All right, well, welcome to the 44th Annual TD Cowen Healthcare Conference. I'm Yaron Werber on the biotech team here with my colleague, and it's a great pleasure to moderate the next panel with BeiGene. To my left is Julia Wang, Chief Financial Officer, and then to her left is Mark Lanasa, who is the SVP and Chief Medical Officer of Solid Tumors. So team, thanks so much for joining us. We appreciate it. Thanks for having us. Thank you. It's great to be here. So lots to talk about, especially on the heels of Q4. Brukinsa continues to do very well. It grew 150% year-over-year, and 16% quarter-over-quarter. We're continuing to see a nice trend with top line growing faster than our OpEx. Maybe Julia, to you, still the predominant sales for Brukinsa are now driven by the U.S. China has been growing, obviously, Europe is now growing, but Europe is not fully ramped yet. Give us a sense on the U.S. launch, kind of where are you relative to the competition, which is mostly AstraZeneca's Calquence, in terms of taking share really in first line in the relapsed/refractory setting? Yeah, great. Always happy to talk about Brukinsa. We are pleased with our global launch trajectory, particularly in the US and EU, as you just said, Yaron. For perspective, if you look at last year, our global revenue for Brukinsa achieved the blockbuster status of $1.3 billion, which represented a growth of well over 100%. And equally importantly, US alone generated revenue of almost $1 billion. Now, before we get into the specifics, it might be helpful to remember that if you look at the largest indication of CLL approval in the U.S., being late January of last year, 2023 was really the first full year of real launch of Brukinsa in the US, right? In terms of the launch journey, we definitely anticipate that for a disease area that tends to compound revenue over time with a large prevalence pool of patients that tend to stay on therapy over time, we anticipate to continue the very robust growth for Brukinsa into 2024 and beyond. Now, if you look at the key drivers and, you know, kind of the enablers for our share gains that have already taken place and going forward, there are really a couple of dimensions. First of all, within oncology, we have the broadest label approvals globally speaking. We have five, and then in the United States, we so far have had approvals for four, with the fifth one in follicular pending, and the PDUFA date is in March of this year. Now, in addition to that, the totality of the data is just extremely superior, differentiated, and compelling. So you've seen the PFS data superiority actually was included into the label. But more importantly, if you look at the follow-up data that we presented at the ASH conference in December of last year, we believe we have fundamentally addressed the question that the separation in the PFS superiority between Brukinsa and ibrutinib has sustained with the follow-up data. So with all of this and our commercial execution, we are optimistic about Brukinsa truly becoming a BTK inhibitor of choice. And in terms of the share, in the U.S., I would say that, for the relapsed and the refractory setting, we are essentially on par in new patient share versus the kinda... In terms of the frontline setting, we continue to gain shares throughout 2023, and we expect that trend to continue into 2024. Great. Just remind us, in Europe, where are you in the launch right now? Where have you launched? Yeah. I think Europe is a relatively similar story in the sense that we are also at the very early beginning of a long journey of a successful launch. So last year, our total revenue for Europe reached $122 million, and the $46 million of that was in the fourth quarter, which represented a sequential quarter-over-quarter growth of about 50% when you compare versus Q3. So at this point in time, we've achieved reimbursement in all the major markets in Europe, including Germany, Austria, Spain, Italy, although Spain and Italy came online for reimbursement towards the tail end of last year. And then at the very beginning of this year, we secured the reimbursement for France. At this moment in time, we are all hands on deck, and we are very optimistic about our ability to drive patient adoption, and to very meaningful growth in Europe in 2024 and beyond. Okay. When you're looking at your sort of financial dynamics right now, revenues are growing faster than OpEx. You're definitely growing in the SG&A side more than R&D. R&D has been healthy, and you're maintaining that health investment, but you're not growing that as much. Really, SG&A is where you're investing globally. How do you think that trend continuing? Yeah, absolutely. So the financial excellence and the focus towards transitioning from cash consumption to cash generation has been a focus of our company. Over the last few years, we have invested significantly in building a end-to-end value chain, all the way inclusive of research, global development, manufacturing for both small molecule and biologics, as well as a global commercial organization in China, U.S., Europe, and other parts of the world. But we also have reached a point where we have the global scale in driving very meaningful operating efficiency. So for example, in 2023, as you just mentioned, we grew revenue very, very fast. As a matter of fact, in 2023, our product revenue grew 75% versus 2022. And I might also add, that was on top of a revenue growth of 100% in 2022 versus 2021. So the trajectory of the top line growth is absolutely there. Then if you walk down the P&L into the gross margin, we are also pleased with the progress. Last year, our absolute gross margin was 83%, and that was an improvement of 550 basis points versus 2022. So last but not least, operating expense on a non-GAAP basis, last year grew 11% versus the year before. So as you can see, the top line product revenue growth, the pace of it, was almost 7 x as fast as the operating expense growth. So fast forward to this year and next few years, the trend line in terms of continued robust top line growth coming from product revenue around the world, with a particular focus in the US, EU, and other parts of the world, in addition to China, as well as continued trending into gross margin improvement, and then continue the discipline on OpEx, management, we are confident that we have line of sight of transitioning from cash consumption to cash generation in the foreseeable future. Because in 2023, we were able to reduce our operating loss by 50% on a non-GAAP basis versus 2022. Then in terms of the resource allocation, as you just mentioned, I mean, obviously, with our scale of revenue as well as the anticipated top-line growth going forward, the deployment of our resource allocation is going to first and foremost, go to maximizing that top-line potential. Then from R&D standpoint, our growth has moderated over time for sure, versus historical levels. To get the profitability, do you need to launch more products like Brukinsa and Tevimbra? We have not been guiding, but I would say that given our current trajectory, we are optimistic that our current commercial portfolio should be able to get us there. Yeah. I want to maybe move to one area we're getting a lot of questions is the House proposed draft bill for the BioSecure Act, specifically looking at WuXi AppTec, that is the maker of APIs for Brukinsa, I believe for all the BTKs in the class and as well as many APIs. Based on our Washington Research team, it does look like that bill is gaining a lot of bipartisan support and will go into law. The question is what it's gonna look like. As you're thinking about, you know, how WuXi AppTec specifically is handled, as one of the many companies that's listed, still TBD whether there's gonna be a grandfathering period or not, still TBD. They're saying that on average, if you look at the semiconductor previous bills, ones they've put into law, there's 1.5 years to implement that. At the earliest, if they implement that by the end of the year, that gives you another year between now. So let's say a 2.5-year visibility to getting into another supplier on board. Can you give us a sense how you're thinking about that internally? Yeah, absolutely. So, as you mentioned, I think the process is still evolving, and there is time for us to take in order to get more clarity. But with that being said, you know, like many other pharmaceutical companies and biopharma, and biotech companies, we have an API, a business relationship with WuXi AppTec, a subsidiary of the company. But in that particular regard, actually, over the last few years, we have spent tremendous efforts in our globalization process as it relates to supply chain management. So, we have disclosed in our recent annual report filing last week, that we have an alternative supplier that is outside of China, and the full qualification of that is near completion. We anticipate that supplier coming online, very shortly. In short, we do not anticipate any disruption to our business with respect to the dynamic associated with the WuXi AppTec. Okay. Can that supplier handle the global chain, or is that supplier more, let's say, European, and can you ultimately qualify? Would they have more capacity? Yeah. So the idea is over time to really meet the global demand, but this is a supplier we've already made tremendous progress. But in addition to this, we have been also in very due diligence phase with other alternative suppliers, in different locations around the world as well. In terms of your internal small molecule production capabilities, can you discuss what those are? Yeah. So at this point in time, we have a small molecule manufacturing packaging capability in China, supplying the China market. And then for ex-China, we have been in partnerships with Catalent as a contract manufacturer in the United States, and that supplies the rest of the world for Brukinsa small molecule need. That's on the API side, or is that on the fill-finish? That's on the fill- finish. On the fill-finish. Yeah. ... Okay, well, Mark, let me, maybe- Let me ask about the MAIC first. Yeah, sorry. Before we move on to solid tumors, I just wanted to ask one final question about Brukinsa while we're on the topic. You reported a new matching-adjusted indirect comparison analysis for Brukinsa versus Calquence in the relapse/refractory CLL setting. This is based on the Phase 3 trials for Alpine and Ascend, and this suggested that Brukinsa had an advantage over Calquence, actually, in terms of PFS, in terms of CR, in terms of OS. Could you walk us through this analysis and how safety might have compared between the two? Great. Thank you very much for the question. So, people may recall or be familiar that, AstraZeneca sponsored a MAIC that was presented at last year's ASCO, that suggested that there was ultimately comparability between, Calquence and Brukinsa. This is something that has, been a continued point of discussion. So we believe that there are, significant limitations in that analysis, and perhaps the most important limitation is the fact that the Ascend dataset essentially ends right before the onset of the global COVID-19 pandemic, whereas much of the conduct of the Alpine study was actually during COVID-19. And there was no adjustment made for, both overall survival, as well as other safety events related to COVID-19. And, fundamentally, we think that that's a really important limitation in terms of comparing those two datasets. There are other limitations that we see in that dataset as well, for example, not adjusting for certain prognostic variables that are known to be important in CLL. So when we repeated this MAIC analysis and made adjustments for those factors, what we found was that indeed, Brukinsa does show superior progression-free survival compared to Calquence. And furthermore, we also provided data that was not previously shared, as it relates to response rate, which was superior, and also a trend to an improved overall survival. This was an efficacy analysis. There was not safety that was presented in this MAIC analysis. However, there are real-world datasets that we'll be presenting shortly that can speak to the overall experience with Brukinsa in terms of patient experience, and how that compares to both Calquence and Imbruvica. Great. Back to you, Yaron. Great. Thanks. Mark, this year, you're going to advance 5 new NMEs, and I think you just advanced, like, the CDK4 already into the clinic. Yeah. And I'm sorry, that was last year. This year, it's more than 10, including a pan-KRAS inhibitor, an MTAP co-op PRMT5, EGFR degrader, CDK, CDK2, 1 bispecific, and 4 different ADCs, and it's gonna be a huge pipeline. Yeah. On top of your BCL-2 and your BTK degrader, this is one of the best, you know, oncology pipelines in the business. Can you talk about... That's a lot to take on, right? And I think you've deprioritized a few things. But maybe strategically, how are you thinking about phase I and then a, to a quick expansion? Because these are all validated targets. Right. It's a question of getting the therapeutic window and then moving quickly into an expansion cohort. Great. Thank you very much. So, our belief is that between July of 2023 and the end of 2024, we'll bring something like 15 or 16 NMEs into the clinic for solid tumors. We believe that that is the largest number of NMEs of any sponsor in oncology, so, we realize that this is a huge transition for us. This is a really, really exciting time for us, both in terms of diversification of tumor types, our first in-house development, deep effort in breast cancer. It's important diversification in terms of targets and also modalities. You mentioned not only bispecific antibodies, additional degraders, our first degrader in solid tumor, our first in-house ADC, so it's a really exciting time. Now, I think perhaps the core of the question is, in a way, we're a mid-sized organization with a large-sized pipeline at this point. So this is something that the team and I have been thinking a lot about, is how can we confidently deliver all of this new work? I would simply say that I am confident that we have the resources, the systems, the structure, and the people in place to deliver these phase I studies. Internally, what we're calling it is our fast to POC strategy. So as we bring these molecules into the clinic, we ask very specific questions about safety and PK, of course, but also have specific translational aims to make sure that we're hitting the biology in the way that we expect to, based on our preclinical data, but also that we ultimately have clinical go/no-go criteria that are anchored to what we think would be differentiated and clinically meaningful. We have also built umbrella studies that we're now leveraging in the phase II space, that we think we can quickly move molecules from phase I into these multi-cohort studies, which again, have both speed and operational advantages. So I, I do think that we're in a very good space as it relates to delivery this year. Next year will be another story indeed as, as you said, we're optimistic that a number of these targets will be successful. So as we think about ramping up multiple programs concurrently and having more NMEs again next year, it's going to be a very exciting ride. So if I could ask about some of these assets specifically, I wanna start off with your CDK4 inhibitor, which is now in phase I. How do you think your molecule stacks up against Pfizer's, which recently entered a phase III study in breast cancer? Right. So, we're very excited about CDK4 and believe that it has potential to be a foundational asset in breast cancer. CDK4/6 inhibitors have had tremendous benefit to women with hormone receptor-positive breast cancer. The preclinical data or the translational data suggests that most of the cell cycle benefit comes from CDK4, and a lot of the hematologic toxicity comes from CDK6. Therefore, having a more potent CDK4 with greater selectivity over 6 has the potential to improve upon CDK4/6. We acknowledge that we're behind Pfizer by 18-24 months, and that they're already in phase III. Nevertheless, in vitro cellular assays, our molecule is approximately four times more potent in terms of CDK4 targeting and is about twice as selective, four versus six, in the Pfizer molecule. It is our belief that that magnitude of preclinical differentiation makes it reasonably likely that we'll have clinical differentiation. And so far, this is a two-horse race, so we believe that we have the potential to have a best-in-class molecule. Again, it comes back to, timely and essentially excellent delivery, but that study is off to a great start. It has been in the clinic since December of last year. We're quickly progressing through our early dose escalation, and we're confident we'll be able to maintain competitive timelines. Any sense for when we can get data for this? I wouldn't want to promise, but acknowledging that this is a really important molecule, we are hoping in an upside case, we'll be able to share our initial data at the San Antonio Breast Cancer Symposium. I see. And then moving on to your PRMT5 inhibitor, I mean, this is another situation where you're going to have based on competition from Amgen and Mirati- Yeah. which is already right out of phase I data from there, also MTAP-cooperative PRMT5 inhibitors. Yes. So why did you decide to pursue this program, despite the fact that there are these other assets here, and what are some differentiating features between yours and their molecules? Right. So a point I'd like to make is that, for things that we're bringing in the clinic, we must have an internal belief in preclinical differentiation, that we think that there's something that has the opportunity to give us a best-in-class molecule. We really are not interested in doing me-too work. So for PRMT5, we think the key attributes of the molecule, given the likely tumor types for development, including lung and head and neck cancer, perhaps GBM, are potency, selectivity, and CNS penetration. And we believe that our molecule is potentially, again, best in class and has preclinical differentiation around all of those parameters. We do think that we have meaningfully greater potency than the Amgen molecule. The Mirati molecule is a relatively potent molecule, however, our belief is that it does not have CNS penetration, and that's ultimately going to be a challenge, again, in these tumor types, particularly in lung cancer, where CNS metastases are common. So, again, if we didn't have belief in this preclinical differentiation, we probably wouldn't bring it into the clinic. But we, again, do believe we have a potential best-in-class molecule, and that's why we're proceeding into the clinic, even though we're behind these important competitor molecules. All right, that makes sense. And then, sorry, to kind of hit through all of these- Please. -targets. Another one I want to talk about is your pan-KRAS inhibitor, and I kind of want to talk about the approach more for this one. What do you think are the advantages of doing pan-KRAS, as opposed to a KRAS mutant selective or even kind of pan-RAS? Right. So it is a bit of a Goldilocks position in that you're in between the two ends of having mutant-specific, potentially covalent inhibitors, like the initial G12C inhibitors, again, from Amgen and Mirati, versus the Revolution Medicines pan-RAS molecule. So for the advantages over the mutant-specific inhibitors, ultimately, our molecule is a non-covalent on/off inhibitor, so it covers all KRAS. When this journey started preclinically 18 months, 2 years ago, there was concern about the safety of broadly inhibiting KRAS, but I think with the advent of moving pan-RAS inhibitors into the clinic, there's increasing confidence that the preclinical data, which showed that that's likely to be safe, is correct. So it really is going to come down to efficacy and durability. So I think the advantage over the mutant-selective inhibitors, of course, is simply breadth. That in lung cancer, yes, G12C is the most common single mutation, but that only covers about half of the KRAS mutations in non-small cell lung cancer. So wouldn't it be ideal to have a molecule that could more broadly cover all the KRAS mutations? This also would cover important mutations in colon cancer and pancreatic cancer and others. Now, as it relates to the differentiation between KRAS and a pan-RAS inhibitor, all of these RAS signaling molecules have relatively pleiotropic effects. So we think that having a KRAS-specific molecule will have advantages over a molecule that also inhibits NRAS and HRAS. That is reasonably likely to have safety differentiation, and then there's also some clinical data that shows that HRAS and NRAS are important in immune function, and having broad RAS inhibition could impact both T cell proliferation as well as T cell activation. So, we think that we're on, again, a good middle path with a pan-KRAS inhibitor and excited to get that molecule into the clinic in the second half of this year. Great. Yaron? Can you talk a little bit... You also have a, an EGFR degrader. Yes. Can you talk about that and how that could be ultimately differentiated by indication, even from the inhibitors? Yes. So, we have a degrader that's already in clinic that's targeting BTK, and we're very excited about that molecule. We shared some data at ASH. We'll have more data at EHA, so we have great belief in our platform. Now, the EGFR degrader is fundamentally different from a BTK degrader in that for BTK, we know that it's okay to just essentially degrade all the BTK. But for EGFR, we don't want to degrade all the EGFR, so our degrader does have selectivity for mutant over wild-type EGFR, and therefore, this will be a lung cancer drug. It'll be specifically for the spectrum of mutations that occur in exons 19, 20, and 21, so we will be developing this in lung cancer. The clinical challenge today is for patients who have had a third-generation inhibitor, that there is essentially a spectrum of resistance mutations that occur after treatment with the third-generation inhibitors. It's very difficult to address a substantial proportion of those patients with a conventional tyrosine kinase inhibitor, and therefore, a degrader provides potentially a new way to approach this, and we believe that we have the opportunity to have a first-in-class EGFR degrader that could have big potential. Now, if you go a step further and think, well, this could cover many of the EGFR intrinsic resistance mutations, and it reduces or it eliminates the scaffold function, which is to say, when it degrades mutant EGFR, that complex dissociates, and it covers the primary mutations in exon 19 and exon 21. Shouldn't it also have the potential to be better than the third-generation inhibitors? So that's our hope, that's our aspiration for the molecule. We will initiate development in later lines in EGFR pretreated patients, but certainly we'll look to have line of sight to thinking about early line, earlier line opportunities in EGFR mutant, but EGFR naive patients. All right. Kind of saving some of the best for last, it's the ADC platform. So you have four new compounds coming through, an FGFR2b, a B7-H4, B7-H3, and a CEA. Of those three are internal, I believe one's from Duality, correct? Yep, the B7-H4. The B7-H4. Can you talk about how is your platform and, and Duality frankly differentiated from, let's say, Daiichi, from... There's a lot of competition in these spaces. Right. So all of our internal and the Duality molecule have a TOPO1 payload. What we have built in our internal platform technology for ADCs is we have proprietary technology related to the hydrophilic linker, which we think will help with the bystander effect. We also have proprietary technology related to site-specific conjugation, which allows us to have a high DAR with very high consistency, meaning that all of the molecules have DAR of 8. So our 3 internal molecules have a DAR of 8. The Duality molecule has a DAR of 6, and we think that these features make, again, make it reasonably likely that we will have differentiation from the Daiichi DS-7300 molecule, which is currently being evaluated in B7-H3. And then we think CEA and FGFR2b are potential first-in-class or co-first-in-class molecules. There's other announced CEA targeting TOPO1 ADCs, but it's very early days in that space. Can you give us a sense, is that pipeline and that technology de novo developed in-house in BeiGene? Yes. Is this something you can license in and then build? This is internal technology. And we have also, importantly, we have developed in-house manufacturing as well, so we have large capacity for in-house manufacturing, which people may be aware is a challenge for some other sponsors in terms of the high degree of complexity that's associated with ADC manufacturing. You manufacture in Guangzhou, the same facility we do your biologics, or? Uh, yes. Yes. Yeah, that's right. Yes. It's expected to go live, as we speak, like, in the second quarter- Yeah -to go live. That's for clinical supply? Right. Do you have enough capacity for commercial or on TBD at this point? I believe the answer is yes. I believe so. Yes. Okay. How do you go about, I mean, this is such a competitive area, building this from scratch. I mean, you, you've had antibody engineering capability. Mm-hmm. You obviously have small molecule capability. Can you talk about how do you put together an ADC platform? Again, the credit goes to the research organization and the desire to have differentiation. So thinking about what were opportunities to build a differentiated platform that, again, is reasonably likely to yield clinical differentiation. We do think that there's the opportunities, particularly for interval improvements in the linker technology. As I mentioned, not only the hydrophilicity but the stability. It, it's all about, fundamentally, what we're trying to do is deliver chemotherapy in a highly targeted and selective way, and incremental improvements in the technology can improve that therapeutic window, again, which has the potential to improve the clinical responses and durability of those responses. So the- TOPO1, some are inhibitors, so it's good. TOPO1, is that differentiated? That's fully commoditized, isn't it? This is a unique TOPO1 inhibitor, but my understanding is that there's only so many ways you can tweak TOPO1 and still retain some of the activity, and still retain the core activity. But it is a potent TOPO1 inhibitor. Yeah. Maybe finally, atezolizumab, Roche recently released some positive data in gastric, considered to be positive. Yeah. We're still waiting for the final lung threshold and cut. I think for you, you're really only focusing on lung at this point in combination with this. They have the head against Keytruda. We might get the data next year. I think you'll complete enrollment soon. How are you thinking about TIGIT as a partner? We had moved quickly into phase III, in the PD-L1 high non-small cell lung cancer population, based upon the strength of proof of concept in Cityscape data. But from there, we started a group of five randomized phase II studies. We presented, unfortunately, at ESMO last year, that there was not incremental benefit, with the combination of tislelizumab plus atezolizumab in cervix cancer, hepatocellular carcinoma, esophageal carcinoma. Nevertheless, as you point out, we will complete enrollment in our phase III study in non-small cell lung cancer this year. While that is, we acknowledge the risk in that study, it has tremendous upside, both in terms of a co-first-in-class opportunity, in non-small cell lung cancer for atezolizumab, but also for tislelizumab as well. Well, Julia and Mark, great to see you. Thanks for joining us. We really appreciate it.