BeOne Medicines AG

Good day, everyone. Welcome to B1 Medicine's Q4 and full year 2025 earnings call webcast. All lines have been placed on mute to prevent any background noise. After the speaker's remarks, there will be a question and answer session. At this time, I would like to turn the call over to the company.

Hello and welcome. Thanks for joining us today. I'm Dan Maller, head of investor relations at B1 Medicines. Before we begin, please note that you can find additional materials, including a replay of today's webcast and presentation on the investor relations section of our website, ir.b1medicines.com. I would like to remind all participants that during this call, we may make forward-looking statements regarding, among other things, the company's future prospects and business strategy. Actual results may differ materially from those indicated in the forward-looking statements as a result of various factors, including those risks discussed in our most recent periodic report filed with the SEC. Please also carefully review the forward-looking statements disclaimer on the slide deck that accompanies this presentation. Reconciliations between GAAP and non-GAAP financial measures discussed on this call are provided in the appendix to our presentation, which is posted to our investor relations website, along with our earnings release. And all information in this presentation is as of the date of this presentation, we undertake no duty to update such information unless required by law. Now turning to today's call is outlined on slide three. John Euler, our co-founder, chairman, and CEO, will provide a business update, including commentary on our foundational CLL franchise. Aaron Rosenberg, our CFO, will provide an update on our fourth quarter financial results and 2026 financial guidance. And Lai Wong, president and global head of R&D, will discuss our R&D and pipeline progress. We will then open the call to questions. Joining the team for the Q&A portion of the call will be Xiaobin Wu, President and Chief Operating Officer, Matt Chalas, General Manager of North America, Mark Lanasa, CMO for Solid Tumors, and Amit Agarwal, CMO for Hematology. I'll now pass the call over to John. John?

Thanks, Dan, and thank you everyone for joining us today. Q4 marked another solid quarter of execution and a really strong finish to the year. And what a year it was. 2025 certainly lived up to its promise as a year of inflection for B1. From a financial perspective, we delivered on our commitments, achieving significant product revenue growth, gap profitability, and meaningful cash flow generation. In 2025, our foundational BTK inhibitor Brukinza became number one, both in the US and globally. And as you can see on this slide, the gap between Brukinza and the competition is widening. And that's not just a commercial achievement, it's a scientific one. Brukinza's long-term data have consistently raised the bar in CLL, setting a new standard for efficacy and safety. These results are reinforced by an expanding body of clinical and real-world evidence, all of which support the program's best-in-class hypothesis. CLL is a $12 billion and growing market due to remarkable therapeutic innovation and improvement in patient outcomes over the past 15 years, but it wasn't always that way. As recently as the mid-2000s, patients with CLL received fixed-duration chemo, and outcomes were quite poor. In fact, the median progression-free survival for patients taking chlorambucil was less than one year. In 2008, bendamustine was approved and used in combination with rituximab, and the use became widespread, providing substantial benefit over the first chemo-based regimens. Six-year progression-free survival increased to 32%, which was better, but still not great. The FDA approval of ibrutinib in 2016 marked the first chemo-free option and a seminal innovation for patients. Anchored by data that were superior to chemo, the field switched away from fixed-duration approaches to continuous BTK inhibition. Why? Because it provided the best long-term outcomes for patients. you can see ibrutinib's six-year progression-free survival and overall survival of approximately 61% and 77%, respectively. At the same time, the field was developing new fixed-duration treatments that were enabled by the discovery of BCL2 inhibition and the approval of venetoclax. These ven-based approaches greatly improved upon historic chemo-based regimens And they began to approach the long-term benefits provided by the two continuous BTKIs, albeit with approximately 10% delta in six-year progression-free survival. However, the VI regimen was not approved by the FDA, and the addition of obinutuzumab to Venn has significant safety challenges, which I'm going to touch on later. As good as continuous use of Brutinib was, the molecule was not optimized for potency or selectivity. The second approved BTK inhibitor, Acala Brutinib, was designed to be more selective than Abrutinib and to have a very short half-life of roughly one hour, with the hypothesis that these changes would translate to a more favorable safety profile, including fewer cardiac adverse events. And in that respect, Acala achieved its goals. demonstrating statistically significant improvement in AFib in the Elevate-RR study. However, in that same study, Acala demonstrated non-inferior PFS compared to Ibrutinib. As shown on this scatterplot, Acala's six-year progression-free survival and overall survival of 62% and 76% in treatment-naive CLL is nearly superimposable on Ibrutinib. But innovation never stops. The bar set by the first two continuous treatments would be raised yet again by a differentiated foundational medicine. Enter Brukinza. Brukinza was designed from inception to be both more potent and more selective than Ibrutinib with complete 24-7 target coverage. We took that preclinical hypothesis into the clinic where in head-to-head global phase III trial, Brukinza demonstrated superior efficacy to ibrutinib and a more favorable safety profile. And this includes statistically significant improvement in AFib. And at ASH 2025, Brukinza set a new bar for long-term patient outcomes. Here, we can see six-year progression-free survival and overall survival of 74% and 84%. And adjusting these for COVID, those are 77% and 87%, respectively. Now, I really appreciate you bearing with me as I know I've spent a lot of time on this slide, but the data, as you can see here, is really important. These data clearly establish Brukinza as a foundational standard against which all current and all future regimens must be compared, and the long-term outcomes that patients and physicians should expect and demand. At B1, we believe that true innovation comes from improving upon the best. Rukinza did just that when it demonstrated superiority in terms of safety and efficacy over Abrutinib. No other BTK inhibitor can make that claim. Here we see the Kaplan-Meier curves from head-to-head trials of Brukinza and other BTK inhibitors versus Ibrutinib in relapsed refractory BTK-naive CLL patients, and this is as assessed by Independent Review Committee, or IRC. In all of these studies, the IRC-assessed PFS is the predefined key secondary endpoint to demonstrate superiority over Ibrutinib. In the Alpine trial, Brukinza showed the greatest early separation from Ibrutinib and remained separated, with a hazard ratio of 0.69 and a p-value of 0.001, demonstrating statistical superiority on PFS. We presented longer-term follow-up data from that study at ASH just a few months ago. In the ElevateRR study, Acala showed early PFS separation from Ibrutinib, albeit less than Brukinza. But that early separation was not sustained. As you can see in the middle chart, Acala crossed over and became numerically worse than Ibrutinib at roughly 33 months. Elevate RR ultimately reported a hazard ratio of 1. And this brings me to Pertobrutinib, a non-covalent BTK inhibitor, which recently reported data from its head-to-head trial against Ibrutinib in CLL. On the right, we see the curves from relapsed refractory BTKI-naive cohort of BRUIN 314, which comprised two-thirds of the enrolled patients in that trial. You can see that PERTO, with only 18 months of follow-up, shows the least early separation versus ibrutinib, with a hazard ratio of 0.845 and a p-value of 0.4102. We need to see much longer follow-up from Bruin 314 based on the minimal early separation in these short-term curves, and PERTO may face an uphill battle in showing statistical superiority to Ibrutinib in PFS. Now, if you've learned anything about B1 medicines over our 15 years of existence, it's that we're never satisfied with the status quo. And despite the incredible progress the industry has made, it's hard not to dream about the next chapter of CLL innovation. And we think it's time to start talking about a cure. And with that, we propose three aspirational goals for the next wave of innovation in CLL. The first one is an obvious one, life expectancy equal to that of the general population, match for geography and age, for any patient diagnosed with CLL. Second, for patients who prefer a time-limited therapy, any regimen must deliver long-term outcomes that are at least as good as the best continuous treatment available. And finally, any treatment designed to offer long-term life expectancy must also deliver quality of life, ease of use, and convenience. Applying these aspirations to the scatterplot clearly implies the need for further improvements on what's currently available. And we do believe that B1 is the only company with the foundational assets in our CLL portfolio and pipeline to take us there. The next chapter of CLL innovation is going to come from options that address the unmet needs and deliver the best long-term outcomes for patients. So what about fixed durations? There's a clear desire from some patients and physicians for fixed duration options that provide a break from treatment. For fixed duration to change the treatment paradigm, it must elicit a deep response, demonstrate sustained progression-free survival, be safe with only minimal affection risk over continuous BTKI, and be convenient to administer. And we would argue it must be compared to the foundational CLL medicine, Brukinza. Naturally, patients want to be off treatment, but just as they want to know what they're gaining, every patient also wants to know what they're giving up. If that's overall survival, it's important that this is considered in the shared decision-making. So how do current fixed-duration options compare to Brukinza? In our opinion, not very well. Existing Venn-based BTKI regimens have liabilities that have limited their uptake and approval. These include underwhelming efficacy as seen in the Amplify trial, where the AV combination had an inferior depth of response compared to chemo, demonstrating an undetectable MRD of only 34%, despite Amplify enrolling a young, fit, and low-risk frontline population. In fact, AV's PFS at three years follow-up was roughly the same as Brukinza's at six years. And it's quite noteworthy that we haven't seen an updated cut from Amplify for nearly two years. And similarly, with respect to safety, AV and VI have limitations due to VEN, a less potent and less selective first-generation BCL2 inhibitor. In terms of convenience, the low depth of response for AV may result in most patients having to be treated for far longer than one year to reach an undetectable MRD. In addition, VEN requires cumbersome patient monitoring due to its long half-life and TLS risk, which calls into question the convenience benefit of this all-oral regimen. At the highest level, the primary benefit of fixed-duration therapy is the treatment-free interval, during which patients are not exposed to the potential side effects of ongoing therapy. In CLL, this means avoiding the agents that suppress rapid B-cell expansion, which allow for immune recovery and a reduced risk of infection. So fixed-duration therapies should lower infection risk over time, not raise it. The CLL17 trial studied fixed-duration VO and VI versus continuous ibrutinib, and it was presented at ASH a few months ago. The chart on the left shows the CLL17 trial data, which tells a clear and quite concerning story. First, after one year of VO, severe infections continue to climb for three years while the patient was off treatment. as seen in blue. These infections are serious, often requiring hospitalization and IV antibiotics. Second, even after four years, severe infections were still higher with VO than with continuous ibrutinib, despite the three-year treatment-free period. As a reminder, Rukinza demonstrated roughly one-third fewer grade 3-4 infections versus ibrutinib in the Alpine study. The VO arm also showed a 67% nominally increased risk of death versus abrutinib. These findings are quite consistent with data from other recent studies, such as Amplify, where the AVO regimen was not FDA approved. In fact, the FDA specifically called out the higher death rate due to infections from the AVO arm. In our view, this profile stands in direct opposition to what patients want and deserve from a fixed duration treatment. And if you now look at the table on the right, for the highest risk patients, roughly half of all CLL patients, VO shows notably lower PFS. This data shows that patients have an approximately 50% higher chance of progressing within six years. 50%. Look, there's a narrative that the current fixed duration options are good. And if someone I love was diagnosed with CLL, my first inclination might also be towards fixed duration. But if I knew the disease had potentially 50% higher chance of progressing within six years, and If I knew that fixed duration wasn't reducing the risk of serious infection over four years, just accelerating it into the earlier years, I certainly would encourage them to think twice. The risk-benefit profile of current fixed duration regimens simply does not justify a shift away from established continuous BTKI therapy. The evidence that existing time-limited therapies may not provide long-term outcomes comparable with Brukinza continues to build. Here we can see three recently published match-adjusted indirect comparisons of Brukinza versus AV, VI, and VO, which reach that conclusion. And these reflect the early trends we're seeing in real-world data. Our goal for patients that prefer a fixed-duration treatment option is simple. We aim to develop a more efficacious, time-limited regimen that does not come with caveats or accommodations. And we believe ZS is that therapy. The clinical data being generated by combining the best-in-class BTK inhibitor with a potentially best-in-class BCL2 inhibitor just looks different. With all the caveats of cross-trial comparison, ZS has demonstrated the highest undetectable MRD rate, the highest PFS for the respective follow-up when compared to other Venn-based fixed duration therapies. ZS shows a favorable safety profile with fewer high-grade adverse events and no deaths. And in terms of patient convenience, we've not yet observed any clinical or laboratory TLS, and we're very optimistic that for most patients, Only one clinic visit during ramp-up will be required after Xanu lead-in. Today, the CLL landscape is roughly split evenly into patients who receive continuous BTK inhibitors and those who receive some form of fixed duration treatment. And currently, Rukinza captures approximately half of the continuous BTK segment of the market. CS will enable B1 to participate in the other half of the market where today we have no presence. In summary, B1 remains the only company with fully owned, potentially best-in-class assets across three foundational MOAs in CLL, Brukinza, Sonro, and our BTK CDAC. As I said earlier, we think it is time to start talking about a cure. All three of these foundational assets, whether as monotherapy or in combination, represent the next chapter in CLL innovation, raising the bar for patients everywhere. Now I'll pass it over to Aaron to provide the financial update.