe BRUKINSA plus sonro has the opportunity to deliver on the promise of fixed duration and expand its role in the treatment paradigm. Similarly, our BTK CDAC has the potential to surpass the other existing treatment options and fulfill the unmet need of patients with CLL. On that note, I'll now pass it over to Lai.

Lai Wang, Global Head of R&D

Thanks, Matt. I would like to take a few minutes to highlight key aspects of our portfolio, starting with our hematology franchise. Our CLL franchise is evolving quickly. We're relentlessly pursuing the best-in-class treatment options from frontline to late lines, including both continuous and fixed duration treatments. We believe that to advance the standard of care, the fundamental question of whether a potential medicine is better than the existing best treatment options must be answered. The clinical trial needs to be designed accordingly. You can see this in our past trials, including ALPINE and our current Phase III trials for sonro and BTK CDAC, which I will review today. BRUKINSA was designed from inception to provide 24/7 inhibition of BTK in more disease-relevant compartments and to address efficacy challenges of ibrutinib. This led to a Phase III victory over ibrutinib in a direct comparison in relapsed refractory CLL. Furthermore, this enhanced selectivity has resulted in improved tolerability in clinical settings. Similarly, sonro exhibits higher potency and selectivity compared to venetoclax, offering potential advantages in efficacy and safety supported by clinical data. With a short half-life and no drug accumulation, sonro may allow for a more patient-friendly TRS launch, which would serve as a key differentiator for venetoclax. We believe that the vast majority of CLL patients will require only one single hospital visit for sonro ramp-up of the zanu BD. Our BTK CDAC is the most advanced BTK degrader currently in the clinic. With preclinical properties indicating safety and efficacy benefits for patients, this novel mechanism of action offers distinct advantages over traditional inhibitors by overcoming and preventing the emerging resistant mutations and disrupting skillful functions. Next, I would like to discuss the fixed duration treatment landscape and its significance in enhancing our leadership in CLL. To establish a compelling fixed duration therapy, you must achieve higher efficacy and safety standards. In terms of efficacy, it must deliver extended PFS, allowing patients to experience a general drug holiday quality. This requires deep responses, enabling doctors to feel confident that the risk of relapse is minimal when therapy is discontinued, which is measured by undetectable uMRD. Furthermore, it should not present any additional clinical meaning for safety concerns during the treatment period. Our potential best-in-class fixed duration combination of zanu with sonro has demonstrated deep MRD rates, impressive and sustained PFS, and acceptable safety profiles. We are progressing rapidly with the development of this fixed duration combination therapy. In line with our standard practice, the CELESTIAL 301 trial was designed to demonstrate the PFS superiority of sonro plus zanu over the current best standard care in fixed duration treatment VO in treatment-naive CLL. This trial completed enrollment in February within just 14 months, marking a significant milestone for the sonro program and showcasing strong interest from patients and clinicians in our clinical execution capabilities. In addition to treatment-naive CLL, we are also advancing the development of sonro for relapsed refractory CLL patients through our CELESTIAL 303 study, which combines sonro with CD20. This is a true head-to-head trial designed to demonstrate the superiority of sonro over venetoclax. For mantle cell lymphoma, a Phase III trial has been initiated to evaluate the treatment effect of two years of sonro combined with continuous zanu in relapsed refractory settings. This trial will also serve as a confirming trial for CELESTIAL-202, a single-arm Phase II study of sonro monotherapy in relapsed refractory mantle cell lymphoma post BTKi, which we plan to file globally for accelerated approval in the second half of this year if the results are positive. Moving on to our BTK CDAC, we presented compelling early efficacy and safety data in a heavily pretreated population at ASH. As you can see here on this slide, the evolution of our data together with strong KOL feedback gives us confidence to initiate a head-to-head trial Phase III study against pirtobrutinib. The details of the trial design are shown on this slide. The first patient is expected to be enrolled in the second half of this year; we have met with the FDA and obtained agreement on our dose for Phase III in CLL. I'm very excited to announce that our first Phase III study for the BTK CDAC CaDAnCe-302 versus physician's choice in relapsed refractory cell patients had its first patient enrolled this week. We have also started a multi-cohort platform study to combine BTK CDAC with internal and external assets like sonro, zanu, and the CD20 bispecifics. These combinations have the potential to expand the treatment options for patients with B-cell malignancies. Our solid tumor portfolio has evolved over the last two years with 19 new molecules in the clinic across three major tumor types: lung, breast, gynecological cancers, and GI cancers. We have refined our portfolio to focus on targeted therapy utilizing various modalities, including ADCs, degraders, and multispecifics to deliver highly efficacious treatments for our patients. Our commitment to industry-leading speed is evidenced by our Fast to PoC strategy, which continues to drive the rapid development of these molecules. I'd like to highlight several key pipeline value inflection points. During the presentation, I addressed some of our significant late-stage milestones. In addition, we had a successful Phase II readout for sonro in relapsed refractory CLL and achieved expedited NDA submission in China, completing the process in an impressive 11 weeks from the data cutoff to the NDA acceptance. We anticipate our global filing in relapsed refractory mantle cell lymphoma in the second half of this year. Additional Phase III pivotal trials for both sonro and our BTK CDAC will be initiated later this year. Turning to our early-stage pipeline, we have several PoC catalysts expected throughout the year. I will provide more details regarding our innovative scientific advancements and portfolio progression during our R&D Day on June 26. With that, I'd like to pass it over to Aaron.

Aaron Rosenberg, CFO

Thanks, Lai. We had a strong start to the year with first-quarter 2025 revenue of $1.1 billion compared to $752 million in Q1 2024. Revenue growth was 49% with meaningful contributions across all of our key brands. These top-line results are consistent with our communicated guidance expectations and set us up well for the balance of 2025. This quarter demonstrates our dual mandate in action, as we are driving significant top-line growth with material operating leverage to support long-term business sustainability. As a result of this focus, we delivered positive GAAP operating profit and net income for the quarter. You can see the year-over-year improvement in GAAP and non-GAAP operating profit measures of $272 million and $286 million, respectively. And as a result of our value-focused investment philosophy, we achieved a third consecutive quarter of positive operating cash flow. This is notable as the first quarter typically has a seasonally high use of capital. When looking at our operating cash generation performance compared to Q1 2024, we improved by $353 million. Sales of BRUKINSA totaled $792 million in Q1, representing 62% growth compared to Q1 2024. Growth continues to be primarily driven by demand from our leading new patient share in the United States, coupled with year-over-year increased volume following a full year of use from patients who began treatment in 2024. This is layered on top of the stable base of patients who remain on therapy from prior years given BRUKINSA's long duration of therapy. Growth contributions were seen across all geographies, including Europe, China, and rest of the world markets. TEVIMBRA sales of $171 million resulted in 18% revenue growth when compared to Q1 2024, driven primarily by our leading market position in China. We're in the early stages of our commercial expansion in other markets. Amgen in-licensed products were key contributors to performance, coming in at $114 million and growing 58% year-over-year. Finally, we are also seeing year-over-year growth contributions from collaboration revenue given our global royalties for IMDELLTRA. Now moving to the GAAP income statement. Product gross margin increased nearly 2 percentage points to 85% this quarter compared to 83% in Q1 2024. This was largely due to favorable mix and cost of sales productivity for both TEVIMBRA and BRUKINSA. Operating expenses totaled $941 million, representing growth of 6% compared to Q1 2024. Growth was seen in both SG&A and R&D as we continue to invest with discipline to support our commercial businesses and our robust pipeline. Note that Q1 2024 included $35 million of business development expenses, which should be considered when interpreting the period-over-period change. Taken together, our focus on top-line growth with meaningful operating leverage led to our achievement of GAAP profitability for the quarter. Our non-GAAP P&L includes adjustments for typical items with a full reconciliation provided in the appendix. Focusing on the bottom line, non-GAAP net income totaled $136 million in Q1 2025, an increase of $282 million versus the prior year. This equates to non-GAAP earnings of $1.22 per ADS. Switching to guidance, our full-year 2025 guidance remains unchanged. We project revenue to be between $4.9 billion to $5.3 billion. Movement in exchange rates, while volatile at the start of 2025, have largely offset and current rates are contemplated in this affirmed range. Our GAAP gross margin percentage is projected to be in the mid-80 percentile range, benefiting from mix and production efficiencies. Operating expenses on a GAAP basis are anticipated to be between $4.1 billion and $4.4 billion, non-GAAP operating expenses are expected to track with our GAAP guidance with reconciling items remaining unchanged from existing projections. As we have demonstrated in the first quarter of 2025, we are committed to achieving full-year GAAP operating income breakeven and generating positive cash flow from operations for the full year. Recognizing uncertainty remains, our guidance includes our estimates of the impacts of announced tariffs to our 2025 results. We do not expect the tariff impact associated with our partnered products. Our exposure has been mitigated by our significant investments and partnerships to build a true global production network, including our commitment to manufacturing in the United States for U.S. supply of BRUKINSA, TEVIMBRA, and the commercialization of our pipeline assets. This includes our 42-acre Hopewell, New Jersey campus, which is currently being qualified for biologics production and could be expanded to other modalities as needed to support our advancing pipeline. We will continue to take action to build supply chain resiliency to ensure patients around the world have uninterrupted access to our critically important life-saving medicines. And with that, I'll turn the call back to Dan.

Operator, Operator

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

Operator, Operator

Our first question comes from Andrew Berens at Leerink Partners.

Andrew Berens, Analyst

Congrats on all the progress. I had a question on the CDK4 program. Can you just remind us how 43395 differs from Pfizer's atirmociclib? And I know it's early, but where do you see the CDK4 agents being used in HR-positive breast cancer in terms of lines of therapy and potential combination partners? And then maybe another question on BRUKINSA, just wondering if you have any appetite to develop the drug beyond oncology. Do you think there's a potential role in autoimmune diseases? And is this something that you would consider doing yourself or with a partner potentially?

Lai Wang, Global Head of R&D

Yes. Thanks for the question. For the CDK4, our molecule was designed benchmarking against Pfizer's atirmociclib to be more potent as well as more selective. Right now, we are still in the process of dose escalation. We're actually moving this program very aggressively. Even in just the last month or so, we have enrolled 100 patients. We still plan to move this forward into the Phase III trials aggressively. The current thinking around this molecule is to initiate a Phase III trial in the second-line settings in combination with SERD. So that's the plan. In addition to that, we are also contemplating the play in the earlier lines. As for your question related to BRUKINSA outside of oncology, we have a Phase III ongoing, which is in membranous nephropathy, which is the first point Wu mentioned about in the eye indication.

Andrew Berens, Analyst

Okay. And do you have an oral SERD in your portfolio that has been disclosed?

Lai Wang, Global Head of R&D

We do not have an oral SERD.

Operator, Operator

Our next question comes from Yaron Werber at Cowen and Company.

Yaron Werber, Analyst

Congrats on a lot of pipeline progress. Maybe for Matt or Aaron, can you give us a sense of BRUKINSA in Q1? Any sense how much was the weakness in the class related to the Part D redesign? And then for TEVIMBRA, is there any way you can split out sales in the U.S., Europe, sort of rest of world and China?

Matt Shaulis, General Manager of North America

Do you want to go ahead?

Aaron Rosenberg, CFO

Sure. This is Aaron. Thanks for the question, Yaron. I would start by speaking to the broader industry. Obviously, Part D redesign has some impact as it relates to pricing. We've talked about a relatively stable net pricing environment for our company. This is coming from a couple of factors. Of course, with the redesign, as we look at our business, we do see some Q1 favorability driven by the redesign in part as a result of the elimination of the manufacturer liability for the coverage gap. As you know, that would largely be experienced earlier in the year as patients work through the donut hole and then obviously, manufacturers had the liability associated with that coverage gap. For us, with the redesign, we do benefit, as we've spoken about from the specified small manufacturer designation, which layers in our manufacturing liability over a five-year period. So on balance, as you think about Q1, you get a little bit of favorability given the lapping of the pricing in the base from 2024. And that's offset to a degree by the manufacturer liability on the Part D redesign for us, which will be consistent over the balance of this year. So other than that, Matt, anything to add?

Matt Shaulis, General Manager of North America

Maybe I'll just add a little bit of commentary about Q1 related to seasonality. I think that kind of goes hand in hand with the Medicare Part D piece. And then I'll gladly address the U.S. TEVIMBRA component of the question as well. We talked about some things back in the fourth quarter related to what we anticipated in Q1 on seasonality. There's a typical customer inventory build in the fourth quarter with a drawdown that we then see in the first quarter. We disclosed about a $30 million buy-in. And then we have also noted one less shipping week in the first quarter of this year than for other typical quarters. So really, in the first quarter, we typically see a slight drop in new starts due to changes in patients' insurance and out-of-pocket resets and other factors. So this first quarter was really no different than that. On the TEVIMBRA U.S. piece, we don't report separate breakouts for that, but we're very encouraged with the progress that's been made on TEVIMBRA in the U.S. We were very pleased to receive our frontline esophageal approval. That was our third approval in the U.S. within a year coming after second-line esophageal and frontline gastric. We were also very pleased to see listing in the NCCN guidelines. More recently, our alternative dosing Q2W and Q4W came in line as well. So what we now see is initial experiences, patient starts, all in line with launch expectations. And we'll see the second quarter really be the starting point for TEVIMBRA in the U.S. now that all those other factors have come into line.

Yaron Werber, Analyst

I would like to follow up on BRUKINSA. The EMA approval from Switzerland is significant. How much inventory can they manage? Will they be able to supply the U.S. market too? Or are you discussing a partnership with another manufacturer for the U.S.? Any updates on that?

Aaron Rosenberg, CFO

Yes. So thanks for the question. We are pleased with our approval for our second source of API from our Swiss supplier, as you mentioned. And we are working to continue to broaden out our supply chain resiliency with securing sourcing from another supplier in Spain. So that's a portion of our API usage. We've taken assertive action to ensure we have significant stockpiles, both for regular run demand but also to have additional security as it relates to our API stockpile. So we're confident in our position in that regard.

Operator, Operator

Our next question comes from Jessica Fye at JPMorgan.

Jessica Fye, Analyst

On the CDK4 program, just to confirm, is it fair to think that efficacy data could come during your R&D Day in late June? And can you maybe set the stage a little bit for what kind of data you'll share, i.e., is there going to be enough follow-up to get a look at durability here? Or should we mainly be expecting more safety and response rates? And then also, related to that program, can you just remind us where you are in terms of starting or enrolling a CDK4/6 naive cohort with that molecule?

Lai Wang, Global Head of R&D

Jessica, thanks for the question. In terms of data disclosure at R&D Day, we will be mainly focused on the dose escalation cohorts. We're certainly including the efficacy data in addition to the safety PK. However, as you noticed, this program has moved very quickly. Actually, just in the last two months, we enrolled over 100 patients. So the durability side of that, as you can imagine, will be limited. In terms of the molecules, the second part of your question was about CDK4/6 naive treatment. We actually have enrolled patients already in that setting, so we began to accumulate data in that setting. So we're eagerly waiting for that data to help us to make the decision in the frontline.

Jessica Fye, Analyst

And will we see any of that at R&D Day?

Lai Wang, Global Head of R&D

That's too early to be disclosed at R&D Day.

Operator, Operator

Our next question comes from Reni Benjamin at Citizens.

Reni Benjamin, Analyst

Congratulations on all the progress. As you look at the ten proof-of-concept readouts this year, can you maybe highlight the top ones that you think could really drive your excitement as you move forward? And then separately, the MANGROVE trial you mentioned has an interim analysis of the Phase III trial. Can you just provide an overview of what your expectations are from that interim analysis?

Lai Wang, Global Head of R&D

Yes. Thanks for the question. I got this question a lot. Where do I start? There are so many really exciting programs with very good progress. We actually anticipate that most molecules entered the clinic last year. We should expect the data this year. I wouldn’t say which one is my favorite; I actually like them all. In terms of the MANGROVE study, it’s an event-driven study. So we’re waiting—eagerly waiting for the events to happen. So we hope that will happen in the second half of this year.

Operator, Operator

Our next question comes from Michael Schmidt at Guggenheim Partners.

Michael Schmidt, Analyst

I just had a follow-up on the first-line mantle cell lymphoma opportunity for BRUKINSA based on MANGROVE. Could you just help us understand the size of that opportunity? And do you plan on submitting regulatory filings based on this interim data here in the second half? And then a question just longer-term on the CLL market. What is your view on how BRUKINSA is positioned longer term with the pirtobrutinib first-line data reading out here later this year from Lilly? What gives you confidence in BRUKINSA's best-in-class market position long term in CLL?

Lai Wang, Global Head of R&D

Yes. I will probably start and then probably ask Matt to comment on the commercial side of it. In terms of the first-line MANGROVE study, I just want to remind everybody about the study design. This is—we're using a chemo-free regimen, which is rituximab plus zanubrutinib. The control arm is BR. This is a little bit different from the ACCO study, which adds a column on top of BR. We do believe this is providing really probably a preferred option ultimately for patients if the trial is successful to be chemo-free. One thing to highlight is in the frontline therapies, the treatment duration will be very long. So if it is successful, it can further expand our market in the mantle cell. Moving on to your question around pirtobrutinib; the pirtobre study in the frontline is against the BR. That's the first study. The second study was enrolling about one-third of patients, which is in the treatment-naive but it's a mixed population also with the second line and the later line. The competitor there is ibrutinib. So we do not believe this presents a significant threat to our BRUKINSA because the comparator is not BRUKINSA.

Matt Shaulis, General Manager of North America

Yes. And I’ll just briefly comment on mantle cell and then move over to the pirtobrutinib-related element of the question. We clearly see a reasonable size opportunity in mantle cell. In fact, we continue to see opportunities for the BTK class in that segment and also continue to have a strong share position there. Regarding pirtobrutinib and the future outlook for the class and for BRUKINSA, we fully expect to continue to maintain and expand market share with our BTK therapy. Based on pirtobrutinib's recent readouts, we think it’s really unlikely to see significant shifts to earlier lines of therapy. We believe that we’ve heard the competitor make similar remarks regarding sequencing and really believe that continuous BTK therapy is going to continue to be the best option in those earlier lines of therapy. We also see that utilization aligns with that and then pirtobrutinib is really being utilized in those later lines of therapy.

Operator, Operator

Our next question comes from Ziyi Chen at Goldman Sachs.

Ziyi Chen, Analyst

Two questions, one on IRA and the other one on expenses. So how do you see the potential impact of Calquence getting into IRA negotiation this year? Will the new price be effective in 2027? And also for your BRUKINSA's IRA, what is going to be your base case scenario? In terms of expenses, we actually see a major wave of proof-of-concept data coming from the solid tumor pipeline, and we believe there are going to be a lot more trials being initiated and a lot more potentially pivotal studies being initiated. So how should we see the trend of R&D spending? In the first quarter, it's down a little bit quarter-over-quarter, but do you still have the flexibility in spending, given you have the target of profit-making in this year and potentially beyond 2025?

Matt Shaulis, General Manager of North America

Yes. I guess I'll just start out with IRA and your question related to Calquence. We won't see Calquence's IRA implications until 2026. We may see some indirect marketplace impact regardless of that price negotiation status. We think that, that's going to be manageable. Obviously, with respect to IMBRUVICA, we don't see it as a credible substitute for BRUKINSA due to safety and efficacy, particularly given our ALPINE trial showing head-to-head superiority and also the known cardiac toxicity profile for IMBRUVICA. We see substantial differentiation there. Of course, later with Calquence, we see less cardiac issue than IMBRUVICA, but also questionable efficacy across multiple studies. Clearly, at best, we see that as a poor substitute for BRUKINSA. So we continue to be pleased with our leadership position in new starts, in relapsed and refractory, and in frontline and are the most prescribed across the B-cell malignancies. We think that continued strong market performance will be critical as we head into the IRA time frame.

Aaron Rosenberg, CFO

Great. Thank you. With respect to our R&D investment, as you see in our 2025 guidance, we are investing significantly to rapidly advance our pipeline. You did reference our dual mandate of being a growth company, but doing it in a sustainable way, and you see that in our operating results, not just this quarter, but in the preceding quarters as well. So we will continue to operate against that dual mandate of growth with margin expansion. We're committed to developing the pipeline. What we've talked about historically is having a strong top line with disciplined investment that still allows us to invest with growth against that emerging pipeline. As we’ve talked about, we have a significant investment already, and we have a pipeline that has a portfolio of late-stage investments. You think about TEVIMBRA, BRUKINSA, our TIGIT program; those are significant investments. They’re rolling over, and as we go, they’re being replaced by our investments in our current late-stage pipeline and our great opportunities in front of us with sonro and then degrader. That also provides opportunity with respect to our early-stage program. We’ve talked about how BD is in our DNA. We’re fortunate to have such a robust pipeline. Lai talked about how many favorites we do have. That provides a lot of optionality for us. These are all fully owned assets. We’re obviously, there’s no shortage of interest in our pipeline. We’re open to the optionality that affords. Given our strong balance sheet and our capital discipline, we’re not obligated to do anything. So we’re really in a strong position as it relates to advancing the pipeline and maximizing value for our shareholders.

Operator, Operator

Our next question comes from Kelly Shi at Jefferies.

Clara Dong, Analyst

This is Clara on for Kelly. Congrats on the progress for the quarter. So for the Phase II data readout for sonrotoclax in refractory mantle cell lymphoma in the second half of the year and the BTK CDAC Phase II data in 2026. I just wanted to clarify what are the endpoints you and the regulatory agency are looking at to potentially support the registration? And also for the filing of sonrotoclax in China, maybe walk us through what kind of the typical review timeline there?

Lai Wang, Global Head of R&D

Yes. Okay, thanks for the question. For both sonro and BTK CDAC, those are typical single-arm monotherapy Phase II studies. The primary endpoints are ORR and DOR. This will support potential accelerated approval. In terms of the sonrotoclax filing, we have already received a priority review from the CDE that’s listed on the CDE website. We’re anticipating potential approval probably in the first half of next year.

Operator, Operator

Our next question comes from Gregory Renza at RBC Capital.

Gregory Renza, Analyst

Congrats on the progress. Maybe just on the quest for serial innovation and just around CLL and on the BTK CDAC. I'm just curious if you could comment on that relative positioning to the CDAC to routine BTKs in the longer term. One, what gives you confidence that 16673 may have the ability to beat pirtobrutinib in a head-to-head study? And secondly, certainly, with discussion around maybe some risks regarding using degraders earlier in treatment lines—in treatment settings, just curious about potential mechanism resistance, how that could preclude other treatment options. Just curious on your view with respect to that sequencing.

Lai Wang, Global Head of R&D

Yes. Thanks for the question. Related to our confidence in our BTK degrader, I can tell you that's increasing daily. With more data coming, this gives us assurance this drug is doing what it's supposed to do: to truly fully complete degrade BTK protein and provide patients with sustained clinical benefits. With the additional data coming in and also our feedback from the KOLs really gives us confidence to start this head-to-head trial versus pirtobrutinib. This trial will be initiated in the second half of this year. In terms of utilizing the BTK degrader in earlier lines, I think that that's your second question. We're gaining data on that. We're opening a cohort in the BTKi-naive patient population to test this out. This is a different MOA versus the traditional BTK inhibitor. It's very early to say which one is better and what's the right sequence. So we're going to do the scientific experiment to test it out, but it's great to have the option of both traditional BTK inhibitors and a BTK degrader pipeline. In addition to that, I just want to highlight that our potentially best-in-class BCL-2 gives us a lot of different options to play in this space, which we think is very important. We really want to provide the best option for patients, not just in the front line, but also in the later lines.

Gregory Renza, Analyst

That's great. And if I may, an earlier question on BTK and PMN. I'm just curious how you're thinking about the I&I portfolio, certainly with the IRAK4. Is that an area that you want to expand upon as you think about internal and even external development?

Lai Wang, Global Head of R&D

Yes. Thanks for that question. I didn’t spend time discussing our I&I portfolio during the call. This is actually a very exciting portfolio for BeiGene. We have a dozen preclinical programs which we’re developing in the I&I space. Again, we’re utilizing a variety of different modalities, trying to create the best-in-class molecules as well as potentially first-in-class molecules. Related to the IRAK4 inhibitor—IRAK4 degrader, we’re super excited about this molecule. The early data we have seen with this molecule again suggest it has best-in-class potential with its PK and its level of degradation. We believe we can achieve complete target degradation at a very low dose level. We’re also eagerly anticipating our data in the tissue PD, which should come in the second half of this year. But as I mentioned, we also have other I&I portfolio, which we really began to develop. Hopefully, you will see molecules coming from our I&I pipeline in the next couple of years.

Operator, Operator

Our next question comes from Sean Laaman at Morgan Stanley.

Sean Laaman, Analyst

I hope you're all well. Some simple benchmarking questions to start. If you look at the revenue reported by Venclexta, how would you size the opportunity for sonrotoclax against that given potential better safety issues, broadening for improving efficacy, and what other combination opportunities there might be?

Lai Wang, Global Head of R&D

Yes. Thanks for the question. Unlike the BTKi field, there's not as much competition in the B-cell field—there are truly only two molecules: one is venetoclax, and one is sonrotoclax. We're very excited about the profile of our sonrotoclax. It's much more potent and also more selective. Right now, you are seeing that in the different indication with the response rate with the duration of response. This is why it gives us the confidence to start more than just one head-to-head trial. The first trial we mentioned, which was our CELESTIAL-301, we already finished enrollment. We are very excited about the second trial as well, which is in the relapsed/refractory CLL setting to test sonrotoclax versus venetoclax in the CD20 combination setting, but this is truly a head-to-head trial. We believe with those two trials can really establish sonrotoclax as potentially the best-in-class BCL-2. This is critical. But in addition to that, we are also exploring indications where venetoclax hasn't had success, that's including multiple myeloma. We cannot talk about that trial for a while now, but that trial is moving along very nicely. We're anticipating reporting more data later this year. Now I'll hand over to Matt.

Matt Shaulis, General Manager of North America

Yes. I can just offer some commentary on the market opportunity. We currently see the opportunity for BCL-2 and a CD20 to be about one-fourth of that frontline opportunity in CLL. We have said a number of times that we believe there are three necessary components for success, particularly with fixed duration: deep response, and undetectable MRD, long PFS, and strong safety. More recently, we’ve seen some of the fixed duration regimens fail to meet that high bar. For some of the reasons that Lai has outlined, we're very confident that there’ll be opportunities with zanu and sonro to meet that high bar and then ultimately lead to some expansion of the use of BCL-2s and CD20s in that setting. So that's a possibility. We see both zanu and sonro as being the real drivers for expansion in that setting.

Sean Laaman, Analyst

And one more quick one, if I may, more on the commercial side. But historically, when you do benchmarking against BRUKINSA revenue against peers across Europe, you seem sort of underweight, if you like. But I'm just wondering if you—there's good momentum it appears in this quarter. Do you think you've got the investment about right in terms of salespeople to really grow that European revenue? Or can you just sort of map that out for me a little bit would be awesome.

Xiaobin Wu, President and COO

Yes. European business is growing nicely, and you have seen that we grow 75% on the BRUKINSA side and increasingly—we also—we have also seen that we have more new patient share for BRUKINSA. In terms of TEVIMBRA, we got new product launch in Germany, in Austria, Spain, and also some other countries like Switzerland, Norway; we also got reimbursement, and reimbursement countries keep increasing, and the launch activity is on track. In the rest of the world, and you can see our BRUKINSA business growth of 146%, remarkable. We have also launched BRUKINSA in Japan, and we also got approval of TEVIMBRA in multiple countries including Brazil, in South Korea reimbursement, Australia reimbursement. We see significant progress in TEVIMBRA.

Operator, Operator

Our final question comes from Yigal Nochomovitz from Citigroup.

Yigal Nochomovitz, Analyst

I had a few questions. First, on sonro plus zanu pricing, I know it's early, but I'd like to get your early thoughts if you're expecting that to be price neutral with BRUKINSA with the idea to take more share with a better profile or possibly a premium? And then you talked a lot about supply chain resiliency, and you mentioned the sourcing of API in Switzerland and Spain. Obviously, you have the fill and finish in the United States. I'm wondering if there's some long-range plans to additionally introduce an API supply within the United States. And then finally, John, you talked a lot about resiliency. I'm curious about geographic resiliency, specifically with respect to R&D. With the redomicile in Switzerland, do you expect to move more of the core R&D outside of China to Switzerland as well as the U.S.?

Aaron Rosenberg, CFO

So thanks for the question, Yigal. I'll take the first couple and then hand it over to John. It's too early to talk pricing with respect to our pipeline assets. All I'll say is we're really confident in the profiles that these assets have in front of them, and we will price them accordingly relative to the value they're creating for patients. With respect to supply chain resiliency, yes, we're very enthused by the efforts we've taken in the past to ensure that we have set up supply and resilience for patients all around the world. Obviously, we are monitoring all the activity that's happening in the environment, and we'll be sure that we take measures to proactively ensure that supply for U.S. patients, but really importantly, patients everywhere around the globe.

John Oyler, CEO

Yes, we’re excited about things from a global perspective. The organization is always in this global expansion mode. Last quarter, I think you heard us talk about opening operations in South Africa, for example. Today, the management team is sitting here in our San Carlos office and R&D center and excited to be interviewing and recruiting people here for the R&D perspective too. It’s an inevitable expansion process as we try to work globally with everyone and from research, from clinical and getting great medicines to patients’ perspective.

Operator, Operator

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

John Oyler, CEO

Thanks so much. I think our first quarter execution across the key priorities really sets a strong foundation for 2025, and I'm really looking forward to sharing more updates and milestones with all of you throughout the year. So thanks so much for joining us today and taking your time and energy for the very thoughtful process, and have a wonderful day.