Excellent. Good afternoon, everyone, and thank you for joining us at the Citizens JMP Hematology and Oncology Summit. It's my absolute pleasure to welcome the next presenting company, BeiGene, presenting for the company, not one, but two, you know, of the key members from management, Mark Lanasa and Mehrdad Mobasher. Welcome, guys. Thank you very much for joining us. As you know, you know, when I'm doing these webcasts, I never know exactly who's in the audience, whether they know BeiGene or not. So for those who might not know, I would love for, you know, one or other of you to take maybe two to five minutes to give us a high-level overview of the company and, you know, kind of what are the most promising key pipeline candidates before we dig into some of the specifics. Thank you very much, Ryan. And Mehrdad, okay, if I start? Sure, you start and we'll tag team, yeah. Okay, super. Thank you. So thank you again for having us today. So BeiGene is a mid-sized oncology company. We're a global company with approximately 1,100 employees globally. We have two globally approved commercial medicines, those being Brukinsa and Tevimbra, our BTK inhibitor and our PD-1 inhibitor, respectively. We have a very large and growing pipeline. We have a preclinical research team that's one of the largest oncology dedicated teams in all of pharma, with over 1,100 preclinical research scientists. This group is our discovery engine that fills our pipeline with what we think are compelling new molecular entities. And we've taken a bit of a different approach where we are modality agnostic, and really what we think about are priority tumor types and targets. And it is our stated vision to bring eight to ten NMEs into the clinic each year. Indeed, this year in 2024, it's been a very exciting year. We've already brought ten NMEs into the clinic, nine for solid tumors and one for immunology and inflammation. And we are in the solid tumor area, very excited that we're building franchises in lung, GI, and new this year, breast cancer. Some of the molecules we're excited about that hopefully we'll touch on later today. In addition to our immuno-oncology portfolio is our CDK4 selective inhibitor. We recently had our first patient dosed with our pan-KRAS inhibitor. And we have a series of in-house ADCs targeting CEA and B7-H3, as well as a licensed ADC targeting B7-H4 that are progressing well through early phase development. Thank you, Mark. And if I may chime in, so great background from Mark about BeiGene. But BeiGene is still a relatively young company. That's why some of your audience might not know a lot about us. When you think about only 10, 14 years and achieving all this, I think it's important to mention. And I think one of the reasons that we are successful is that from the beginning, we were built differently. There was a vision and mission to really focus on science and make medicines based on the deep science and understanding of our unmet needs of patients and our unmet needs of targets to make these innovative medicines and make them accessible around the world. And I want to talk about hematology now. I want to talk about Brukinsa, our BTK inhibitor that Mark also mentioned. I think that's a testament to how BeiGene worked. It's now best-in-class BTK inhibitor, five labels, which is the largest label of its class, including a follicular lymphoma label that no other BTK has, but it also shows how the asset was actually designed and engineered and developed globally. And now it's approved in more than 70 countries. And most importantly, is also, you know, for patients, it's not just approval for them to be able to have access. So with all of that, it's really differentiated how we worked on developing Brukinsa, generating data that showed its true best-in-class status. And then, we think now that we have our cornerstone asset, now that we claim to be leaders in hematology and particularly cemented our leadership in CLL, how we can grow and expand our leadership. And that's where our best-in-class BCL-2 inhibitor and a novel approach to the target, the degrader, our BTK degrader comes to play. Excellent. Well, you know, before we jump into, you know, maybe some of the specifics of some pipeline products, I'd be remiss if I didn't ask at least some questions about your flagship product, Brukinsa. We just were on a KOL call right before this where Brukinsa was mentioned and was given as a great example of, you know, not necessarily first to market, but best in class, you know, and clearly kind of taking over the market, and I believe from the last, you know, earnings call, you mentioned that this was the number one BTK prescribed in the U.S. I think you reached that status. It seems to me that, you know, the ALPINE study was extremely well received by the physician community, continues to, you know, generate a lot of usage. Can you talk a little bit about the longer-term follow-up from these studies or even newer studies, you know, that you think investors should be focused on that will continue to drive Brukinsa's upward trajectory? Thanks, Reni, and thanks for mentioning Brukinsa. If you didn't, I would have. But actually, this is a good slide to put up for several perspectives. First of all, this is our head-to-head study of Brukinsa versus ibrutinib. And to your left, you see the PFS curve in ITT in overall population because ALPINE enrolled all relapse refractory patients. And you see the hazard ratio of 0.68 and the p-value that's associated, statistically significant and really meaningful clinically for patients. And here you see that this follow-up was at 42.5 months. So this is the data which was just recently published in Blood. So we showed at ASH 2022, the first time ALPINE PFS came out, we showed at ASH 2023, the second time that we had a follow-up of ALPINE, and we just published, even with more follow-up compared to the ASH presentation in Blood Journal. That actually shows one of our, you know, commitments to continue to generate data when the data is important to put it out for physicians and patients to know it. So this is a very long follow-up of that head-to-head study that you see. And on the right, you have put the panel of the specifically high-risk patient population of del(17p) and TP53. Now, with this very long follow-up of 42 months, you see that the risk reduction is almost 50%, meaning the risk of death and progression for patients who receive Brukinsa compared to those who got ibrutinib is 50% less. And these two are same drugs from the same class. So this is a really clear indication that the Brukinsa is a differentiated drug compared to ibrutinib. And also important because acalabrutinib did a study in del(17p) population and that published, and actually the only published their primary analysis. We haven't seen further follow-up of that study, but as you have put in the slide, the hazard ratio was one, so basically non-inferiority. And you can look at our curves, how they continue to be nice and split. But when you look at ELEVATE-RR at that 42-month landmark, it seems like the curves are going in the wrong direction. But again, like I said, we haven't seen the follow-up, but we are committed to do that. SEQUOIA is another important study that we have in frontline CLL. And at this ASH, we have an abstract, and I was talking to one of the KOLs, and he was saying SEQUOIA is by far one of the most important and relevant CLL studies at this ASH because, of course, we published a primary analysis of SEQUOIA too. But with those frontline patients, they want to see longer follow-up in CLL. And now we are showing them this very long follow-up and makes them very comfortable that the PFS that we saw with Brukinsa is sustained now after 60 months of follow-up and competitive to other drugs. And interestingly, you see here in ALPINE del(17p), also in Sequoia, we see whether the patients have high-risk features or don't have high-risk features. So in Sequoia, we show IGHV status. Brukinsa still does very well in patients that have sustained PFS. There are some interesting dynamics that we're trying to wrap our heads, you know, around, and I'd love to kind of get your thoughts. In the BTK space, right, there's some new approvals, there's patent expirations that are coming up. You know, can you talk a little bit about how you see these playing out and what your expectations might be, you know, for, call it like the next year? Sure. In terms of Brukinsa's patent, we know that the patent is strong and has a pretty, you know, good runway. So we are not nervous or worried about our own patent. There's some other BTK inhibitors that the patents are expiring or reaching IRA, but we have shown that Brukinsa is a differentiated drug. When you see the risk reduction of 50%, it is very difficult to assume these two drugs are the same. So Brukinsa is a different drug than the drug that is on IRA or the patent that has expired. And we're only showing efficacy here. We have shown safety as well. So in ALPINE, we had six patients who had sudden cardiac death among many, many others of cardiac toxicity of AFib,A- flutter, and all that. And that's not something that we want our patients to have, the sudden cardiac death, some of them without any cardiac history. So both in terms of safety and efficacy, Brukinsa is a very differentiated drug. And we don't have a head-to-head study of Brukinsa versus acalabrutinib. I just mentioned the difference of the same curve in ELEVATE-RR analysis. We have done matched adjusted analysis. And in fact, independent of us, Mayo Clinic did a network meta-analysis for efficacy and safety. And they actually point out to many of the safety superiorities of Brukinsa, including atrial fibrillation, because we always knew about ibrutinib. Acalabrutinib was specifically made to be a safer drug. But even when you compare our numbers versus their numbers, we have the lowest number of all-grade and particularly high-grade atrial fibrillation. The cleanest cardiac profile, not a high risk of infection, those adverse events that really bother patients' daily life, like GI toxicities, diarrheas, headaches, all those. That all plays into the distinct safety profile of Brukinsa. That's why I think this extent of risk reduction and efficacy coupled with the very distinct safety makes the drug very different. In terms of approvals, one of the approvals that are coming, we expect to be non-covalent BTK inhibitor, pirtobrutinib. We know they have an accelerated approval post-BTK inhibitors and post-BCL-2 inhibitors, and that's where they are being used. They have a phase 3 study that has read out actually for quite a while. At ASH this year, we will see the data for the first time. I have only seen the abstract. I haven't seen the full data set to make a better assessment. But what we have seen, what is known, it seems like they had their primary analysis, and then for some reason, they had to extend their analysis from that first six months to 11 months. And they haven't given us much data in that abstract other than the hazard ratios. But again, I really need to see the curves and see how pirto is behaving as a salvage treatment because that study was also a salvage treatment. But we think now for first-line treatment, Brukinsa stays as a best-in-class drug. And with KOL discussions that we have, even those who know the pirto data, they all really believe about how they're going to sequence their treatments. And they want to make sure they use their covalent BTKs, and they want to use their BCL-2s that they have in hand. And then for salvaging those patients, those patients use pirto. So the expectation is, we'll see the data, but the expectation is usage will be there for those later-line patients. Got it. So before we switch to the solid tumor franchise, maybe, you know, we have ASH coming up at the end of this week. Can you maybe help guide investors, maybe help us hone in on what might be the one or two most important kind of Brukinsa posters that you think, you know, are a must-see for investors? I would imagine the follow-up for SEQUOIA is one of them, but correct me if I'm wrong. And then also related to the pipeline, you know, you had mentioned the BTK degrader, right? You have a BCL-2 degrader. Would love to kind of get, you know, kind of the key maybe things at ASH that we should be focusing on for the pipeline as well. Sounds good. You're absolutely correct. I love that you put our new publication from Blood on ALPINE here. I want to make sure everybody is aware that it's published in Blood and they have more data. SEQUOIA will be a key abstract and presentation at ASH, and I want everybody to look at the abstract and look at the presentation. And again, it really shows Brukinsa continues to have sustained efficacy regardless of risk features. Safety is very tolerable. We have done exposure-adjusted analysis of safety and received, for example, rates of hypertension, AFib, and all that in Brukinsa is similar to background. So pretty much at that age, you expect some of these things. So it gives a lot more confidence to physicians out there about prolonged and long-term follow-up of safety and efficacy. In fact, as I mentioned, we are really committed to look at a lot of to present data. We have gone even to our phase one and phase twos that we started with Brukinsa because we always put them in what we call them a long-term extension, a rollover study. We looked at our patients and now published data on, you know, 70-something, 80-something month follow-up of those patients with monotherapy or in combination with obinutuzumab, anti-CD20, and I think what is the PFS curves look like the same as these, so a really nice extension of PFS. PFS is sustained. Safety remains the same. No real increased toxicity, and in fact, some of rates toxicities decreases with time, which happens a lot with CLL patients, but really, really deep responses, which is what across the board we have seen in ALPINE, we have seen in SEQUOIA. But now we are looking at some CR rates that we have never seen before with this monotherapy of BTK inhibitor and a combination of BTK and an anti-CD20 antibody. Going to the pipeline, I think there are a couple of things that I want everybody to be aware of. We have our BCL-2 inhibitor, sonrotoclax. We also believe that sonrotoclax is a best-in-class BCL-2 inhibitor. We now have 1,300 patients treated in that program across different diseases and indications in monotherapy and combinations. And given what we know about its potency and selectivity, and particularly its PK profile and no drug accumulation, we see deep responses, durable responses, and a very safe and tolerable regimen. So at ASH, we are putting a treatment naive cohort of more than 100-something patients that were treated with doublets of Brukinsa and sonrotoclax in frontline CLL. Safety is really, I think, the most important part to compare because we know venetoclax ibrutinib has so much toxicity that wasn't approved. No COVID death with this combination, no TLS, and we showed really high rates of undetectable MRD. You have seen even the abstract, about 90% plus by the end of one year. That gave us confidence to start our phase 3 study, CELESTIAL-TNCLL study, which compares our doublet versus fixed duration versus fixed duration of venetoclax obinutuzumab, which is the only study of head-to-head superiority versus the real standard of care fixed duration, which is venetoclax obinutuzumab, and it's doing very well. I also want to briefly talk about our BTK degrader. We really believe about the promise of degraders and how they can be more potent than inhibitors and also overcome or address or prevent the mutations that might arise when patients are on inhibitors. We have a pretty comprehensive phase 1/2 already. We have enrolled more than 350 patients on that. We are presenting three cohorts from that study. One is in CLL, which is our first focus. The second one is in Waldenström macroglobulinemia. We have really exciting data and also in indolent lymphomas of follicular lymphoma and marginal zone lymphoma. We are very excited with the data that we see some striking efficacy in terms of very deep responses of CRs. Responses are early. Patients feel great. The cytopenias resolve very fast. The responses, as I mentioned, are deep, deepen, and are very durable among all these diseases. So we have all these three abstracts being presented at ASH, and I think it would be one of the highlights of ASH, at least for us. Excellent. Well, thank you very much for that. Looking forward to seeing that when we get down there. Maybe switching gears to solid tumors. Without even getting into Tevimbra just yet, I know, Mark, you mentioned that, hey, this is one of the approved drugs that are there, and you just got European approval, if I remember correctly. So congratulations on that. Thank you. But you do have some pretty impressive, or sorry, some novel data coming out at the San Antonio Breast Cancer Conference that I'd love to kind of spend the remaining time chatting about. Can you talk to us a little bit about what to expect, you know, at San Antonio Breast Cancer regarding the CDK4 inhibitor and maybe what kind of advantages you feel, because all your molecules, right, ultimately are kind of like fast followers, but have the potential to be best in class. So what kind of advantages do you think your molecule might have over currently, you know, marketed CDK4, CDK6 therapeutics? Great. Thank you for the question. And I would agree that many of our molecules are fast followers designed to be best in class, but we are also aspiring to develop first-in-class medicines as well. For example, we're hoping to have our EGFR degrader have its first human dose before the end of the year. We believe that it will be a potentially first-in-class medicine for patients with EGFR mutant non-small cell lung cancer. But going back to CDK4, CDK4/6 inhibitors have had tremendous positive impact for patients with advanced and now adjuvant breast cancer. However, the challenge that's encountered is that about a third of women will have to down-dose because of toxicity, either GI or hematologic toxicity that's largely driven by the CDK6 component. Most of the cell cycle inhibition effect comes from the CDK4 component. Therefore, by having a highly selective CDK4 over CDK6, it has the potential to be a better-in-class medicine than CDK4/6 inhibitors. We're very proud and excited that we have enrolled over 100 patients into our phase 1 study in just under a year. We'll be sharing our first data at San Antonio next week because it turns out that, of course, we were enrolling monotherapy before we enrolled combinations. We have generated data in combination with both fulvestrant and with letrozole to give us line of sight to second and first-line opportunities. The majority of data that we have with some reasonable level of maturity is monotherapy data. Therefore, the focus of our upcoming presentation at San Antonio will be largely on monotherapy safety and PK. Nevertheless, we're excited about the data that we are sharing, and we think that the emerging data are consistent with our clinical hypothesis of what a CDK4 selective inhibitor might be able to deliver compared to a CDK4/6 inhibitor. Something that we always ask, and I know the full data will be reported, is just maybe to help set investor expectations, right? You mentioned how many patients, I believe you said, you know, 100 have already been enrolled. You know, are we expecting to see both safety and efficacy data, or is it primarily a safety update? And kind of as we think about, or as you, you know, evaluate this drug kind of going forward, what's kind of your go, no-go, you know, hurdle, if you will, right? Or expectations that you'd like to meet? So we are sharing principally safety data. There's essentially no efficacy data in the upcoming poster to be presented. It's simply too immature. We did not have an expectation of monotherapy efficacy, so that's why we're focused on primarily safety and PK. We think that the key efficacy data are going to come out of the combination cohorts, which are enrolling extremely well. But the reality is we need to have at least, say, three months of follow-up on patients to have any sense of how the efficacy data are emerging. Again, we're pleased with what we're seeing, but we're not ready to present those data yet and are hoping to share those at an upcoming conference in 2025. It's certainly our interest to have those data be in the public domain so we can engage investigators in a conversation of why they would want to participate in phase three studies with our molecule. So the go, no-go criteria, that's a very important point. I would say there's three components. So one, of course, is safety, that we have a core hypothesis about improvement of a safety profile. Another is PD, pharmacodynamic activity. There are measures of detecting the level of cell cycle inhibition that we think are important. And then finally, of course, is efficacy. We would want to have confidence that we can provide a better treatment option initially for patients in a second-line setting, but ultimately for patients who are CDK4/6 naive in a frontline setting. Mark, so what would be that? Yeah, I just don't know it offhand, right? If I'm thinking about second line, what's currently being used, right? Like we always have our bug of, oh, I want to be like 25% better, 50% better, you know, those, you know, are all there. Can you help us maybe think about that? Yeah, I think that in breast cancer, certainly there is substantial unmet medical need, but the current therapies are reasonably effective, and therefore, really what we're looking for in the breast cancer space is duration of disease control. Objective responses are important, but durability is as important or is more important. This is a place where there's a lot of change right now, so the SERDs are coming online for patients who have ESR mutations. There are other biomarker-selected treatments that are becoming available for patients with PIK3CA alpha mutations, so therefore, we think that we're in a great situation that prescribers will have a menu of different options they can consider for their patient, and therefore, we want to offer a fairly substantial benefit in terms of efficacy to have a patient switch their 4/6 to a 4 plus ovarian suppression as their next line of therapy. Ultimately, in due course, we would like to enable optionality with these other mechanisms, so what are we looking for? Yes, 30% improvement in terms of durability in that type of setting, and then that magnitude of benefit is a very large magnitude of benefit indeed in a frontline setting. Got it. You have, you know, quite an impressive, you know, just solid tumor oncology portfolio. You know, I kind of just thought about the CDK2 inhibitor that you're, you know, developing as well as probably the ideal combination agent. But I guess I'd love to kind of, you know, get your thoughts on that as well as frankly, there's a lot of focus in the investment world, right, for ADCs and degraders like your CDAC. Maybe in the, you know, in a couple of minutes, maybe talk through what excites you most. In breast cancer, absolutely combinations are going to be critical. Those combinations by and large, or I shouldn't say that, those combinations will be selected based upon two components. One are intrinsic mutations in the tumor, and then the second are what are acquired mutations related to the prior exposures that the patient was having. CDK2, we think likely falls into that second group that cyclin E is overexpressed based once women have had exposure to a 4/6 inhibitor. Therefore, adding a CDK2 inhibitor to that treatment combination has the potential to improve durability of responses. CDK2 is also progressing well through early phase investigation, now looking at that in combinations as well. For sure, it is our intent to begin a combination with our CDK4 selective inhibitor in the first quarter of next year. Also very interested in looking at our next generation BCL-2 inhibitor to revisit the question of could a more potent BCL-2 inhibitor bring benefit to patients who have BCL-2 overexpression with breast cancer, and then again, this is a snapshot of our portfolio today, but we will have more molecules entering the clinic next year, so there's other biomarker-selected subgroups that we have not yet disclosed yet that we're also very interested in approaching with novel agents in 2025 and beyond. And just from the, I guess, ADC, you know, portfolio, anything in particular that we should be kind of focused on? We are very happy with the characteristics of our internal portfolio. Again, sort of carrying on with the breast cancer theme, our B7-H4 ADC is progressing really nicely through early development. I believe we have a trial in progress poster at San Antonio next week. We think that B7-H4 has good developability not only in gynecologic tumors, but also in breast cancer for patients who are high expressors of B7-H4. We're very committed to ADCs as a platform technology. What you see from us in 2024 are monospecific, Topo I conjugated ADCs, but you also see that we can develop bispecific antibodies. So in 2025, you're likely to see multi-specific ADCs from us. And then in the future, we're very interested in novel payloads as well. So lots of optionality comes from our research organization as we continue to look to advance on both known as well as novel targets and novel payloads. It is one of the most exciting pipelines that we follow. So looking forward to seeing, you know, a lot of this data. And powering this is, of course, $2.7 billion in cash, which, you know, we'd be remiss if we didn't mention. These are the big milestones that we have, you know, listed for you guys, maybe just in the last minute. Anything that we're missing or, you know, maybe which are the ones that you feel are, you know, very important should definitely be, you know, we should definitely be focused on? Maybe very quickly, again, we're very pleased that we have brought the large number of molecules into the clinic for solid tumors this year. It substantially diversifies our portfolio both in terms of tumor types, targets, and modalities. Realistically, it takes about a year to have public disclosure of those data sets. So in terms of externally disclosed milestones, it'll be the things that entered the clinic earlier, CDK4, CDK2, B7-H4 that we'll be sharing early next year. But certainly, we hope to share data from some of these other programs in the second half of 2025. Excellent. I can very quickly talk about the degrader because we have a large expansion already open that can be potentially pivotal as fast track designation. And we know how the field is. So we are very quickly as that's enrolling and we're following the data with the health authorities starting the phase 3 study that you mentioned in relapse refractory CLL. We're also starting a relapse refractory CLL study with the sonrotoclax in our BCL-2 inhibitor. Also a phase 3 study in mantle cell lymphoma and also the mantle cell lymphoma is a doublet of our two drugs. And these are very important studies for you to watch, including combinations of CDAC. We have the most advanced BTK degrader, and we have started our combinations already. Excellent. Mark, we want to thank you guys very much for the update. Look forward to seeing you soon. Thanks very much. Thank you for having us.