BeOne Medicines AG (ONC) Earnings Call Transcript & Summary

Hello, everyone. Welcome to BeiGene 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 presentation, 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.

Thanks so much, Julia, and thanks, everyone, for coming. We're not here to hear me give a few opening remarks, we're here for the real content. Just quick reminder for BeiGene. Our goals as a company, first and foremost, are to have a 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 were doing that. For us as a company, we always believe, if you want to 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'll try to do it through incorporating and adopting great technology. Clinical trials, at the end the day, comprise 75% to 90% of the delivered cost 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. And 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 [ Kirlin's ] here, but [ going ] in Europe, and we're building out throughout the rest of the country and 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 the clinic, and we've done that for a while. And 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 dogs in the clinic.So congratulations [ lie ] for not putting duds in the clinic." And those were kind words. And I think we'll continue to do that, but we large innovators. And 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 need to hear more from me, I'll introduce Lai Wang, who is heading our Research & Development.

Thank you. Thanks, John, and good evening, everyone. Hope you have been enjoying us so far, and I hope you will enjoy tonight as well. So John gave you a introduction about our company's capability. I'm just going to zoom in a little bit about innovation. To achieve innovation, I think BeiGene has done two things: Number one, we have built really one of the largest oncology-focused research team. We have over 1,100 scientists working on that. This is why we can be so productive. Secondly, the oncology is really not just on [ oncology ], our entire industry have been really driven by biotechnology. So BeiGene believes 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 than we also with our [ BCL-2 ] inhibitor. But now on a small [ molecule ] side of today, you're also going to hear about we're doing the protein [ depth ] data. One of the protein [ depth data ], we're choosing the [ clinic ] as 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 in 3 months, every dose level 6 to 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 do -- deliver innovation as much greater efficiency probably compared to most of the peers in this industry. I know today is about heme. But before we talk about heme side of it, I do want to mention a few things about emerging and really the solid tumor pipeline. What you can see on the 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. And I do want to highlight 4 of them: The first one is panKRAS [ inhibitor ]. We probably have this first-in-class panKRAS [ inhibitor ], which hits all KRAS mutations by sparing the NRAS and HRAS. This is extremely interesting. The second one is MTA-cooperative PRMT5 inhibitor. This is a second-generation PRMT5 inhibitor. So it's not going to 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 molecule right now in the clinic. The third one, CDK4i inhibitor. You all know about CDK46 has been doing extremely well in the breast cancer, but CDK6 is believed to bring more toxicity than efficacy, a CDK4i inhibitor can retain the efficacy and sparing the hematology toxicity, which is associated with CDK6. On the EGFR-CDAC is our second protect -- the protein [ catheter ] we're taking to connect. This one, we do believe, have a chance to ultimately compete against the third-generation EGFR inhibitor. With that, I'm going to 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 at this ASH, BeiGene has been present with 24 abstracts. And this is on the 4 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 higher CRs that we have reported among different indications. We have the broadest label globally for any BTK inhibitor. You see the 5 indications that we have now. And we are currently continuing to work on, what we call, the 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 BCL-2 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 greater. 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 will 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 going to 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, and we'll talk about the abstract and presentation that we heard about yesterday in Richter's transformation and 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 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 BCL-2 inhibitor, our 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 at the way that we are putting our assets in develop 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 want to 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 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 seen 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 investigators that you see here. We even did 2 head-to-head studies versus ibrutinib. One of them is ALPINE study that we saw superior PFS and ORR and safety in CLL. And the other one, the ASPEN study, was done in Waldenstrom's macroglobulinemia that we saw a 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 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 described it, you always want to 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 around 24 hours, we remain above the IC50. And you can compare that with ibrutinib and acalabrutinib, neither of those two have this to -- 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 would be patients that would be even below this median. But in BRUKINSA, with 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. We truly believe that's why we have head-to-head superiority, and we believe that our medicine is the best in class compared to other two that you see here. These are the three 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 to 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. And 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 2 arms. But ultimately, the 2 curves merged, and they had a non-inferiority with hazard ratio 1. And 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, switching from another BTK inhibitor to BRUKINSA, both for patients who are not tolerant to the BTK that they're 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? So we are presenting 2 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 with the acalabrutinib. Intolerance events that we have, we don't see then 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 BRUKINSA. And even though they were on ibrutinib for more than the median of [ 50 ] months or 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. Mazyar Shadman, who's a professor of Fred Hutchinson Cancer Center at the University of Washington University, 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 3 presentations about zanubrutinib that we saw and we will see actually in this meeting, starting with ALPINE, a very important study that was first -- 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-milligram twice a day or ibrutinib at the standard dose of 420-milligram daily until progression or toxicity. As you see the number of patients in each arm, and the patients who are receiving ongoing therapy on 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 -- and for adverse events. So kind of looking at what we saw last year, this is a 2-year landmark, and I was just showing that zanubrutinib had a superior efficacy compared to ibrutinib, 2-year PFS up 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 a longer follow-up. The reason for that is that naturally, we would compare this study with a similar study, ELEVATE-RR that compare the acalabrutinib with ibrutinib in the relapse setting, different study, different settings, different time. But the fact that the curves cross around the 33 months raised the question of what would happen to those curves with a longer follow-up. So this year, with the 30 -- or almost 40 months of follow-up, you're seeing that those 2 curves are continuing to separate. And at 3 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. This study was not limited to any molecular feature or chromosomal abnormality. So there was a predefined and preplanned analysis for patients with high-risk disease, defined by having deletion in chromosome 17 or having a mutation of the p53 gene. And again, at 3 years, we are seeing that superior efficacy of zanubrutinib, now at 3 years, is at 59% versus 41%, again in favor of zanubrutinib. We did not see this difference in the ELEVATE-RR in that 17P group. And as mentioned, 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 look at all comers they intend 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, the only looks at -- 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 ratio is that we remove 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 -- started taking another medication. With a classic PFS analysis, those patients actually remain under care. So when those patients were eliminated, again, we are still seeing that hazard ratio in favor of the zanubrutinib. And lastly, when -- because this study was done during the COVID time, unlike ELEVATE-RR study and the [ deaths ] that were as a result of COVID-19, although the numbers were equal between the 2 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 consistent improvement of the quality of response and something that I am personally very interested in looking at the rate of complete responses. This is not something that we're used to see with BTK inhibitors as monotherapy, and 10% is something that we have at 48 months. Just in parenthesis, the SEQUOIA trial, the first line study, there is also a very relatively high rate of CR rates in that case, [ 17% ], which is not something that, again, we see, again, in 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 -- the treatment options that are effective these days, it takes a long follow-up to see overall survival advantage, if it exists. So in terms of adverse events and the safety and tolerability of these 2 drugs, just briefly, any grade toxicity, high-grade toxicity, Grade 3 to 5 dose reductions, discontinuation or those interruptions were all in favor of zanubrutinib, meaning that fewer patients have interruption or discontinuation or reduction of the dose, just another indicator of the safety profile of this drug. One of the primary -- well, one of the secondary endpoints of this study was to look specifically at the cumulative incidence of atrial fibrillation or flutter. And you see in the red color, zanubrutinib is continuing to be significantly associated with lower risk of atrial fibrillation/flutter. 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 [ death ], which is always great news. And overall, 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, to have 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 in a way, it's a complicated or complex procedure for the grading of block per share. 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 more. And as I mentioned here, you see an outline, 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 chemoimmunotherapy. So if you can consider rate of hypertension in the chemotherapy, probably similar to the back -- 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 maybe an outlier finding in general when we look at zanubrutinib as a drug. So the conclusion, zanubrutinib continues to show both efficacy and safety superior over ibrutinib in this study, which was done in relapsed CLL setting. And I think all 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 2 presentations, we're moving from comparing 2 BTK inhibitors to now looking at patients who are already exposed to a BTK inhibitor. And 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 a study that we have been working on for a while. It had 2 cohorts. The first cohort has been now published. And 2 patients who were intolerant of ibrutinib, 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. And this study, given the opportunity of going -- staying on BTK inhibitor as a class and taking zanubrutinib, an interesting feature of the drug is the they had the option of taking once a day or twice a day, which is a unique feature with zanubrutinib, and again, to [ top ] the drug into progression as it's a standard for zanubrutinib. The study took patients with different diagnosis not limited to CLL, so patients with mantle cell, Waldenstrom 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 but 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 on 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 of -- each 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, important point about this study at this point with the current follow-up is the following: One of the questions when we first presented that 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 had exposure to acalabrutinib. So in average degree on acalabrutinib for 5 months, they have 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 as a follow-up study, not a long-term follow-up but kind of an analysis based on the ASPEN trial. And again, this was a trial that compared zanubrutinib to ibrutinib for Waldenstrom. 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 if they stopped ibrutinib, run on zanubrutinib. And there were 42 patients -- 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 it 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. The 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 there were switched to zanubrutinib, those adverse events went away. A more interesting finding is that if you 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 the two best outcomes you can have when you're treating a patient with Waldenstrom. And both CR and VGPR rates went up in patients who were switched from ibrutinib to zanubrutinib. Again, an important point is time on treatment. So these are patients who are on treatment on ibrutinib for an average of 50 months and only 15 months on zanubrutinib. So with a shorter exposure time to zanubrutinib, the quality of response is improved. And I think this, basically, is a 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 2 studies, we showed that even in patients who are already driving clinical benefit from BTK inhibitors and either have to stop because of side effects or we just offered 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 Waldenstrom. And with that, I think we'll have time for question and answers at the end.

Thank you. Thank you, Mazyar. 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 befor. 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 plot, the sustained inhibition of BTK that now has led to the superior clinical efficacy and the safety that you saw across the board. As Mazyar mentioned, this, now with this longer, really answers the question that in a head-to-head fashion, the superiority of zanubrutinib and also with those subgroup analysis truly, the efficacy comes from the disease and not intolerance or anything else. Mazyar mentioned about the COVID subgroup analysis that we had because that was one of the questions, because ALPINE was done during COVID. In fact, 1/3 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 no acala or other medicines that were done -- enrolled before COVID or the follow-ups and analyses were done before COVID happened. So some of the analysis that we see out there, for example, [ MAICs ] that are compared 2 medicines together, they are inherently -- you can put in any factors that you want and not include 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 remain 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 their 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 2 features of venetoclax can lead to safety issues that we typically see with venetoclax. And sonrotoclax because of the short-term 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 monitoring 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 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. And we do see that preclinical promise that we knew about the molecule is now translating to clinic. And we are at a point that we are switching now to the registration of the stages with this medicine. Specifically important, when we combine sonrotoclax with BRUKINSA in frontline CLL. And part of it is that because we knew about other time-limited therapies that combined with venetoclax, both combination of venetoclax and obinutuzumab and venetoclax plus ibrutinib. These 2 relatively have similar efficacy in terms of PFS, but there are all some safety issues associated with both of these combinations. And we will 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 our Phase III study in frontline CLL that we think it really can enable us to have a best-in-disease combination of -- for sonrotoclax. With monotherapy we have pivotal opportunities in post BTK in some indications, which include relapsed/refractory CLL, mantle cell and Waldenstrom macroglobulinemia. As I mentioned before, we have compelling data, both in the AML, MDS setting, myeloid malignancies and also multiple myeloma, we'll hear a little bit more about that tonight. Also, we have chosen 3 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. So for the first time, we are presenting data in 107 patients with treatment-naive, and you'll see that we are pleased to see the safety profile, deep and doable responses and particularly, again, as I mentioned, safety has been issued 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. And 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 -- reported with venetoclax. In fact, venetoclax hasn't reported any complete remission. And last but not least, a subset of multiple myeloma with translocation with 11, 14, they are very dependent on BCL-2. And it's proven that BCL-2 inhibition works in those subsets. Unfortunately, with venetoclax study, given design and conduct of those studies, they have not met their primary endpoints. 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 search is focused on B-cell malignancies, including CLL and lymphomas. He has been involved in a lot of novel medicine developments, 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 is joining us tonight from Monash University in Melbourne, Australia.

Thank you for the very timed 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 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 to mutations; or you can have limited duration of treatment, which involves venetoclax, but that involves antibody intravenously and involves a difficult ramp-up. So I really think with this combination, we actually have the best of both worlds. Its going to be all tablets and issued in a limited duration, and we saw at the other ASH this year that we use the combinations in limited-duration exposure that you do not get resistance to mutations. So this is potentially the best of all worlds. All right. So on venetoclax, this is obviously a Phase I study. As I heard from Mehrdad, its's about 10x 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 patient, 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 we've shorter ramp-up schedule that we can develop a ramp-up schedule that will require minimal blood test that can be done in office hours and a much more friendly 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 yes, we saw very few GI side effects. The neutropenia was actually quite mild, despite the very deep BCL-2 inhibition. So I think that's showed as a single agent. The drug works, is highly potent, has a very good safety profile. Based on that, we then talk 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 the world. But I've ibrutinib, venetoclax has problems with GI toxicity. It's not easy to take. And here we have an ability to combine a second-generation BTK inhibitor with a better side-effect profile with second-generation BCL-2 with a benign soft 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 development zanubrutinib as well as 2 doses of sonrotoclax, 160 milligrams and 320 milligrams daily, and we use this as a first-line treatment of CLL. So this is the baseline characteristics of the patients. 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 a 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. I mean you go over the age of 70, the side effects suddenly become limited. And you can see here that the median age is 62, but we have got 10% of patients over 75, and there's even a 84-year-old enrolled on this study. The other thing about this study that is quite different from the other -- from other studies out there is that there's a really big proportional patient worth 17p deletion or p53 mutation. So that's 26% of high-risk patients in this study as opposed to most frontline studies in CLL, where that usually -- that rate is usually about 10%. So these are older patients, these are patients with high-risk disease, and they're not easy to treat. This is 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 frontline regimen. And I think it speaks to how, if you ignore the minor details about individual side effects and the rates, I think this overall statement really says that this is an extraordinarily well-tolerated regimen that we have. Basically 99% patients still on treatment. The other thing to note is that there is no real difference in toxicity, right, between 160-milligram 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 2 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 [ gray ], 1 to 2 side effect profile. And when you look at those site profile, pretty much looks like what you expect for single-agent zanubrutinib. So this contusion is the most common side effect profile, that's a zanu 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 a 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 your potential be better than ibrutinib, venetoclax because there are stronger drugs for both -- on both the BTK and the BCL-2 side? And the data is early but is [ tantalizing ]. If you look at the -- in particular, if you laser work, if you look at the MRD clearance rate of 78% at 6 months. So what does that mean? Well, we don't read and sleep CLL, it may not mean anything to you. But if you look across all the ibrutinib, venetoclax studies and you say, at what -- 6 months of combination, how many clear the MRD for ibrutinib, venetoclax? That rate is consistently around 40% to 50%. So here, we've got an MRD clearance rate at the same time point of 78%. So that seems higher, and I think it will be really nice to get further follow-up to see if that rate stays at the high because it speaks to a very high MRD clearance at a 12 month as the drug works a bit more. We know all of these drugs that the MRD clearance takes time, but the speed of MRD clearance feels faster with this combination so far, which I think points to this combination being more potent and potentially working better. And a bit off topic, there was a study called [ FLARE ] 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 [ FLARE ] used somewhere between 3 to 6 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 [ FLARE ] does in 3 years, hopefully, within 1 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 we've got that 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 noted before, 1 patient had to stop treatment so far. We had no [ tumor ] toxicity and no cardiac toxicity. The GI side effects were very mild, milder than that of ibrutinib, venetoclax. The most common site effect is neutropenia, which, to be honest, is quite easily managed. The outcome looks very promising. And especially in MRD clearance, I think that number is worth watching a further follow-up. If the MRD clearance is indeed faster than ibrutinib, venetoclax, then I think that this is going to be a winner of a combination. And this combination is now in a registration global Phase III study against venetoclax, obinutuzumab. And 2 of my patients signed a consent form 10 days ago, so it would be very soon that we will have the first patient on treatment on the Phase III study. Thank you. Sure. I'm batting on, I'm 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 since study design is we can remind 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 include marginal zone patients. And then in the expansion cohort, which is between 320 milligrams daily and 640 milligrams daily, we also have margins zone lymphoma. So this is picking up 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 margins zone, but there has not been a complete remission reported within next 2 days. So what do we see? So these are 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, as of 4 patients only, of 10 in variable, but you can see that we've got 4 complete remissions already. But you can see that we've got 4 complete remissions already. So even though very few patients have been treated with marginal zone so far, and that is by design. When we do a Phase I study, we recruit a 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 4 patients in complete remission. And what looks like an improving rate of response with an increasing dose, suggesting that as you get a more intense BCL-2 inhibition that you can get responses in histologies that are considered traditionally resistant to venetoclax. And as I reminded you before, 640 milligrams of sonrotoclax is over 3,000 milligrams of venetoclax in equivalence. It's not following here. So in conclusion, so sonrotoclax dose is as high as 640 milligrams daily, it's well tolerated. We have not reached a maximum tolerant dose. And this is the highest dose that we have assessed by design in the protocol. I think that the significant margin zone is really interesting. It's a histology that we consider typically to not be either venetoclax sensitive, and yes, at a highest dose level, we've got 4 out of 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 tumor lysis, no clinical tumor lysis syndrome. We did see some patients who have laboratory, tumor lysis syndrome and these are patients with very high white cell count. So 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 BeiGene event, we have multiple myeloma expert, and as I mentioned, we are changing and adding the diseases that we can have an impact too. 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 the 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. I'm going to 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 drives 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. Okay. Is there a way I can move the slide forward? Someone can move it for me. I can go next. 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 Con 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. And because of the embargo rules, I'm going to just summarize the data from the abstract. Next, please. 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. And 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's had the 1114 translocation, which is the biomarker that predicts response to BCL-2 inhibitors as a whole. These patients have failed at least 3 prior lines of therapy including a proteasome inhibitor, an immunomodulatory drug and an anti-CD38 monoclonal antibody. And 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% to 50%, it's a real winner. So just keep that in mind. So based on a dose escalation design, patients were enrolled in a sequential cohorts of 80 milligram, then 160 milligrams, 320 milligrams and 640 milligram, and the treatment was combined with dexamethasone, 40-milligram weekly, until disease progression or intolerable side effects. And upon the determination of the recommended Phase II dose, the study was then continued on to an expansion phase at that dose as well as different arms, dose-finding arms in combination with carfilzomib. And so this here is the preliminary safety data. And as you can see here, 19 patients were enrolled in the dose escalation cohort so far. And 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. And 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%. And then there were a smattering of other side effects that are low grade, low incidents. And so there's really not any one strong signal. Grade 3, 4 adverse events only occurred in 3 patients, i.e., 16%, only 3 patients had COVID-19 infection, 3 patients had an adverse event that led to treatment discontinuation. But most importantly, there were no DLTs observed in any cohort including the highest cohort of 640 milligram. There were 4 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 5 and a bit months of treatment up to 21 months of treatment. And you can see there the response rate, in death of response per cohort. There were no response at the 80-milligram cohort but responses started to occur at 160-milligram cohort and this will be updated tomorrow, but 2 out of 3 patients responded with one complete remission. And in the 320-milligram cohort, 2 out of 3 patients had a partial response and of the 10 patients in the 640-milligram 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 -- sorry, a Phase Ib study is quite remarkable. The longest duration of response thus far is -- was 18.9 months and that was that patient there in the 160-milligram cohort, who achieved a CR, and that patient had high recited genetics, 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. And 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 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 triplets and infection was very low. In fact, only one patient had a grade 3 or more infection of COVID-19. So sonrotoclax, 640-milligram 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 that abstract data, please make sure that you see the actual overall 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 3 Phase IIs that have been ongoing in 3 indications that we think we have the potential to have fast to market registration, post BTK inhibitors, which include mantle cell lymphoma, Waldenstrom's macroglobulinemia and relapsed/refractory CLL in areas of the world that venetoclax is not approved, including China. And 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. And 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're going to start -- and then one of them is a front -- relapsed/refractory CLL study that we think we are 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 [indiscernible] approval in mantle cell lymphoma and Waldenstrom's 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 2 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, in myelodysplastic syndrome. And last but not least, as 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 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% to 20% -- 20%, 25% of these patient's population. And this is the frontline CLL study. We have showed the design, the tentative design before, but now this is confirmed better than 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 you have a study [indiscernible] 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 will be progression-free survival. We have a series of key secondary endpoint and other endpoints, including the rate of undetectable MRD eradication, deep responses CRs and of course, overall survival. And 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 potential 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. We talked about marginal zone lymphoma, the depth of responses and the lack of such deep responses and other BCL-2 inhibitor, venetoclax to really confirms what we have been thinking about this medicine. Same thing in terms of that potential in safety and delivery of this medicine, so far, what we have thought about the half-life and then also new drug accumulation has panned out to better tolerability as we heard. And 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. And 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 side. 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 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 BeiGene internally, very simplistically showing it in that cartoon that these are bi-balanced molecules and 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 heard about the other ones that are following. It's very important, given the specific mode of action that is agnostic of mutations. You heard from Dr. Tam earlier that BTK monotherapy, up to progression, has led to some identified mutations that you see here from this that we know and those that we might actually come up later, this model 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 emit properties and some of those other medicines that have the emit 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 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 valuable and enrolled at that time. This study is now moving very quickly and nearly 100 patients have been enrolled. So it's a 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. This 2 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 in other -- with other inhibitors such as pirtobrutinib that may have been aware of that received registration in the U.S. in 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 2 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 produce [indiscernible] 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 1:1 binding activity. So the platform, let's ignore BTK, is 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-milligram and the modeling and our clinical responses have led us to take forward 200 and 320-milligram -- 200 and 350-milligram dosing and continuing to explore doses up to 500 milligrams. These are very heavily pretreated 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 phenomena 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 and 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 available 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 7 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 Waldenstrom's macroglobulinemia from the [indiscernible] lymphoma. This is so-called [indiscernible] 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. And as I mentioned, we've begun the expansion cohorts in CLL and mantle cell lymphoma and a continuing exploring higher doses in those less intrinsically BTK responsive diseases, but we have seen responses across all histologies at this stage. So I look forward to questions. Thank you.

Thank you so much, Dr. Seymour. As I mentioned, we have already established what 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 those finding purposes in China. And below that, you see the 2 expansion cohorts that now that the recommended Phase II doses identified, we are starting an expansion, relatively large expansion in mantle cell lymphoma that has the potential to be registration and also a large cohort in relapsed refractory CLL. Obviously, 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 2 Phase III studies, both in mantle cell and relapse refractory mantle cell and relapsed 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 thinking 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 continuity as we escalated the dose, we see promising efficacy in our patients and the clinical responses that are independent of the -- prior as a dead therapy, particularly importantly in patients who have received covalent BTK inhibitors or noncovalent blood pirtobrutinib and time to response is very short, as you saw in the swim lanes, favorable safety so far, probably, I believe, is because of the lack of in it 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 we can move us to other diseases in hematological 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 what we call the mini oral, presented by Professor Seymour, equally, eloquently online, that after that, you can actually listen to. And the last asset that I want to talk about is tevimbra, our PD-1 inhibitor, again, also a BeiGene-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, also from the German CLL study group. This is an IIS that was conducted by the German CLL study group. And we see that the 2 medicines, BRUKINSA and tecelizumab or tevimbra are combined in a disease, in Richter scale transformation, specifically important because Richter transformation is a high unmet need disease. A lot of the CLL patients with all these great treatments that we heard about too 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. And there is 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, clear sample size collection. They enrolled 48 patients and their study met the primary endpoint, which was the ORR that you see here that had an overall response rate of 58%. And at the media of about a year, we see meaningful duration of response that you can see at 6 months, they have highlighted that 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 medicine that this time you put the 2 of them together, and we can develop a regimen for a high unmet need population of patients. And with that, I would like to close the presentation part of tonight and soon move to question and answers. But I want to see that at BeiGene, we think that we are developing medicines, here I put CLLs 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 field patients and all the really 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 that 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 being progression-free. And as a take-home message, as a leader in hematology, we are accelerating the development of all these assets that you 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 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 diseases. And most importantly, we want to have a better impact in patients' outcome with better treatment and options for these patients. With that, I will hand the podium back to Julia, my colleague to talk about the Q&A.

All right. As we move to Q&A and let's wait our panelists to come on to the stage, maybe I can go through a few logistical items. [Operator Instructions].

I was worried that was one of those. There was 1, 2 chairs for a second.

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 I'll hand over to the experts. So venetoclax and ibrutinib is not globally approved. So it's not really considered as a global standard of care. And because our Phase III study will be a global study, we chose the comparator arm to be venetoclax and obinutuzumab, which is globally accepted as a standard of care in a fixed-duration treatment. And 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 any?

No. That's basically -- is the global standard.

It's Michael Schmidt with Guggenheim. A question on...

We can't hear...

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 sort of a path registration in myeloma specifically?

That would be a question for Dr. Quach.

You might want to -- can I hear -- repeat question because I can see -- hear CANOVA, that's all I could hear.

I was wondering about the learnings of the CANOVA study of venetoclax in multiple myeloma and how that affects strategy for sonrotoclax, specifically in myeloma.

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 [indiscernible] and dexamethasone. The issue for that study was the fact that while there was a numerical difference, there was no significant progression-free survival based on the P value. And one of the problem unfortunately was the fact that there were excess sensoring in the control arm because people were moving on from the control arm. So if you had a BCL, if you had a 11:14 translocation, the feeling out there is that you need to have a BCL-2 inhibitor, and therefore, if you get randomized 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 the 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 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 serve. I hope that answers your question.

Jess Fye, JPMorgan. A 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?

So the first step is to start it. And obviously, we want to make sure that it's acceptable by the health authorities -- we have to see how the data will pan out. So 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 mental cell lymphoma patients. It's about 100 patients. Maybe I can ask Doc Seymour to comment on the enthusiasm right now about perhaps for the PI putting patients into this study.

Yes. I'll speak in 2 elements. One, not involved with the U.S. FDA or any regulatory agency, but the pirtobrutinib in the U.S. received approval in mantle cell lymphoma based on a single cohort from the 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 U.S., 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 cohort 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 covenants, BTK inhibitors stop working, but mutation is a great problem. You can see now from multiple presentations that when you start on pirto, you get this huge range of mutations across the BTK enzyme. That brand is potentially resistant to everything else. So Professor Seymour pointed out, he said, you now have a potential to erase these mutations with a protein destroyer. We do not inhibit the protein, we actually destroy the protein. And I think that, that's really what's differentiate the CDAC from everything else that we've had before. And is the new mechanism of action, where there's been no real CDAC [indiscernible] any other disease. And to me, it's amazing that you can actually destroy a protein, have very few side effects and get results.

Yes, you have a question, Yigal, go ahead.

Yigal Nochomovitz from Citigroup. Just following on the BTK degrader discussion, Dr. Seymour. Just curious with respect to the 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 -- are you going to see much less mutational pressure there given that you're degrading the protein so fast that the cell doesn't really have a chance to fight?

Yes. 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 BeiGene speak about specific preclinical work. So yes, the hypothetical risk with any targeted molecule is that changes in the structure of 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, 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 BeiGene people to speak about that.

Yes. Maybe I can also comment on that. We actually have done quite bit work, through working for emerging resistance, from under [indiscernible] to apply drug pressure to cell lines to see whether you can generate with also increase mutogenesis pressures. So what we found very interestingly, when you treat the cells with BTK degrader, you actually don't see BTK-resistant immersion. Why if you do that same thing with any of the reversible or reversible BTK inhibitor, you do see that emerging. The underlying mechanism, we're still not completely understand what's happening. But I think that has something to do with the BTK protein get completely eliminate, the cell just probably die much, much quicker. So that's our hypothesis, but we still don't have the hardcore evidence behind it. But resistant does seems to be much, much less associated with BTK degrader.

Yes. 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 knock down 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 it? Are we allowed to disclose that information?

I think the [indiscernible]...

We have...

Yes. So there's been very high levels of degradation. The median is above 95%. The -- and that's at doses at 100-milligram and above. We seem to be seeing a plateau in the degradation of that 200 to 350. 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 the PD market 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. So there is one online. It is asking for the rationale of tevimbra and BRUKINSA working in Richter's transformation.

So there's a preclinical data about each of these drugs, classes, both BTK inhibitors and also PD-1, PD-L1 and also preclinical data about the combination of the 2. One thing that is exciting about this data is the degree of responses and also the durability in the number of patients 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.

Yes. So I mean the BTK inhibitors do have effect in Richter 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, PD-1 inhibitor has been effective in Richter's although never at the sole range 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 are, the more new antigens you express. And the more you have to rely on immune evasion to survive. So to me, it actually basically makes sense to use this combination. I have to say that I was presently surprised at how well it worked, which I think is the reason why I led to a nature medicine publication based on the modest number of patients.

Yes. I'd just get 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 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 do they specifiy or about the degree?

I think so. Yes.

Yes. So that I -- thanks for clarifying. That IFS does have an amendment as they were presented yesterday that they are adding on sonrotoclax, so there will be a triplet in Richter's transformation.

Any other questions in the room. So going once, going twice, going 3 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.