Hello, everyone. Welcome to BeiGene's Investor Event at the 2023 ASH Conference. My name is Julia Wang, and I am the Chief Financial Officer for BeiGene. Thank you for joining us today, and we are very excited about today's presentations. But before we start, please be reminded, during today's presentations, we will be making some forward-looking statements, and our business carries risks. You can find more details in our filings with the SEC, the Hong Kong Stock Exchange, and the Shanghai Stock Exchange. With that, here is today's agenda. To begin with, John Oyler, our Co-founder, Chairman, and CEO, will kick off with an opening remark. Hi, John. Thanks so much, Julia, and thanks, everyone, for coming. You're not here to hear me give a few opening remarks, you're here for the real content. Just a quick reminder for BeiGene, you know, our goals as a company, first and foremost, are to have huge impact, and I think we're trying to become the most impactful oncology company over time. I know that's a great aspiration. I know it's bold, but it's what we've been trying to do. And for us, by most impact, that's about patients and real impact to patients. It's not dollars, it's not revenue, it's true impact, and we're really trying to do that. We're also trying to transform the industry. We're trying to do that to find a way to enable more affordable medicine and to dramatically lower the cost in the industry to do so, so that we can speed new medicine to patients, not just in the traditional places where it's landed, but all across the globe. And lastly, and of course, most importantly, we're trying to innovate, and I think today you get to see some exciting data around some of the assets where we're doing that. You know, for us, as a company, we always believe if you wanna be successful, it's nice to have a vision, but it's also helpful to have a strategy. And again, our strategy is really around a few competitive advantages. The first is trying to truly be a leader in how to do fast, cost-effective, well-designed clinical trials. We're trying to do that differently than a lot of the industry by doing it ourselves, CRO-free, working more broadly across the globe and more inclusively with more centers and more countries than has been done before. And we're trying to do it through incorporating and adopting great technology. Clinical trials, at the end of the day, comprise 75% to 90% of the delivered cost of most oncology medicines to patients, so the industry becoming as cost-effective as it can here is really, really important to be able to get medicines to patients all over the world. Secondly, it's important to get them to patients. When you have a medicine, how do you get them distributed? And I think we've built an incredible commercial organization in the second-largest market in the world, led by Eva, who's taking a picture right now, as I say her name. It's a wonderful, leading, innovative oncology organization in the second-largest market. In addition to that, in hematology, we now have built out our own organization, led by Josh, and I don't know if Gerwin's here, but Gerwin in Europe, and we're building out throughout the rest of the country. Incredible organization, doing a great job with a very successful launch of Brukinsa, and soon to launch Tevimbra, our PD-1. From an innovation perspective, we have great medicines we've put in clinic, and we've done that for a while, and the highest compliment I could get was the one I got 30 minutes ago, which was, "We like working with you because you don't put duds in the clinic." So congratulations, Lai, for not putting duds in the clinic, and those were kind words. I think we'll continue to do that, but we're one of the large innovators. Last piece is manufacturing. We learned the hard way. This is really important, the CMC, the formulation, and being able to control your destiny so that you can quickly and affordably and reliably move things rapidly as you try to develop medicines. So with that said, you don't even need to hear more from me. I'll introduce Lai Wang, who is heading our research and development. Thank you. Thanks, John. Good evening, everyone. Hope you have been enjoying us so far, and I hope you will enjoying tonight as well. So John gave you an introduction about our company's capability. I'm just gonna zoom in a little bit about innovation. To achieve innovation, I think BeiGene has done two things. Number one, we have built a really one of the largest oncology-focused research team. We have over 1,100 scientists working in the lab. This is why we can be so productive. Secondly, you know, the oncology is really not just oncology, our entire industry have been really driven by biotechnology. So BeiGene believe in biotechnology, and we're investing in the technology platform. So we have diversified the modalities being really established at BeiGene. You guys have seen we have been able to make really great small molecules with our BTK inhibitor, then later on also with our BCL-2 inhibitor. But now on the small molecule side of it, today you're also gonna hear about we're doing the protein degrader. One of the protein degraders we're choosing for the clinic is our BTK CDAC. In addition to that, BeiGene has built really a global clinical development capability. We can do everything in-house, and we're trying to really be the industry standard. We're really moving things very fast. From the protocol finalization to first patient, three months. Every dose level, 6-8 weeks. We really want to be the best in this industry in terms of execution for clinical trials. In addition to that, BeiGene has a really focused disease area, so we focus on our oncology tumor types, really build a deep portfolio based on science, and we're trying to drive to clinical POC. The value inflection points really help us to the major prioritization decisions. So with all this, we believe we can deliver innovation at much greater efficiency, probably compared to most peers in this industry. I know today is about hem, but before we talk about hem side of it, I do want to mention a few things about our emerging and really the solid tumor pipeline. What you can see on the left-hand side, there's a lot of interesting new molecule we are taking to the clinic or already in the clinic for non-small cell lung cancer, for the GI cancer, breast cancer, as well as head and neck cancer. I do want to highlight four of them. The first one is a pan-HER inhibitor. We probably have this first-in-class pan-HER inhibitor, which hits all KRAS mutations by sparing the NRAS and HRAS. This is extremely interesting. The second one is MTAP-cooperative PRMT5 inhibitor. This is a second-generation PRMT5 inhibitor, so it's not gonna hit the wild-type normal tissues. At the same time, this molecule has great brain penetration, which I think can differentiate from some of the other molecule right now in the clinic. The third one, a CDK4 inhibitor. You all know about CDK4/6 has been doing extremely well in the breast cancer, but CDK6 is believed to bring more toxicity than efficacy. A CDK4 inhibitor can retain the efficacy and sparing the hematologic toxicity, which is associated with CDK6. The EGFR CDAC is our second, the protein degrader we're taking to clinic. This one we do believe have a chance to ultimately compete against the third-generation EGFR inhibitor. With that, I'm gonna hand this over to Mehrdad to talk about hematology franchise. Thank you, Lai. Hello, everyone, and welcome to BeiGene's ASH IR this evening here in San Diego. I just wanted to start with this slide and discuss that this BeiGene ASH has been present with 24 abstracts, and this is on the four assets that you see listed on this slide, that we believe all of them have the potential differentiation and best-in-class options. So the first one is obviously our BTK inhibitor, Brukinsa. You're all probably very familiar with Brukinsa. It's the only BTK that has shown superior efficacy and safety across different indications that we have tested it, including highest CRs that we have reported among different indications. We have the broadest label globally for any BTK inhibitor. You see the five indications that we have now, and we are currently continuing to work on the, what we call it, life cycle opportunities with Brukinsa, doing other studies to maximize the way that this medicine will work for our patients. The second asset is our BCL-2 inhibitor or sonrotoclax. We have enrolled more than 600 patients in different trials with this program, and we think we have collected enough data to understand its differentiation both in terms of clinical efficacy and safety. That has enabled us to put together a pretty broad registration program, and we are at the pivotal stage that we have started a first phase III study. You saw our indications with Brukinsa, but with sonrotoclax, given the BCL2 inhibition, now we are present in different diseases. We are present in AML, MDS, and a subset of multiple myeloma that we'll discuss about a little bit later. Lai discussed about our CDAC or degrader platform. We have a BTK degrader. We have enrolled, as of today, 128 patients on this program with a lot of enthusiasm from the clinical community, and we see really clinical meaningful both in terms of efficacy and safety data, that we'll talk about that tonight as well. With the data that we have collected, we have also put a pretty robust clinical development program with our degrader, with a fast-to-market opportunity, and in the next year, we'll start combination studies and also Phase III pivotal studies. And again, with this asset, given the distinct mode of action and the potency that we see, we are gonna be present in a few new diseases, including large cell malignancies, large B-cell lymphomas, and Richter's transformation. This BTK degrader is the most clinically advanced BTK degrader, and with the way that we think we are talking about a registration, potentially might be even the first degrader to be developed and registered. And last but not least, is our PD-1 inhibitor, Tevimbra, that you heard from John. We'll talk about the abstract and presentation that we heard about yesterday in Richter's transformation in a high unmet need disease that you saw it was combined with Brukinsa, our other asset. Just briefly about BeiGene Hematology and what we are trying to do. We really think that we have cemented our leadership with Brukinsa, both in CLL and other B-cell NHLs that I talked about. Given the fact that Brukinsa is the only BTK inhibitor with superior head-to-head data and all the efficacy and safety that we have seen, and we'll continue to gain market share with other opportunities that we are doing, that I'll talk about later. The next step is that we are solidifying the leadership that we have built, both in B-cell malignancies with other assets, including our sonrotoclax, our BCL2 inhibitor, and BTK degrader, and then Tevimbra. And we are doing a few things in terms of the strategies that we are doing to increase our leadership. One of them is best-in-disease combinations. The other one is a strategic sequencing, the way that we are putting our assets in development for our patients, and also the fixed-duration therapy. And we are expanding and extending to new indications of high unmet need, as I mentioned before. And lastly, as you heard from John, we really wanna expand our footprint, both in terms of disease and the market. And I'll briefly talk about Brukinsa before we start talking about the ASH data. Again, I'm pretty sure that all of you are very familiar with Brukinsa. Well, we had a reason to believe in Brukinsa, and that was because Brukinsa was specifically engineered to be specific and potent, and most importantly, have sustained BTK inhibition. In the next slide, I'll talk about that. And now, with the clinical data that we have, we have seen the that superiority in clinical data. We have a lot of patients treated in clinical trials. We have more than 5,000 patients treated in different clinical trials with Brukinsa, so we think we have a very good understanding of superior safety and efficacy of this asset, and these are all global studies that we have done with some of the investigators that you see here. We even did two head-to-head studies versus ibrutinib. One of them is the ALPINE study that we saw superior PFS and ORR and safety in CLL, and the other one, the Aspen study, was done in Waldenström macroglobulinemia, that we saw deeper and more durable responses. I talked about the broad usage of this medicine and how we are trying to expand the usage of Brukinsa at next steps. And I discussed the reason to believe in Brukinsa, and that's how this drug was initially engineered and designed. As physicians, every time we treat any patient with a targeted medicine in hematology and oncology, we know that we like to inhibit that target as much as we can, round the clock, and as hard as we can. And that's how the Brukinsa was really designed. So, to your left, you see Brukinsa peak coverage profile, so BTK coverage over 24 hours. And the line, as you see, the flat line is what we call it, IC50. And the way that I describe it, you always wanna be above this line. So specifically for Brukinsa, that you see that both in our BID dosing and daily dosing, around the clock, so all day round, all 24 hours, we remain above the IC50. And you can compare that with ibrutinib and acalabrutinib, that neither of those two have this too coverage around 24 hours. In fact, if you look at these different curves from different publications, each of them are maximum around 6 hours of coverage. This is median, so there will be patients that will be even below this median. But in Brukinsa, with the way that this curve looks, we are confident that. And we have data that in all of our patients, we have round-the-clock inhibition. And we truly believe that's why we have head-to-head superiority, and we believe our medicine is a best in class compared to other two that you see here. These are the three clinical presentations that we have chosen to discuss tonight. The first one is ALPINE study. This year, we showed an extended follow-up of the ALPINE study, and we showed a sustained PFS response and safety profile of Brukinsa in the head-to-head study that we had done versus ibrutinib. The reason that we showed this extended follow-up was that the community, the physicians, were asking for extended follow-up. There were some discussions about the potential that, for example, ELEVATE-RR in their head-to-head study in the subset of CLL that they had, they had a smaller difference between the two R's, but ultimately, the two curves merged, and they had a non-inferiority with a hazard ratio one. Now we are showing at the similar follow-up as PFS superiority is sustained. The other question that often physicians think about and ask us is switching from another BTK inhibitor to Brukinsa. Both for patients who are not tolerant to the BTK that they are currently taking, and also if they are taking ibrutinib specifically, and they're tolerating it well, but should they switch, and what happens if they switch? We are presenting two presentations here. One is in acalabrutinib-intolerant patients, and now we see with a longer exposure to Brukinsa, this medicine is actually tolerable for patients. So the acalabrutinib intolerance events that we have, we don't see them recur, and in fact, we are sustaining efficacy. The last one, we had Aspen study, as I mentioned. Patients who were enrolled in the ibrutinib arm of the Aspen study now are within our study that we call it long-term extension, and we have switched them to Brukinsa. And even though they were on ibrutinib for more than with a median of 50 months, so a longer time, now that we have switched them to Brukinsa, we see advantage in terms of safety and efficacy. So the safety profile looks better, and in fact, we see deepening of responses. So with that brief summary, it is my distinct pleasure to introduce Dr. Maziar Shadman, who's a professor of Fred Hutchinson Cancer Center at the University of Washington. And his research and clinical focus is on B-cell malignancies and then CLL, and he will present the few Brukinsa studies that I mentioned. Thank you. Thank you, Mehrdad. Good evening. It's a pleasure to be here to briefly talk about the three presentations about zanubrutinib that we saw, and we will see actually in this meeting. Starting with Alpine, a very important study. The superiority of zanubrutinib over ibrutinib was first presented last year and created a lot of excitement in the field for the first time seeing a BTK inhibitor showing superior efficacy and safety compared to ibrutinib. So Alpine, very briefly, was a study that enrolled patients with CLL or SLL in the relapse setting. So these patients were previously treated, and they got randomized in a one-to-one fashion to receive either zanubrutinib at the standard dose of 160 milligrams twice a day, or ibrutinib at the standard dose of 420 milligrams daily until progression or toxicity. As you see, the number of patients in each arm and the patients who are receiving ongoing therapy in the zanubrutinib arm are basically 59% of patients versus 47% of ibrutinib arm patients. And these patients who discontinued therapy, there is a higher number of discontinuation in the ibrutinib arm, both because of disease progression and also for adverse events. Kind of looking at what we saw last year, this is the two-year landmark analysis showing that zanubrutinib had a superior efficacy compared to ibrutinib, with two-year PFS of 78% compared to 65% with ibrutinib. This is with a median follow-up of 30 months. As mentioned, one of the questions that the CLL field was really eager to have the answer for was: what would happen with the longer follow-up? The reason for that is that naturally we would compare this study with a similar study, ELEVATE-RR, that compared acalabrutinib with ibrutinib in the relapse setting. Different study, different setting, different time, but the fact that the curves crossed around the 33 months raised the question of what would happen to those curves with the longer follow-up. So this year, with the 39 or almost 40 months of follow-up, we're seeing that those two curves are continuing to separate, and at three years landmark now, we have 65% versus 55% progression-free survival in favor of zanubrutinib compared to ibrutinib. So one of the questions that we had in mind is now answered, and this is promising. So this is in all comers. This is the entire study population. The study was not limited to any specific molecular feature or chromosomal abnormality. So there was a predefined and pre-planned analysis for patients with high-risk disease, defined by having deletion in chromosome 17 or having a mutation of the P53 gene. Again, at three years, we're seeing that superior efficacy of zanubrutinib now at three years with 59% versus 41%, again, in favor of zanubrutinib. We did not see this difference in the ELEVATE-RR in that 17p group. As mentioned, the acalabrutinib and ibrutinib had efficacy that were kind of similar. Now, this year, one of the new set of analysis that was done in this data set, which was also very important, was to look at the outcome with different, basically, from different angles. So we saw that when you looked at all comers intent to treat, there was clearly a benefit in favor of zanubrutinib. What if we only look at patients who had disease progression while taking the drug? So eliminating the likelihood of the difference being because of not taking the medication. So when you see the first row of this table, it only limited the analysis to patients who had progression while taking the medication, and you see that hazard ratio remains to be statistically significant in favor of zanubrutinib. The second row shows that we removed patients from the analysis if they started treatment without having a progression. So some patients, for example, could have adverse event from one of the drugs and continued take, or started taking another medication. With a classic PFS analysis, those patients actually remain on the curve. So when those patients were eliminated, again, we are still seeing that hazard ratio in favor of zanubrutinib. And lastly, when... Because this study was done during the COVID time, unlike the ELEVATE-RR study, and there were deaths that were as a result of COVID-19, although the numbers were equal between the two arms. So when you remove those deaths that were related to COVID-19, again, you see that advantage of efficacy in favor of zanubrutinib. So this was one of the other questions that our colleagues in different meetings were asking us, so it was very important to have that information available for the field. We're seeing continued improvement of quality of responses. This is something that we know that happens with BTK inhibitors, but as you see with the red color being zanubrutinib versus blue ibrutinib, there is consistently improvement of the quality of response. Something that I am personally very interested in, looking at the rate of complete responses. This is not something that we're used to seeing with BTK inhibitors as monotherapy, and, you know, 10% is something that we have at 48 months. Just in parentheses, the Sequoia trial, the first-line study, there's also a very relatively high rate of CR rates, in that case, 17%, which is, not something that, again, we see. Again, different clinical trials, but I think for acalabrutinib, it's in the range of 5% in the relapse setting in the ASCEND trial. So that was another finding. And then, overall survival, there's no statistical difference, although, as you see, 82% versus 79%. But again, this p-value and it's with treatment options that are effective these days, it takes a long follow-up to see an overall survival advantage if it exists, so. In terms of adverse events and the safety and tolerability of these two drugs, just briefly, any grade toxicity, high-grade toxicity, Grade 3-5, dose reductions, discontinuation, or dose interruptions were all in favor of zanubrutinib, meaning that fewer patients had interruption or discontinuation or reduction of the dose, just another indicator of the safety profile of this drug. One of the primary or... Well, one of the secondary endpoints of this study was to look specifically at the cumulative incidence of atrial fibrillation or AFib flutter, and you see in the red color, zanubrutinib is continuing to be significantly associated with a lower risk of AFib and AFib/flutter, so. And again, cardiovascular profile remains very favorable for zanubrutinib. Very important that there's no cardiac death in the zanubrutinib arm, which is important, and we actually, in either arm, zanubrutinib or ibrutinib, since last report, there's no cardiac deaths, which is always great news. And overall, as when you look at the table, you see more favorable safety profile in kind of focusing on the cardiovascular events in the zanubrutinib arm. Hypertension, on the left, you look at the cumulative incidence of hypertension, the curves look similar. This was one of the findings from the ALPINE that has been discussed, and part of the discussion was the fact that the ALPINE was the first study that was showing that zanubrutinib had a hypertension rate, in this case, equal to ibrutinib. So the hypertension question kind of came with this study. So there's a lot of work that is being done to really investigate that and find out what are the details of kind of this finding. So for example, on the right you see kind of just as a background there, to have a hypertension, which is graded in a standard way, it's a combination of the systolic or diastolic numbers and also the number of medications that patients are on. So it is, in a way, it's a complicated, or a complex procedure for the grading of blood pressure. But here you see the... On the right, you see that the changes in the systolic blood pressure were lower with zanubrutinib. Again, this is only, I believe, a piece of all the work that is happening right now to investigate the hypertension question more. And as I mentioned here, you see in Alpine, this is the curve that we showed in the prior slide. But in Aspen, for example, which was another head-to-head trial between zanubrutinib and ibrutinib in a different disease, the rate of hypertension was lower with zanubrutinib compared to ibrutinib. Sequoia was a study that compared zanubrutinib with chemo immunotherapy. So you can consider rate of hypertension in the chemotherapy, probably similar to the background, and the zanubrutinib rate of hypertension was not higher than chemotherapy. Again, this is the data in Alpine, and it's being investigated, but kind of a maybe an outlier finding, in general, when we look at zanubrutinib as a drug. So the conclusion is zanubrutinib continues to show both efficacy and safety superiority over ibrutinib in this study, which was done in relapsed CLL setting. And I think, personally, this study was important, showing a longer follow-up and also trying to address a number of questions that were raised since last year, and I think it will be helpful for our community. For the next two presentations, we're moving from comparing two BTK inhibitors to now looking at patients who are already exposed to a BTK inhibitor. In the first case, they were having clinical benefits from a drug but had to stop it because of adverse events, and now they're taking zanubrutinib. So this is in a study. This is a study that we have been working on for a while. It had two cohorts. The first cohort has been now published, and it took patients who were intolerant of ibrutinib and took zanubrutinib, and we showed that these patients can take zanubrutinib, and the adverse events either don't come back, and if they do, they will be at lower or same grade. The second cohort, which is the focus of this presentation, is looking at patients who took acalabrutinib, and they were having clinical benefit from the drug, but for different reasons, had to stop it for side effects. This study gave them the opportunity of staying on BTK inhibitor as a class and taking zanubrutinib. An interesting feature of the drug was the fact that they had the option of taking once a day or twice a day, which is a unique feature with zanubrutinib again and again, they took the drug until progression, as it's a standard for zanubrutinib. The study took patients with different diagnosis, not limited to CLL, so patients with mantle cell, Waldenström, and marginal zone were included, and here we have 27 patients who are being reported from the acalabrutinib cohort. I should mention that almost half of these patients who did not tolerate ibrutinib, I'm sorry, acalabrutinib, were intolerant of ibrutinib before going on acalabrutinib. So you're looking at very sensitive patients to the side effects of BTK inhibitors here. Really, the take-home point from this really colorful image is what I will mention in a second. So on the y-axis, you're looking at the side effects because of which patient came off acalabrutinib, and the color in front of each side effect has a meaning. If you see a dark blue, it means that that side effect did not recur. I believe it's light blue means that it occurred at a lower grade. Yellow is recurrence at the same grade, and what you don't see is the red color, meaning that none of the side effects that occurred on acalabrutinib came back on zanubrutinib. And again, an important point about this study at this point with the current follow-up is the following: One of the questions when we first presented the data was, like, did you give enough time to zanubrutinib to show the side effects? Because the exposure time to zanubrutinib was not that long. With this report, the duration of time on zanubrutinib was twice longer than what they had exposure to acalabrutinib. So in average, they were on acalabrutinib for five months. They had side effects, they came off. They're now on zanubrutinib for 12 months, and this is what happened to the side effect profile. So again, the take-home point being that you could have patients staying on a class of a BTK inhibitor with zanubrutinib, even if they had intolerance to a drug like acalabrutinib. Another interesting study, which would be the last presentation that I'm having here, is a follow-up study, not another long-term follow-up, but a kind of an analysis based on the Aspen trial. And again, this was a trial that compared zanubrutinib to ibrutinib for Waldenström. But really, the point of this study was the following: When patients who were on the ibrutinib arm, when the study ended, they had the option of now going on zanubrutinib. So basically, they stopped ibrutinib, went on zanubrutinib, and there were 42 patients of 47 of those patients and 40 for this analysis. So this really gives us the opportunity of looking at two things. First of all, what happens to their side effect experience? So these are patients who are on ibrutinib, not having progression, but they sometimes have side effects. They don't come off drug for those side effects, but they still bother them. So you see the same kind of figure here, again, with the side effects listed on the y-axis and different colors showing you if the side effect did not come back, that's the dark blue, light blue. Red is if the side effect came back at a higher grade. But again, you see that most of the patients, when they had adverse events on ibrutinib, when they were switched to zanubrutinib, those adverse events went away. A more interesting finding is that you could also look at the quality of remission and responses. Again, these are patients who are already responding to ibrutinib, but if you focus on the red box, that shows the combination of complete responses and very good partial responses. So these are the two best outcomes you can have when you're treating a patient with Waldenström. And both CR and VGPR rates went up in patients who were switched from ibrutinib to zanubrutinib. Again, an important point is the time on treatment. So these are patients who are on treatment on ibrutinib for average of 50 months and only 15 months on zanubrutinib. So with a shorter exposure time to zanubrutinib, the quality of responses improved, and I think this basically is the strategy, which is not uncommon in clinical trials when you kind of offer the control on patients. The winner of this study also lets you kind of explore questions like this. I mean, what happens to the quality of responses? So I think overall, in a head-to-head study, we showed improved efficacy and safety of zanubrutinib over ibrutinib in CLL, and in two studies, we showed that even in patients who are already deriving clinical benefit from BTK inhibitors and either have to stop because of side effects, or we just offer them to switch to another drug, they can have improvement of their side effect profile and also improvement of quality of responses in patients who in the case of Waldenström. And with that, I think we have time for Q&As at the end. Yeah, thank you. Thank you, Maziar. And again, I will just wrap up the Brukinsa section with a summary of everything that we learned at this ASH. And what we knew from before, again, we think when we think about Brukinsa, we have shown the best-in-class opportunity. Given the reason that we believe, given that full coverage around the clock, the sustained inhibition of BTK, that now has led to this superior clinical efficacy and the safety that you saw across the board. As Maziar mentioned, this now, with this longer follow-up, really answers the question that in a head-to-head fashion, that the superiority of zanubrutinib, and also with those subgroup analysis, that truly the efficacy comes from the disease and not intolerance or anything else. Maziar mentioned about the COVID subgroup analysis that we had, because that was one of the questions, because Alpine was done during COVID. In fact, a third of our patients were enrolled during the first year of COVID-19, where patients were not vaccinated and all that, while the other studies that we talk with, you know, Acal or other medicines, they were done before... Enrolled before COVID, or the follow-ups and analysis were done before COVID happened. So some of the analysis that we see out there, for example, MAICs that have compared two medicines together, they are inherently, you can put in any factors that you want, and not include the factors that you don't want. But we really think, COVID-19 is an important factor, to include in such analysis, and we don't see that in the analysis that is, currently out there. The favorable safety, we discussed it, in terms of both the head-to-head studies and in patients who are being switched, and also the broad label and the fact that we continue to have Phase III studies in marginal zone lymphoma, in mantle cell lymphoma, and follicular lymphoma, that will extend and expand our label. And, last but not least, before we move to other assets, Brukinsa remains a cornerstone of our pipeline, as we know that we can combine it with our other assets and also the rational combinations with external medicines in B-cell malignancies. And with that, I would like to switch to our BCL-2 inhibitor, sonrotoclax, and also, reminding you of some background about sonrotoclax, which sounds again, very similar to zanubrutinib, for a vision to believe and specifically design a molecule that can later pan out clinically, to be better. And one of them is that the medicine is more potent and more specific to BCL-2 inhibition compared to venetoclax. So it has more potency. We have specifically looked at a mutation that's known as one of the resistance mechanisms of venetoclax, and we see more potency, and we see more selectivity for BCL-2 rather than other members of the family. And one specific thing, the way that this medicine was designed, was to have a shorter half-life and no drug accumulation. Because we know that venetoclax has a longer half-life of more than 26 hours, and it accumulates in the blood. So we think these two features of venetoclax can lead to safety issues that we typically see with venetoclax. And sonrotoclax, because of the shorter half-life and no accumulation that it has, it can show better safety profile and specifically enable us to work on a better ramp-up and eliminating some of the monitorings that we have to do with venetoclax, and ultimately, a better usage across the board among all practices. I mentioned earlier, we have enrolled more than 600 patients across the different studies of a big clinical development plan that we have with sonrotoclax, and have a good understanding of safety and efficacy of the medicine now. We do see that preclinical promise that we knew about the molecule is now translating to clinic. We are at the point that we are switching now to the registrational stages with this medicine that specifically important when we combine sonrotoclax with Brukinsa in frontline CLL. Part of it is that because we knew about other time-limited therapies that combine with venetoclax, both combination of venetoclax and obinutuzumab, and venetoclax plus ibrutinib. These two relatively have similar efficacy in terms of PFS, but there are some safety issues associated with both of these combinations. We'll hear more about it tonight, but we are very happy with the safety and efficacy profile that we see, to the point that we have initiated a phase III study in frontline CLL, that we think it really can enable us to have a best-in-disease combination for sonrotoclax. With monotherapy, we have pivotal opportunities in post-BTK in some indications, which include relapse refractory CLL, mantle cell, and Waldenström macroglobulinemia. As I mentioned before, we have compelling data both in the AML, MDS setting, myeloid malignancies, and also multiple myeloma, and we'll hear a little bit more about that tonight. Also, we have chosen three clinical abstracts for you that will be presented tonight. We have a phase I/II study of sonrotoclax monotherapy and combination across different B-cell malignancies. At this meeting... Yesterday, we presented a cohort of treatment-naive CLL patients. For the first time, we are presenting data in 107 patients with treatment-naive. You will see that we are pleased to see the safety profile, deep and durable responses, and particularly, again, as I mentioned, safety has been an issue with combinations with venetoclax. The same study has monotherapy cohorts among different B-cell malignancies. We have shown some of them before. This year, specifically, we show a cohort of marginal zone lymphoma. Safety is, as I mentioned, very encouraging, and also from the efficacy standpoint, we see 40% complete remission, which is not anything that we saw with venetoclax or reported with venetoclax. In fact, venetoclax hasn't reported any complete remission. And last but not least, a subset of multiple myeloma with translocation 11;14. They are very dependent on BCL-2, and it's proven that BCL-2 inhibition works in those subset. Unfortunately, with venetoclax studies, given the design and conduct of those studies, they have not met their primary endpoint. But we see in our study of combination of sonrotoclax plus dexamethasone, we see very good safety and deep responses and gives us the opportunity to develop this medicine in the subset of multiple myeloma. And now, again, it's also my really pleasure to introduce Professor Con Tam to present the data on sonrotoclax. His focus and clinical research is focused on B-cell malignancies, including CLL and lymphomas. He has been involved in a lot of novel medicine development, including our very own zanubrutinib, and also combination therapy. I have specifically highlighted here that he's the author of the New England Journal of Medicine paper of venetoclax and ibrutinib, and he's joining us tonight from Monash University in Melbourne, Australia. Kon? Thank you for the very kind introduction. So I'm actually really excited about this combination, and I'm really excited about this combination because I think for the first time, I can see a way how we can have the best of every world in CLL and actually come up with a unifying treatment for frontline CLL. So at the moment, you've got two choices in CLL. You've got continuous oral BTKI, which means you have to be on drug forever, and then you develop resistance mutations, or you can have limited duration, you know, treatment, which involves venetoclax, but that involves antibody intravenously and involves a difficult ramp-up. So I really think that with this combination, we actually have the best of both worlds. It's gonna be all tablets, and it's gonna be, it's gonna be limited duration. We saw data this year, that if you use the combinations in limited duration exposure, that you do not get resistant mutations. So this is potentially the best of all worlds. All right, so the sonrotoclax, this is, obviously, it's a phase I study. It's, as you heard from, Mehrdad, it's about 10 x more potent than venetoclax. It has a shorter half-life, which allows us to actually develop faster ramp-up schedules. And when I prescribe venetoclax to my patients, the most difficult thing about venetoclax is having to get them in for the once-a-week ramp-up or the blood test, getting the blood test results, acting on them after hours. And we're hoping that with a shorter ramp-up schedule, that we can develop a ramp-up schedule that will require minimal blood tests, that can be done in office hours, and a much more friendlier ramp-up schedule. But the first thing is it has to work. So does it work? So the dose was, we started at 40 milligrams as a monotherapy, and the drug was dose escalated all the way up to 640 milligrams. Now, to put this in context, 640 milligrams of sonrotoclax is over 3,000 milligrams of venetoclax. So we have never, ever hit this degree of BCL-2 inhibition in the past. And yet we saw very few GI side effects. The neutropenia was actually quite mild, despite the very deep BCL-2 inhibition. So I think that has showed that as a single agent, the drug works, is highly potent, has a very good safety profile. Based on that, we then took the open-up cohorts, where patients are allowed to have a combination of zanubrutinib, the best-in-class BTK inhibitor, in combination with sonrotoclax. So this is ibrutinib venetoclax, which I love as a combination because we, I was the first person to use this combination in 2014, and it's really nice to watch it develop in a world. But ibrutinib venetoclax has problems with, you know, GI toxicities, it's not easy to take. And here we have the ability to combine a second-generation BTK inhibitor with a better side effect profile, with a second-generation BCL-2 inhibitor, with a benign side effect profile. So this is a really exciting development. This is the next generation ibrutinib venetoclax, which fixed all the problems of that particular combination. So we went on to develop zanubrutinib, as well as two doses of sonrotoclax, 160 milligrams and 320 milligrams daily, and we used this as first-line treatment of CLL. So this is the baseline characteristics of the patient. So about half got 160 milligrams, and one half got 320 milligrams. And note that this is not a small number of patients. So this is not a 20, or 30-patient exploratory study. This is 107 patients treated so far. So this is a big number of patients treated. And these are older patients as well. So much of the IV data, ibrutinib venetoclax data, came from patients under the age of 70, and when you go over the age of 70, side effects start to become limiting. You can see here that the median age is 62, but we have got 10% of patients over 75, and there's even an 84-year-old enrolled on this study. The other thing about this study that is quite different from the others, from other studies out there, is that there's a really big proportion of patients with 17p deletion or p53 mutation. So that's 26%, you know, of high-risk patients in this, in this study, as opposed to most front-line studies in CLL, where that range is usually about 10%. So these are older patients, these are patients with high-risk disease, and they're not easy to treat. These are dose modification and summary of AEs, and I think the most important thing to note about this is one of the best representation for how well tolerated a regimen is, is whether patients have to stop the treatment. And of these 107 patients who started on this regimen, only one of them had to stop treatment so far. So that's an extraordinarily high compliance rate for a front-line regimen. And I think it speaks to how, you know, if you ignore the minor details about individual side effects and the rate, I think this overarching statement really says that, you know, this is an extraordinarily well-tolerated regimen that we have. You know, basically, 99% of patients still on treatment. The other thing to note is that there is no real difference in toxicity rate between 160 milligrams and 320 milligrams. So we know that, and that's, I think, a good example to show that the drug really doesn't have much side effect. The fact that you can double the dose, and you have got pretty much the same side effect profile across the two doses. If you look at the side effect profile, you can see that most of them are in the lighter colors, which means that they are grade 1-2 side effect profile. And when you look at those side effect profile, it pretty much looks like what you expect for single-agent zanubrutinib. So this conclusion is the most common side effect profile. That's a standard side effect. Neutropenia rate, 19% and 25% for grade 3 and higher. This is actually lower than that of ibrutinib venetoclax combination. So even though we've got very high level BTK, very high level BCL-2 inhibition, we're not paying the price in terms of side effect. Now, the question is, has it got potential to be better than ibrutinib venetoclax? Because these are stronger drugs for both, on both the BTK and the BCL-2 side, and the data is early, but it's tantalizing. If you look at the in particular, if the latter worked, if you look at the MRD clearance rate of 78% at six months. So what does that mean? Well, you know, if you don't treat CLL, it may not mean anything to you, but if you look across all the ibrutinib venetoclax studies and you say, "At six months of combination, how many cleared MRD for ibrutinib venetoclax?" That rate is consistently around 40%-50%. So here we've got a MRD clearance rate at the same time point of 78%. So that seems higher, and I think it'd be really nice to get further follow-up to see if that rate stays that high, because it speaks to, you know, a very high MRD clearance at the 12-month mark as the drug works a bit more. We know with all of these drugs that the MRD clearance takes time, but the speed of MRD clearance feels faster with these combinations so far, which I think points to this combination being more potent and potentially working better. A bit off-topic, but there was a study called FLAIR that was presented in the CLL session today, a very impressive, large CLL study, and that used ibrutinib venetoclax, and it had the best progression-free survival curve ever published in a first-line study in CLL. Now, FLAIR used somewhere between three to six years of ibrutinib venetoclax therapy. That's a lot of time of therapy, and we think that we can with this speed and MRD clearance, we may be able to achieve what FLAIR does in three years, hopefully within one year of combination. So I think there's a real chance that this combination may in fact produce some really quite amazing results. So far, follow-up is short, only 9.7 months, but, you know, we've got a flat line for progression-free survival. We've got 100% response. Every single patient responded, and no one has relapsed so far. So I think this is looking very promising. So in conclusion, we think that the combination is safe and well tolerated. As I note before, only one patient had to stop treatment so far. We had no treatment-related toxicity, and no cardiac toxicity. The GI side effects were very mild, and it's milder than that of ibrutinib venetoclax. The most common side effect is neutropenia, which, to be honest, is quite easily managed. The outcome looks very promising and especially the MRD clearance. I think that number is worth watching with further follow-up. If the MRD clearance is indeed faster than ibrutinib venetoclax, then I think that this is gonna be a winner of a combination. And this combination is now in a registration global phase III study against venetoclax obinutuzumab, and two of my patients signed the consent form 10 days ago, so it'll be very soon that we will have the first patient on treatment on the phase III study. Thank you. Sure, I better not. Sure. My apologies, I forgot about that. Okay, so I'm presenting another cohort from this particular study, and this is the marginal zone cohort. So same study design, as you can - reminded you before, that the dose started at 40 milligrams and went all the way up to 640 milligrams. And those patients, some of those patients in dose escalation included marginal zone patients, and then in the expansion cohort, which is between 320 milligrams daily and 640 milligrams daily, we also have marginal zone lymphoma. So this is picking out all the marginal zone lymphoma patients in relapse, who experienced sonrotoclax in the phase I study and looking at the results together. And as Mehrdad reminded the audience, in venetoclax, there have been responses in marginal zone, but there has not been a complete remission reported with venetoclax to date. So what do we see? So these are the different dose levels that we looked at. So, you can see here, I think the aggregate result is the complete remission rate at the highest dose of 640 milligrams. Small numbers, so four patients only of 10 evaluable, but you can see that we've got four complete remissions already. So even though very few patients have been treated with marginal zone so far, and that's just by design, when we do a phase I study, you know, we recruit different type of histologies, and marginal zone is not a common histology in general. But you can see here, with 13 patients treated, we've already got four patients in complete remission, and what looks like a improving rate of response with an increase in dose. So suggesting that, you know, once as you get a more intense BCL-2 inhibition, that you can get responses in histologies that are considered traditionally resistant to venetoclax. As I reminded you before, 640 milligrams of sonrotoclax is over 3,000 milligrams of venetoclax in equivalence. It's not forwarding. Yeah. So as in conclusion, sonrotoclax doses as high as 640 milligrams daily is well-tolerated. We have not reached a maximum tolerated dose, and this is the highest dose that we have assessed by design in the protocol. I think that the signal in marginal zone is really interesting. You know, it's a histology that we consider typically to not be all that venetoclax sensitive, and yet at the highest dose level, we've got 4/10 patients in complete remission. So I think that's, as more data rolls in, this is a really interesting number to look at. And we have not seen any hemolysis as... No clinical hemolysis syndrome. We did see some patients who had laboratory hemolysis syndrome, and these are patients with very high white cell count. So, you know, we are learning how to use this drug in marginal zone lymphoma, but the drug looks really promising so far. Thank you. Thank you, Con. So, we are really honored tonight that at a Beijing event, we have a multiple myeloma expert. And as I mentioned, we are changing, you know, and adding the diseases that we can have an impact to. So Professor Hang Quach is joining us tonight as a multiple myeloma expert and the first author of the oral presentation that we'll have tomorrow. She's a professor of University of Melbourne, and, as I mentioned, the presentation is tomorrow. Therefore, the content of the presentation tonight will be limited to the abstract content. But make sure you actually attend her presentation tomorrow as well. Thank you so much, Dr. Quach. Thank you, Mehrdad. I'm a bit height-challenged, so I'm gonna stand on the side, so you see me. Look, it's an absolute pleasure to be here and be part of the excitement that is sonrotoclax, so I'd like to thank BeiGene for involving me. And I must say, as a clinician, I am very excited to be riding this wave with BeiGene because I see firsthand the kind of impact that the drugs, not only sonrotoclax, but some of the drugs you've mentioned, on my patients. So it's been an incredible privilege. So as mentioned... Now, this won't move forward. I hope this won't happen tomorrow. I'm not having any luck here. Okay. Is there a way I can move the slide forward? Someone can move it for me? I can go next. Aha! Oh, I see, you need to... No, someone did it for me. Thank you. I'll go next. All right. So as Mehrdad mentioned, you've heard from Kon just now eloquently talking about sonrotoclax in the role in lymphoma, but I, for one, am incredibly excited about this agent in multiple myeloma. Not only because BCL-2 inhibitors as a whole is the only class of drug to which there is a robust predictive marker for multiple myeloma, but more importantly, the efficacy and importantly even more, the tolerability of this drug, which is very important in multiple myeloma because the majority of people in multiple myeloma are frail and elderly patients. So the data I'm about to show you here will be updated tomorrow, so I will hold you to what you attend. Because of the embargo rules, I'm going to just summarize the data from the abstract. Next, please. Oh, it works now. So this is the brief outline of the study design. It is a phase Ib/II design with a dose escalation cohort, followed by a dose expansion cohort. The data I'm outlining here will pertaining only to the dose escalation cohort. Here, eligible patients are patients with relapsed refractory multiple myeloma to the last line, who've had the 11-14 translocation, which is the biomarker that predicts response to BCL-2 inhibitors as a whole. These patients have failed at least three prior lines of therapy, including a proteasome inhibitor, an immunomodulatory drug, and an anti-CD38 monoclonal antibody. Traditionally, this group of patients have very poor prognosis. And just to give you a little bit of perspective, if you have this group of patients and you're trialing a new drug and you get a response in the order of 30%-50%, it's a real winner. So just keep that in mind. So based on a dose-escalation design, patients were enrolled in sequential cohorts of 80 mg, then 160 mg, 320 mg, and 640 mg. The treatment was combined with dexamethasone 40 mg weekly until disease progression or intolerable side effects. Upon the determination of the recommended phase II dose, the study was then continued onto an expansion phase at that dose, as well as different arms, dose-finding arms in combination with carfilzomib. So this here is the preliminary safety data. As you can see here, 19 patients were enrolled in the dose escalations cohort so far. What you can see from the tolerability profile is that this is an incredibly well-tolerated drugs with very low levels of Grade 3, Grade 4 adverse events, including low levels of hematologic toxicities as well as infection, which is really the key for all treatments in multiple myeloma. Here, the data will be updated tomorrow, but from the abstract, you can see the main side effect is that of insomnia, 47%, but this is mainly due to corticosteroids. Fatigue is already very common in multiple myeloma, but here you see 32% only, and it is mainly Grade 1, Grade 2. Nausea, 26%. Then there were a smattering of other side effects that are low grade, low incidence, and so there's really not any one strong signal. Grade 3, 4 adverse events only occurred in three patients, i.e., 16%. Only three patients had COVID-19 infection. three patients had a adverse event that led to treatment discontinuation. But most importantly, there were no DLTs observed in any cohorts, including the highest cohort of 640 milligram. There were four deaths, none of which were associated with the drug deemed by the investigator. And so this is quite remarkable. So this here is the preliminary efficacy on the abstract, and it will be updated tomorrow. This is after a median of roughly five and a bit months of treatment, up to 21 months of treatment. And you can see, there, the response rate and depth of response per cohort. There were no response at the 80 mg cohort, but responses started to occur at a 160 mg cohort. And this will be 2/3 patients patients responded with 1 complete remission. And in the 2/3 patients patients had a partial response, and of the 10 patients in the 640 mg cohort, you see a response rate of 70% with stringent complete remission, complete remission, and at least a VGPR in 40% of our patients, a group that is heavily pretreated with at least, with a median of 4 prior lines of treatment and triple class exposed. So this kind of response in what is a first in human study... A phase Ib study is quite remarkable. The longest duration of response thus far is 18.9 months, and that was that patient there in the 160 milligram cohort who achieved a CR, and that patient had high-risk cytogenetics, and she was still responding as of last data cutoff, which was just over 20 months. Now, not that I'm encouraging that you should compare between clinical trials, but just for a bit of perspective, in a very similar patient population, venetoclax monotherapy, you see a response rate in the order of 40%, and even in combination with dexamethasone in a similar cohort of patients, response rate in the order of about 48%. In the recent CANOVA study that you've just heard, venetoclax dexamethasone induced a response rate in the order of 62%, and this was in a patient population that was slightly less heavily pretreated. But what's more important here is the tolerability profile, which is quite favorable compared to what one would expect for traditionally with other BCL-2 inhibitors. So take-home message, the combination of sonrotoclax, dexamethasone very well tolerated in heavily pretreated patients. No DLTs observed so far in the dose escalation phase, and the majority of patients, that's 74% of patients, experiencing only Grade 1, Grade 2 adverse events. And this type of favorable adverse profile has not really been reported with any doublet, let alone triplet, and infection was very low. In fact, only one patient had a grade 3 or more infection of COVID-19. So, sonrotoclax 640 milligrams as the maximum administered dose will be carried forward as a recommended phase II dose with dexamethasone in an expansion phase, and recruitment is ongoing, and we're now going to explore this in combination with other agents in dose exploration arms as well. I'll stop there, and thank you for your attention. Thanks again, Dr. Quach. And again, because the data was limited to the abstract data, please make sure that you see the actual oral presentation tomorrow, and you will see even more encouraging efficacy and continued safety of this combination. With that, I'll close with a couple of closing reminder about sonrotoclax. As I mentioned, we have reached the time with the development of sonrotoclax, but we are changing to the registration studies. On the top, you are seeing the three phase IIs that have been ongoing in three indications that we think we have the potential to have fast-to-market registration. Post BTK inhibitors, which include mantle cell lymphoma, Waldenström macroglobulinemia, and relapsed refractory CLL in areas of the world that the venetoclax is not approved, including China. Also above the line, you see our first phase III study in treatment-naive CLL. I'll talk a little bit about it in the next slide as well, but basically using the combination that Dr. Tam showed earlier, and that study is currently enrolling, and patients are enrolled in the study already. Below the line are the studies that we are currently discussing with the community, with the physicians and fine-tuning the study designs that we think we are gonna start. Then one of them is a frontline relapsed refractory CLL study that we think we will actually start in 2024. Below that, of course, if we are successful with the data and the way that we think we will, and were to get the accelerated approval in mantle cell lymphoma and Waldenström macroglobulinemia, we do need confirmatory study. So we are actually currently working on the design of those phase III studies that will confirm and expand our labels in these two indications that I mentioned. Based on the data that we have seen, we presented actually at last ASH in AML, we do see a clear path on the way to register our medicine in acute myeloid leukemia and myelodysplastic syndrome. Last but not least, as it was presented by Dr. Quach, the encouraging data that we see in multiple myeloma as we are collecting more data opens the path for us for to be the first, hopefully, BCL-2 inhibitor that will be approved in this subset of multiple myeloma, which is actually a relatively large subset of myeloma, with 20%-25% of these patients, so population. This is the frontline CLL study. We have showed the design, the tentative design before, but now this is confirmed, vetted, and accepted by health authorities around the globe. The truly global study is now started. The control arm is pretty much the only globally approved fixed duration standard treatment, which is venetoclax plus obinutuzumab, and the treatment arm is a fixed duration of Brukinsa plus sonrotoclax, based on the data that we heard before. And if this study reads out positive, this will be a new best-in-disease, fixed-duration treatment option for patients. So you see the stratification factors are relevant to these patient population. The primary endpoint of this study would be progression-free survival. We have a series of key secondary endpoint and other secondary endpoints, including the rate of undetectable MRD eradication, deep responses, CRs, and of course, overall survival. Just to briefly summarize everything that you heard about sonrotoclax and what we have talked about before, again, similarly, we think we have the best-in-class potential in efficacy, based on the potency of the medicine, what we know about the potency and drug, and the accumulating data that we see. Again, particularly the most advanced and mature data in treatment-naive CLL and also in these other diseases. You know, we talked about marginal zone lymphoma. The depth of responses and the lack of such deep responses in other BCL-2 inhibitor, venetoclax, really confirms what we have been thinking about this medicine. Same thing in terms of potential in safety and delivery of this medicine. So far, what we had thought about, the half-life and then also no drug accumulation has panned out to better tolerability, as we heard. We'll continue to work on better delivery of this medicine to our patients so that every physician can actually handle this treatment in different combinations. Of course, venetoclax has been a little bit tough in some of the combinations, and we are hopeful that we won't have that problem. Multiple registrational opportunities are now considered, as I showed in the previous slide. But also, again, it really establishes our leadership in hematology, in those B-cell NHLs that I talked about before, but now in multiple myeloma and AML. And, the third, asset that we want to talk about, tonight, and we have a presentation on at ASH this year, is our BTK degrader, that we call it BTK CDAC. So I'll very briefly talk about this molecule, and we'll hear more about it. So the degrader platform, or CDAC platform, is a homegrown platform. We have developed this protein degradation platform at Beijing internally. Very simplistically showing it in that cartoon, that these are bivalent molecules, and that once they are connected to the target, they basically destroy the protein and degrade the protein, and we'll hear more about that. Our BTK degrader that we'll talk about more is our first degrader that has entered clinic. You know, you heard about the other ones that are following. It's very important, given the specific mode of action, that is agnostic of, mutation. You heard from, Dr. Tam earlier that BTK monotherapy up to progression has led to some identified, mutations that you see here. From these that we know and those that we might actually come up later, this mode of action has the potential to be agnostic of this mutation. And even the fact that it destroys the protein has the potential to be more potent, and that is a very important distinction. And when you compare our BTK degrader versus some other BTK degraders that are, in development, we know that our medicine specifically was designed not to have IMiD properties. And some of those other medicines that have the IMiD properties have led to some safety issues, and our drug doesn't have those safety issues. In terms of the clinical development plan, we see a lot of excitement about our medicine. We have enrolled, as I mentioned, 128 patients, so we are the most advanced BTK degrader in clinic. We are imminently starting our expansion cohort in relapsed refractory mantle cell lymphoma that has a potential to be a pivotal cohort and simultaneously thinking about combinations, the rational combinations for this asset and also frontline studies that will get this medicine to our patients as soon as we can. And also, again, we are expanding our leadership in hematology in those diseases that we have been, and also with the mode of action and potency, BTK inhibition should work in some diseases, but conventional BTK inhibitors, so to speak, haven't been able to be successful. But with this mode of action, we are seeing efficacy, and actually, we are enrolling these patients, including Richter's transformation, large B-cell lymphoma, and even follicular lymphoma. This will be the poster presentation that we'll have tomorrow. And again, because the poster presentation is tomorrow, our presentation tonight, the contents will be limited to what we have put in the poster. But I want to make sure that similar to our multiple myeloma session, you attend this presentation as well. And with that, it's my distinct honor to introduce and ask Professor Seymour to join us at the podium to talk about our BTK degrader. He has been a true expert in the disease and development of several assets in hematological malignancies, including a key role in development of venetoclax. Thank you, John. Thank you for the opportunity, and as Mehrdad mentioned, the slides will be based on the data as of the submission of the abstract, which was back in August. This program is moving quite quickly. The poster itself will contain data on 50 patients that were evaluable and enrolled at the time. This study is now moving very quickly, and nearly 100 patients have been enrolled, so it's very dynamic. So I'll verbally update you on impressions on the larger data set, but the slides, as shown, will be based on the data in the abstract. There's two levels of excitement for me with this program. One is this target itself. The second is the degrader platform overall. And this other inhibitors of BTK work by binding to what's called the kinase domain. So they inhibit an enzymatic action of the molecule, but the molecule remains present. We're beginning to understand that one of the additional functions of BTK is the so-called scaffolding function. That's separate from any activity in the kinase domain. The presence of the molecule provides a binding site and a structural scaffold function that leads to other signaling. So with other inhibitors, such as pirtobrutinib, that we're aware of, that received registration in the U.S. and CLL just a couple of days ago. Even when there are mutations that lead to what are called kinase-dead activity, so it doesn't have the enzymatic function, there is still downstream signaling through that scaffolding function. So one of my levels of excitement of this degrader platform is that it physically removes the protein from the cancer cells, and so the completeness of inhibition of that pathway has the potential to be far greater and then has applicability across what are otherwise undruggable targets. So the structure of these molecules is very different to a standard small molecule. It has two binding domains, one that binds to the target protein, in this case, BTK, and the other that then takes the bound BTK and brings it into the proximity and binds to an enzyme called an E3 ligase. That leads to what is called ubiquitination, the addition of a particular chemical signal to the target protein that then marks it for degradation through the proteasomal network. The drug then dissociates from that and can repeat that process over multiple target molecules. So a single drug molecule has the capacity to degrade multiple target molecules. It doesn't need to physically remain bound to it, so you get a greater than one-to-one binding activity. So the platform, let's ignore BTK as the particular target, proof of the clinical activity of this platform also has significant excitement for me. Typical first- in- human dose expansion, beginning at small doses, and we've dosed up to 500 milligrams. We haven't seen any evidence of any dose-related increase in toxicity. We've seen a very compatible, PK and very good pharmacodynamic modeling that tells us we're hitting the target, we are degrading the protein, and, near complete degradation, even at low levels at 100 mg, and the modeling and our, clinical responses have led us to, take forward 200 mg and 320 mg, 200 mg and 350 mg dosing, and continuing to explore doses up to 500 mg. These are very heavily pre-treated patients, multiply relapsed and effectively without, other effective options. We need to keep that in mind when we look at some of the adverse events because, these, the patients generally, have high tumor burden and generally have had multiple prior therapies and cumulative impacts of that. As mentioned, 26 patients in the abstract will be presenting data on 50. The overall toxicity profile remains similar. We have only had one dose-limiting toxicity, a transient rash, and there hasn't been a reproducible rash signal. And we've not seen any toxicity signals preventing dose escalation. The toxicity profile is broadly compatible with that we expect from a BTK inhibitor, contusion. So through a propensity for slight, easy cutaneous bruising or bleeding is manifest at a relatively low grade. There has been what is probably a molecule-specific signal of some elevation of pancreatic enzymes, lipase, and amylase. That has been a biochemical phenomenon only. We've not had any patients with any clinical symptoms nor pancreatitis, and that has been a transient phenomenon, and again, doesn't appear to be dose-related in the range that we've seen. In terms of other potential BTK or, off-target, but related to enzymatic BTK inhibitors, hypertension and arrhythmias have not been seen, albeit small numbers of patients in short follow-up to date. We've seen responses beginning from the lowest dose cohort, and, the highest response rate, where we've got more than one patient evaluable that we've seen, is at the 200 milligram, dose level, which informed, one of the reasons to take that forward. There are 10 patients with CLL, that are evaluable for response, and seven of those 10 have responded. The overall response rate is 56%, and we've seen responses across all, indolent histologies, follicular lymphoma, marginal zone lymphoma, reproducible responses, including complete responses in mantle cell lymphoma, as well as Waldenström's macroglobulinemia follicular lymphoma. This is a so-called swimmer plot, where each individual patient is in a lane, and I won't go through that in substantial detail, but on the left-hand side indicates the prior therapy experience of these patients. So the yellow blocks are those patients who have previously received and their disease is refractory to covalent BTK inhibitors, such as ibrutinib, acalabrutinib, or zanubrutinib. The gray blocks in the middle are those that are also refractory to a BCL-2 inhibitor, nearly exclusively venetoclax. And to me, of most interest, the right-hand lane is patients whose disease is refractory to pirtobrutinib. Now, we also have BTK mutation data, and we've seen responses in all of those categories. So all of the patients with CLL had disease that was refractory to conventional covalent BTK inhibitors and including one response in a patient with disease refractory to pirtobrutinib. And we've also seen effective degradation of multiple types of BTK mutant protein, including the 481 protein, as well as the 474 and the 528, that lead to resistance to pirtobrutinib. So these are small numbers at this stage, but the proof of principle that this novel degrader is active despite the presence of mutations that intrinsically lead to resistance to all of the approved kinase inhibitors of BTK, to me, is very exciting for the platform... I think I've said all of these along the way. The preliminary data is very exciting. We've identified expansion doses. It's very tolerable to date, with no cardiac signal of concern and no dose-limiting toxicity seen. As I mentioned, we've begun the expansion cohorts in CLL and mantle cell lymphoma, and are continuing, exploring higher doses in those less intrinsically BTK, responsive diseases, but we have seen responses across all histologies at this stage. I'll look forward to questions. Thank you. Thank you so much, Dr. Seymour. As I mentioned, we have already established the first steps of development of our BTK degrader would be. All the way on the top, you see the ongoing phase I. In fact, we're doing one global one and one specifically for dose-finding purposes in China. And below that, you see the two expansion cohorts that now that the recommended phase II dose is identified, we are starting a relatively large expansion in mantle cell lymphoma that has the potential to be registrational and also a large cohort in relapsed refractory CLL. Obviously, as we heard and what we have seen, this medicine has a lot of opportunities and registrational pathways. But we have looked about our very next steps, and we think next year we can initiate two phase III studies, both in mantle cell and relapse refractory mantle cell and relapse refractory CLL, to get this medicine approved globally. And also looking at rational combinations, kind of a platform, all of the same study that has different combinations depending on the disease under study. I think most of this was mentioned, but as I have been closing with every asset, these are our current thinkings about our BTK degrader, which is now the most advanced BTK degrader in clinic. We actually saw BTK degradation, and also now you saw clinical efficacy at the very lowest dose that we tested. And continually, as we escalated the dose, we see promising efficacy in our patients and the clinical responses that are independent of the prior lines of the therapy, particularly importantly in patients who have received covalent BTK inhibitors or non-covalent, but pirtobrutinib. And time to response is very short, as you saw in the swim lanes. Favorable safety so far, part of it we believe is because of the lack of IMiD properties. And the fact that we see so many patients enrolled shows the enthusiasm and the safety that our investigators are seeing with this medicine. I talked about the registration plan and how it can move us to other diseases in hematologic malignancies. With that, again, I want to mention that the presentation is tomorrow. I have put the time and location, the session number and poster number, and all of that, to make it easier for you to see. For those of you who are just joining on the broadcast, there is a, what we call it, a mini oral presented by Professor Seymour, equally eloquently online, that after that, you can actually listen to. The last asset that I want to talk about is Tevimbra, our PD-1 inhibitor. Again, also a Beijing-developed asset. It's approved recently in Europe, and also approved in China across different indications, and we are waiting for our first approval in the United States. The reason that you hear about this asset, this medicine tonight is because of the presentation that we all heard yesterday, presented by Dr. Othman Al-Sawaf from the German CLL Study Group. This is an IIS that was conducted by the German CLL Study Group. We see that the two medicines, both Brukinsa and tislelizumab or Tevimbra, are combined in a disease, Richter's transformation. Specifically important because Richter's transformation is a high unmet need disease. A lot of CLL patients with all these great treatments that we heard about do well with the treatments that are available to them, but a subset of CLL patients can transform to an aggressive form of disease that can be large B-cell lymphomas or Hodgkin's lymphomas, and those patients, unfortunately, have a very poor prognosis. There's no even standard of care that we consider that globally as a good option for these patients. So what is unique for this presentation that was done yesterday is that they had a clear hypothesis, a clear sample size collection. They enrolled 48 patients, and they. Their study met the primary endpoint, which was the ORR that you see here, that had an overall response rate of 58%. At the median follow-up of about a year, we see meaningful duration of response that you can see at six months, they have highlighted that as 70%. But overall, we are encouraged with this data, and so was the community. It was very well-received yesterday at this oral presentation. And for us, it's a testimony that we do develop best-in-medicine, best-in-class medicines, but this time we put the two of them together, and we can develop a regimen for an high unmet need population of patients. And with that, I would like to close the presentation part of tonight and soon move to Q&As. But I want to say that at BeiGene, we think that we are developing medicines. Here I've put CLL specifically on how we can cover the journey of the patient as they are diagnosed and get treated, and as with their frontline treatment all the way to their relapses. So here in CLL, we know there is a subset of patients that BTK monotherapy, in our case, Brukinsa monotherapy, would be the preferred treatment for them. We are developing a fixed duration treatment with sonrotoclax, and Brukinsa as the fit patients, and all they really do want a time-limited therapy that's efficacious and safe. Patients do go through progressions, and we think for second line and subsequent lines of treatment, we have treatment options for patients. One of them, again, being sonrotoclax, probably with an anti-CD20, one being the degrader we just talked about, the combinations with the degrader that we are discussing, and also retreatment. Because with some of the venetoclax studies, we have seen that these patients can be retreated after enjoying a long duration of progression-free. As take-home message, as a leader in hematology, we are accelerating the development of all these assets that you've heard about. We really believe that we are leaders in hematology, and we have cemented that, particularly with mature data that we have seen with Brukinsa across the board, with that vision that we had about the molecule and the reason to believe. Our leadership is growing and will continue to grow, not just in B-cell NHLs and also the other diseases that we talked about, and we will expand the way that we have been doing our development in diseases. Most importantly, we want to have a better impact in patients' outcome with better treatments and options for these patients. With that, I will hand the podium back to Julia McCauley to talk about the Q&A. All right. As we move to Q&A and as we wait, our panelists to come onto the stage, maybe I can go through a few logistical items. If you are in the room and you want to ask a question, please raise your hand and then ask your question after you get a microphone. If you are online, you're welcome to submit your questions on Zoom. When asking a question, please start with your name, your company, and then your question. With that, we are ready to open it up. I was worried that was one of those, there was one, two, three chairs for a second. Wow! We did have one from the Zoom. It is, Why is the pivotal trial for Zanu and sonrotoclax not versus a comparator arm of ibrutinib and venetoclax? I'll start that, and then we'll hand off to the experts. So venetoclax and ibrutinib is not globally approved, so it's not really considered as a global standard of care. Because our phase III study will be a global study, we chose a comparator arm to be venetoclax and obinutuzumab, which is globally accepted as a standard of care in a fixed duration treatment. We also wanted to be really comparing our fixed duration regimen versus a globally acceptable fixed duration regimen. Maybe I can ask the panel if there's anything to add. No, that's basically it, is the global standard. Hey, thanks. It's Michael Schmidt with Guggenheim. Question on... Yeah, it doesn't... Because we can't hear where the mic is at. Is it on? Can you hear me? Can you hear me? All right. Question on the sonrotoclax strategy in multiple myeloma. Just curious what the learnings of the CANOVA study are, in your opinion, and how you think about of a path to registration in myeloma, specifically? Good question for Dr. Quach. Thank you. You might wanna - can I hear that repeat question? Because I can see, hear CANOVA, and that's all I could hear. Oh, I was wondering about the learnings of the CANOVA study of venetoclax in multiple myeloma, and how that affects your strategy for sonrotoclax, specifically... Thank you. ...in myeloma. Thank you. Thank you. So just to explain to the whole audience, the CANOVA study was meant to be a registrational phase III study for venetoclax, and it compared venetoclax dexamethasone with pomalidomide and dexamethasone. The issue for that study was the fact that while there was a numerical difference, there was no significance in progression-free survival based on the p-value. And one of the problem, unfortunately, was the fact that there were excess censoring in the control arm because people were moving on from the control arm. So if you had a BCL, if you had an 11-14 translocation, the feeling out there is that you need to have a BCL-2 inhibitor, and therefore, if you get randomized to the control arm, inappropriately, either. The doctor or the patient decides, "Hey, I need to move on." And so the patient, as they were progressing, got removed from the control arm even before they had confirmed progression, and that's called an informative censoring, and that's one thing that we need to avoid in clinical trials. So unfortunately for venetoclax, that has now become a negative study, but just to say that it was a negative study is simplifying it a little bit. Going forward, however, I certainly don't feel that venetoclax personally would be able to make it, given this hiccup, and therefore, the second-generation BCL-2 inhibitor will probably surpass the first-generation proteasome BCL-2 inhibitors going forward. And this will be where sonrotoclax or other second-generation BCL-2 inhibitors will make headways, and it's a matter of who gets there first. Basically, first come, first served. I hope that answers your question. Great. Jessica, JP Morgan. Question on the BTK degrader. I think you mentioned taking that into a potentially pivotal expansion cohort, starting next year. How soon could that product launch? The first step is to start it. Obviously, we want to make sure that it's acceptable by health authorities. We have to see how the data will pan out. There are a lot of steps that we still have to follow, but we think soon. Maybe I can just add a bit more comment. The expansion cohort is in the mantle cell lymphoma patients. It's about 100 patients. Maybe I can ask Dr. Seymour to comment on the enthusiasm right now about perhaps for the PI putting patients into this study. Yeah, I'll speak on two elements. One, and I'm not involved with the U.S. FDA or any regulatory agency, but the pirtobrutinib in the US received approval in mantle cell lymphoma based on, a single arm cohort from their phase Ib study. And received accelerated approval in CLL, in the context of a confirmatory randomized study having been, launched, but on the basis of efficacy data from a single-arm cohort in, a double refractory context, patients with disease refractory to covalent BTK inhibitors and venetoclax. So at least in the US, there's a precedent there for approval based on, high efficacy in single-arm cohorts in early phase studies in a defined area of unmet need. The excitement that I see with the degrader is an early signal of efficacy in patients with disease refractory to not only covalent BTK inhibitors and BCL-2 inhibitors, but also pirtobrutinib itself. So the area of unmet need is potentially, as an initial step, potentially those refractory, and of course, design of what the follow-on study remains with BeiGene. But there certainly is a precedent. The early activity is highly promising, and investigators have substantial numbers of patients that are already queued to be enrolled once those expansion cohorts open. Maybe I can also make a comment because I was one of the investigators on the pirtobrutinib phase I that led to the approval. And pirtobrutinib is a great drug. Love it. It's very specific, easy to give, works when covalent BTK inhibitors stop working, but mutations is a real problem. You can, you can see now, you know, from multiple presentation, that when you start on pirto, you get this huge range of mutations across the BTK enzyme that renders it potentially resistant to everything else. So the excitement, as Professor Seymour pointed out, is that you now have a potential to erase these mutations with a protein destroyer. You know, we do not inhibit the protein, we actually destroy the protein, and I think that that's really what differentiates the CDAC from everything else that we've had before. It's a new mechanism of action, but there's been no real CDAC target in any other disease. To me, it's amazing that you can actually destroy a protein, have very few side effects, and get results. Thank you. Yeah, you have a question, Yigal? Go ahead, please. Hi. Thank you. Yigal Dov Nochomovitz from Citigroup. Just following on the BTK degrader discussion, Dr. Seymour, just curious with respect to that resistance profile, is it possible that eventually you might see something at the handle where the BTK degrader binds this other piece of the molecule, or is that much less. Are you going to see much less mutational pressure there, given that you're degrading the protein so fast that, you know, the cell doesn't really have a chance to fight? Yeah. I've not been involved with any of the preclinical work, so I'll speak about my conceptual perceptions in that area, and I'll let others from Beijing speak about specific preclinical work. So yes, the hypothetical risk with any targeted molecule is that changes in the structure at the binding site. An issue with any molecule is what is the susceptibility or the stringency of binding, and how vulnerable is it to relatively small changes? The kinase inhibitors, because of the precision required of that binding, are highly susceptible to single amino acid changes. Hence, you know, ibrutinib, for example, at that specific binding site. So there's a high selective pressure for that. As I said, I'm not involved with the preclinical work, so I can't speak to the structural nature of the binding side of the degrader. So I'll leave the Beijing people to speak about that. Maybe I can also comment on that. We actually have done quite a bit of work in looking for emerging resistance in preclinical settings to apply drug pressure to cell lines to see whether you can generate with also, you know, increased mutagenesis pressures. So what we found, very interestingly, when you treat the cells with BTK degrader, you actually don't see BTK-resistant emergence. While if you do that same thing with any of the reversible or irreversible BTK inhibitor, you do see that emerging. The underlying mechanism, we still not completely understand what's happening, but I think that has something to do with the BTK protein get completely eliminated. The cell just probably die much, much quicker. So that's our hypothesis, but we still don't have the hard core evidence behind it. But resistant, that seems to be much, much less associated with BTK degrader. Yeah, that would make sense intuitively. What have you seen in terms of the percent of the BTK protein pool that is degraded? Do we know if there's a number? Like, how much knockdown are we getting? And the reason I ask is because in the future, if you were ever to advance this into an earlier line, I know it's for the BTK failure population, for the inhibitors, but eventually, maybe you could advance it, and then you may be able to use a much lower dose of Brukinsa in combo, potentially. Just curious. Are we allowed to say? Are we allowed to disclose that information? I think the PD will have to talk about it. We have... Yes, so there's been very high levels of degradation. The median is above 95%. And that's at doses at 100 mg and above. We seem to be seeing a plateau in the degradation of that 200 mg-350 mg. So the PD data is supportive of the selection of those doses for expansion. So we're seeing above 95% degradation. Again, limited number of samples, given that requires peripheral blood, and that's also reproducible in the few tumor biopsies that we've seen. So we've seen a PD marker in normal tissue in the peripheral blood and confirmation of that in specific biopsies of tumor samples. Thank you. Are there any other questions in the room as we check online? There is one online. It is asking for the rationale of Tevimbra and Brukinsa working in Richter's transformation. So there is deep preclinical data about each of these drugs, you know, classes, both, BTK inhibitors and also PD-1, PD-L1s, and also preclinical data about a combination of the two. One thing that is exciting about this data is the degree of responses and also the durability and the number of patients and, and follow-up that we have seen. But we also have experts in Richter's transformation. I want them to also talk about, preclinical and also clinical rationale for this combination. Yeah. So I mean, the BTK inhibitors do have effect in Richter's transformation, particularly in patients who have not seen a BTK in the past. You do get responses, but the PD-1 probably is the key here. So, there have been several reports now of PD-1 inhibitors being effective in Richter's, although never at the sole rate and the durability that we've seen in this combination. And the reason why is because Richter's transformation is a far more genetically complex cancer than simple CLL. And the more genetically complex you are, the more neoantigens you express, and the more you have to rely on immune evasion to survive. So to me, it actually genetically makes sense to use this combination. I have to say that I was pleasantly surprised at how well it worked, which I think is the reason why it led to a Nature Medicine publication based on a modest number of patients. Yeah, I'd just add briefly, as Con said, there is some on-tumor BTK targeting that may have a role. There's also variable effects of different BTK inhibitors on the activity and longevity of host T and natural killer cells that preclinical data has shown does enhance the PD-1 activity. So in the CLL context, there's a degree of exhaustion and functional impairment of the host immune cells, and that's likely one of the reasons why single-agent responses to PD-1 inhibitors are lower than in other solid tumors, and a putative reason for the synergies through that enhanced functional activity of the host T cells and natural killer cells from the BTK activity. And they also asked: "Is there a plan to amend the protocol to add sonrotoclax, and what would be the registrational pathway for this? So, one of the combinations that we are currently considering in the phase I is combining the sonrotoclax plus the degrader. Obviously, we'll need at least some level of dose finding and make sure that it's safe, and we expect the responses to be deeper and even more durable, and then that will inherently bring the line of treatment earlier. Was that about Richter, or? or? Did they specify, or about the degree? I think so, yeah. Oh, it was about Richter. Yes. So that IIS - I'm sorry. Thanks for clarifying. That IIS does have an amendment, as they were presented yesterday, that they are adding sonrotoclax, so there will be a triplet in Richter's transformation. Any other questions in the room? How about online? Good. So going once, going twice. Going three times. If no more questions, we are concluding tonight's program. I want to thank our presenters and our panelists. I also want to thank all of you for joining us today. So we wish you a good night and a good day. Thank you.