Hello, everyone. Welcome to BeiGene's presentation at the 2022 ASH Conference. My name is Julia Wang, and I'm the Chief Financial Officer of BeiGene. Thank you for joining us today, and we are ready to get the program underway. Before we start, please be reminded that there will be forward-looking statements in our presentations, and our business carries certain risks. Some of the risks are discussed in our filings with the SEC, the Hong Kong Stock Exchange, and the China Stock Exchange. Please refer to those filings for more details. With that, we are excited today that we bring together senior executives from BeiGene and important, highly respected external researchers and clinicians to share their insights with us. To kick it off, please join me in welcoming John Oyler, our Co-Founder, Chairman, and CEO, to give us some opening remarks. John? Great. Welcome, everyone, for being here and joining us remotely. We're excited to be at ASH this year, and really excited and want to thank everyone on our team, all of our collaborators, and all the patients that have been on our trials for everything. We really appreciate working together with the industry to try to get great medicine to patients. I just want to start off for a second about BeiGene. I'm going to be pretty brief today. BeiGene, we say cancer has no borders, neither do we. Really, since our inception, we've been trying to do great science and bring impactful medicines to patients. We have an aspiration to do that in a way that could transform the industry and that could help bring medicine more affordably and more accessibly to patients all around the world. We're striving to do that too, and it's hard. We're well on our way, and we're excited about it. We think that BeiGene is really a very unique company. It always has been since the beginning, but it especially is today. The organization's over 9,000 people. We have a very broad pipeline and portfolio of clinical and commercial assets, and we've been very active in running clinical trials very broadly and very globally all across the world. Our research organization today is one of the largest research organizations in oncology in the world. It's over 900 people, and it has a track record of developing great assets like the ones you'll hear about today. It also has the scale, and it has the experience, and it has a science-based culture and a real passion, and desire to bring great medicines to patients. From a development perspective, we've thought about things very differently. From the beginning, we really wanted to change the way development's done, because development accounts for 90%, more or less, of the cost of most oncology medicines that make it to patients. If you want to be affordable, you have to rethink how you do development, and at BeiGene, we've tried to. We've built our own organization. It's well over 2,000 people, and it's an organization that basically is working largely CRO-free. It's doing that in a belief that we can work more efficiently, that we can go to sites and centers where CROs aren't interested in going, and where we can work with more technology and change the way things are done, which is hard to do if you're working through a third party. That's something that we very strongly have built, and we think we do differently. A perfect example of that is the way, as we started our organization, we did a lot of clinical development work in Australia, we had incredible experiences there, very quickly we realized we wanted to expand this across the world. We became one of the largest clinical trial sponsors in China. We began to do a lot of work in Poland and all across Eastern Europe. We began in Europe and the U.S., and now we're building out in Latin America, the Middle East, all over the globe. We're very committed to that. We think we're different, and we think we have the ability to do things faster and more cost-effectively, again, this is critical if you want to make affordable, accessible medicine. From a commercial perspective, we've really pushed to building our own commercial infrastructure in the two largest markets in the world, the U.S. and in China. In addition to that, we've built an incredible team in Europe. Gerwyn, the gentleman with the hat, is responsible for that. We're off trying to get our medicines, BRUKINSA first, to as many patients as we can there, that's been very successful too. During this time, we've pushed for global accessibility. Even though we've been a little company with our first product, we're approved in over 60 countries and regions around the world. We're building out in many of these ourselves so we can bring medicine the way we want to. The last piece is around manufacturing. I don't think when we started the company, we understood how important this was, but I think we learned very quickly. If you want to be affordable, if you want to be fast, if you want to be flexible, if you want to run many programs at the same time, you're going to need your own capabilities. We've invested very heavily in building our own biologics and small molecule capabilities. That includes bispecifics and ADCs, now we're investing very heavily in building a large biological manufacturing and a clinical center in New Jersey in the Princeton Innovation Center in Hopewell. We're an organization that's blessed with all of these capabilities. We really think about the future. How do you bring medicine in the future? How do we bring as much medicine as we can, become the most impactful company we can across the world, we think we can transform the way we do things. Today, we're really blessed with having the ability to share some of the things we're doing. With that, I would like to introduce Lai Wang, who's our head of R&D, who's joining us remotely, who's going to share a couple thoughts on what we're doing in R&D, then we'll jump back to the room. Thank you. Thank you, John. Good evening, everyone. I wish I can be there in New Orleans with you, but due to many different reasons, I wasn't able to make the trip. This year is special for us for BeiGene. BeiGene R&D really started about 12 years ago. In the past 12 years, we have gone through tremendous growth and have made many significant progresses. Today, the team includes over 3,300 members around the globe, making us one of the largest oncology-focused R&D teams in the world. The growth accelerated in the past four years, not only in the team size, but also at the portfolio level, which are shown at the bottom of the slide. With quadrupling in the research team size and increasing investments in diversified discovery technology platforms, there are now over 60 preclinical programs ongoing, compared to less than 10 just four years ago, including roughly half of programs with first-in-class potential and half with best-in-class potential. We expect starting from 2024, there will be 10+ globally competitive new molecule entities coming from our own lab into the clinic on a yearly basis. On the clinical side, we have brought many capabilities in-house in the past few years and now mostly CRO-free. This provides us with speed, quality, and a cost advantage. We are one of the very few pharmaceutical companies who have the internal capability to run global phase III trials. BeiGene's research has a proven track record. Three out of our first four internal discovery molecules are now proven and launched on the market. Today, you will hear about three key molecules which were discovered in our research lab. Worth to point it out, those molecules all come in with a strong scientific hypothesis, and also they were get into the clinic in very fast speed. All of them took less than 2.5 years from the establishment to get into the clinic. About a decade ago, we started the BTK program out of BeiGene. This program was initiated in 2012 based on a simple hypothesis that I will share with you in the next slide. BRUKINSA, also known as zanubrutinib and BGB-3111, is the 3,111th compound made out of BeiGene. It was selected as the preclinical candidate in 2013 and entered the clinic in 2014. Dr. Con Tam, who is going to present our BCL-2 program later, was the lead PI for zanu phase I program. Thank you, Con, for believing in zanu and its scientific hypothesis. As the clinical data emerged, we got increasingly more confident in zanu as the most efficacious and safer BTK inhibitor. We also understood that we had an uphill battle to fight as ibrutinib has already had a tremendous success in the field. In 2017 and 2018, two global phase III studies were initiated to compare zanubrutinib versus ibrutinib in head-to-head fashion. In November 2019, zanu received its first approval. To date, zanu has been approved in 60+ markets, benefiting patients with B-cell malignancy around the globe. The upfront PFS superiority versus ibrutinib is certainly the highlight of its success in the past 10 years, and it solidifies its position as the best BTK inhibitor. About 10 years ago, as I mentioned, we started this program out of BeiGene. That was based on a simple experiment. We looked at ibrutinib's pharmacodynamic effect in animals, which are shown on the left. ibrutinib had very good BTK occupancy at 4 hours after dosing, but there was a quite significant rebound in free BTK after 12 hours, especially in disease-relevant tissues such as bone marrow, spleen, and the lymph nodes, suggesting BTK signaling was not completely inhibited throughout the 24-hour time period. This is consistent with what was observed in the clinic, shown on the right. We hypothesized that a BTK inhibitor with better exposure or potency can potentially completely shut down BTK signal, therefore achieving better efficacy. In addition, there's also room to improve on safety with a more selective BTK inhibitor. With that, we designed zanubrutinib with better exposure and better selectivity. Its free drug concentration, which is the active portion of a small molecule drug in the body, was much higher than its IC50 throughout 24-hour time periods, with either 160 milligrams twice daily or 320 milligrams once daily dosing. For data not shown here, zanubrutinib treatment resulting complete BTK occupancy, not only in the blood but also in lymph nodes. Throughout the 24-hour time period, there's a very different case for ibrutinib, acalabrutinib, and its major metabolite, M27. acalabrutinib has high Cmax, but it is a much weaker BTK inhibitor compared to zanubrutinib. In addition, its shorter half-life and the fast clearance led to its active drug concentration going below IC50 just a couple of hours after dosing. We believe this explains why Acala has only shown safety advantage over ibrutinib but not efficacy, while Zanu has demonstrated both. I'm going to turn this over to Dr. Mehrdad Mobasher, who is our new Chief Medical Officer for Hematology, to talk about BRUKINSA clinical overview and ALPINE results. Mehrdad? Thank you so much, Lai. Welcome everyone who's here with us tonight, or wherever your time zone is, either in person or virtually. like Lai mentioned, I'm Mehrdad Mobasher. I'm the Chief Medical Officer of Hematology here at BeiGene, and since some of you might not know me, by background, I'm a hematologist oncologist. I was trained at Stanford University. I spent about 9 years at Genentech, division of hematology. I was involved in development of obinutuzumab, or GAZYVA, and then I led development of another class of BCL-2 inhibitor across all the indications. With that, I'll continue what Lai was presenting about BRUKINSA, but focusing on the clinical development program. And just to reiterate what Lai mentioned earlier, we had a hypothesis, and the hypothesis was on sustained inhibition. The molecule was engineered to have high potency and bioavailability and high kinase activity, and specifically be more specific and have lower kinase inhibition of other or off-target kinases. The hypothesis was that this would lead to increased activity and decreased toxicity. With that, we developed a clinical development program that to date we have enrolled more than 4,700 patients across 30 clinical trials around the globe. We developed a pretty bold clinical development program, including two head-to-head studies. Today we'll hear more about the ALPINE study, and it shows that BRUKINSA is the only BTK inhibitor that has been studied and also shown superiority both in terms of PFS and overall response rates in CLL and SLL relapsed/refractory. We had data in Waldenström disease in a head-to-head study called ASPEN, that the longer follow-up of this study showed that patients who were treated with BRUKINSA had more durable and deeper responses compared to ibrutinib. It was mentioned before, we have had approval in more than 60 countries and regions in four diseases, CLL, SLL, Waldenström macroglobulinemia, mantle cell lymphoma, and marginal zone lymphoma. Consistent with that hypothesis that we had and the way that we put the clinical development program, we saw consistently that our efficacy was superior to in-class molecules that you saw the PK and some of the preclinical models before. With that, we've continued to expand our development program. We're combining zanubrutinib with some of our internal molecules and also external molecules in rational combos. For example, I want to draw your attention to our data in follicular lymphoma that we released this summer in combination with obinutuzumab. BRUKINSA has been the only BTK inhibitor that showed exciting data in follicular lymphoma. I just wanted to show you what is currently ongoing in late-stage development with BRUKINSA. All the way on the top, you see our studies in CLL/SLL. It is approved in certain areas, including it was approved by EMA, both in frontline and relapsed/refractory CLL/SLL. Our PDUFA date by the U.S. FDA is January of next year. This is based on the data from two studies, ALPINE study which is the head-to-head in relapsed/refractory CLL/SLL, as well as SEQUOIA study, which studied zanubrutinib in frontline CLL. Below that, you see our study MAHOGANY, which is our phase III study in marginal zone lymphoma. We have approval in marginal zone lymphoma in different regions. This study is a confirmatory study in frontline marginal zone lymphoma. Below that, you see the yellow bar in mantle cell lymphoma. That's the MANGROVE study. Again, we have the approval across the globe. This study will be our study, uniquely a BTK inhibitor plus rituximab, a chemo-free regimen That will get us hopefully approved in frontline mantle cell lymphoma. This study is ongoing very well, and we are looking forward to having the results in a couple of years. We have the Waldenström that I mentioned, the phase III study ASPEN, which we have reported data from this study with those more deeper and sustainable responses in patients that were treated with zanubrutinib in a head-to-head study versus ibrutinib. Phase II follicular lymphoma, I just mentioned in combination with obinutuzumab. We are very excited about the data that we saw in this combination. All the way in the bottom you see our plan that we have ongoing studies. We diffuse large B-cell lymphoma in combination with rituximab and lenalidomide, and other combinations with rituximab. Going back to ASH this year, ASH 2022 is really a pivotal time point for us. It's a very important ASH for BeiGene. You know that we have our late-breaker presentation on ASPEN. We have three oral presentations, and we have 10 poster presentations. For a global biotech company like us, this is really a validation of how productive we have been with our broad pipeline and validated by American Society of Hematology with its presence. Tonight you will see what we'll present today, and you see where we are at the end of Sunday. We have had presentations that already happened on Saturday and Sunday. We'll walk you through the details of those presentations. We have presentations that are pending on Monday and Tuesday. We will limit our presentations to what is already presented in the abstract. Given the ASH embargoes, we really invite you to come to our actual presentations and see more data that will be presented specifically with our BCL-2 inhibitor that will show with more longer follow-up. We will walk you through this data by our expert presenters and expert key opinion leaders. As was mentioned at the end, we have a panel of internal experts from the company executive team and also our experts. We'll answer all your questions. We ask you to hold off your questions at the end. You will see on Saturday we had a couple of presentations on zanubrutinib, for example, our MAGNOLIA study in marginal zone that again, consistently we saw our data is better than in-class competitors and also other benchmarks. We also have data from our exciting BCL-2 inhibitor. Some of it is already presented and some of which in CLL and NHL will be presented tomorrow on Monday. Last but not least, the late-breaker abstract on ALPINE. The ALPINE presentation is a late-breaker abstract, as I mentioned, will be presented on Tuesday during the late-breaker session. The session starts at 9:00 A.M. Our presenter will be Dr. Jennifer Brown from Dana-Farber. This is the sixth abstract that will be presented at that session. Similar to tonight, we'll have another webcast focused on the ALPINE data that will happen at 2:00 P.M. Central Standard Time, so local time. Again, we'll have executives from the company and also experts including Dr. Brown and Dr. Shahman, who's here tonight and is also the senior author of this paper. Will answer your questions about this presentation. Tonight I'll briefly go through the data that we have put in the abstract. Again, as you know, ALPINE is a head-to-head study that studied zanubrutinib versus ibrutinib in relapsed/refractory CLL, SLL. The study enrolled 662 patients, enrolled in a randomized one-to-one fashion between the two arms. As you can see in this slide, the patient demographics and disease characteristics were well-balanced between the two arms. In this study with a median follow-up of 29.6 months, we show superiority of PFS in patients who were treated with zanubrutinib compared with ibrutinib. The hazard ratio in this Kaplan-Meier curve is 0.65. You see the curve as assessed by IRC. This clinically meaningful risk reduction in PFS was also associated with a statistically significant P value of 0.0024. Not shown here, but we had a PFS as assessed by the investigators, and we showed consistent PFS superiority in patients who were treated with zanubrutinib. This study had a predefined subgroup analysis. We looked at different subgroups of disease characteristics and again, demographics, and we showed that the superiority seen in zanubrutinib was across all the subgroups. I am specifically showing one subgroup of 17p deleted and/or TP53 mutated, which is a known high-risk subgroup. Again, you see the superiority of zanubrutinib, this time with a hazard ratio of 0.52, and you see the nominal P value of 0.01 associated with this superiority of zanubrutinib. Briefly on safety and tolerability, you see that high-grade adverse event and serious adverse events were all lower in zanubrutinib arm compared to ibrutinib arm. Specifically, treatment discontinuation to adverse events were 16% in the zanu arm, and it was 22.8% in ibrutinib arm. Important when we think about tolerability, you see adverse events that led to treatment of dose interruptions or adverse events that led to dose reduction were all lower in zanubrutinib arm compared to ibrutinib arm. Rate of atrial fibrillation and atrial flutter were key secondary endpoint in this study. We show that the rate of AFib flutter was lower in zanu at 5.2%, compared to 13.3% in ibrutinib arm. When we think about adverse events that led to death, we had 0 patients in the zanubrutinib arm that had death, but we had six patients in the ibrutinib arm that died due to adverse event of cardiac disorders. In terms of discontinuation due to cardiac events, we had one patient or 0.3% in the zanubrutinib arm, and we had 4.3% of patients treated in the ibrutinib arm who discontinued the treatment due to adverse events. These are the conclusions that authors put together in the abstract. ALPINE is the first study to show PFS superiority in a head-to-head comparison of a BTK inhibitor. In our case, zanubrutinib showed both overall response rate and PFS superiority when combined to another BTK, ibrutinib in CLL and SLL. PFS benefit was consistent across subgroups that were studied. Zanubrutinib safety profile was favorable when compared to ibrutinib, with lower rates of discontinuation and specifically cardiac adverse events, and as I mentioned, no adverse events that led to death. These data suggest that zanu is more efficacious and better tolerated than ibrutinib in patients who were treated for relapsed refractory SLL and CLL. With that, we will deep into a couple of more abstracts and presentations that we have had at this ASH, and it is my honor to introduce Dr. Mazyar Shadman, who is a professor at Fred Hutchinson Cancer Center at University of Washington. His research and clinical practice is focused on high-grade lymphomas and B-cell malignancies, including CLL. He has been key in our development of both BRUKINSA and our BCL-2 inhibitor. Thank you everyone. I will pass the podium to Dr. Shadman. Hello. Thank you, Mehrdad, and thank you for the invitation. It is great to be part of this conversation, congratulations to the BeiGene team for the great ASH meeting. What I will be doing tonight, briefly, I am sorry. I will be covering 2 studies that are already presented, one, the study that was presented by Professor Alpat and looking at the long-term efficacy and safety of venetoclax in patients with relapsed/refractory marginal zone lymphoma. Marginal zone lymphoma is a relatively rare non-Hodgkin lymphoma, especially in advanced stages, is considered incurable. Patients are usually at the higher ages with comorbidities, it is important to have non-chemotherapy options as a treatment choice. This is study patients with relapsed/refractory marginal zone were treated with venetoclax at the standard dose of 160 milligrams twice a day, treatment was continued until either progression or intolerance of the drug, with the primary endpoint of overall response rate assessed by IRC. From the 68 patients who were reported here in this long-term follow-up, some of the highlights, you see the median age of 70, ranging from 37 to 95. It is also important to note that 60% of patients are 65 years old or older, 28% more than 75. Important baseline characteristics and also different subtypes of marginal zone are listed there. Also importantly, 30% of patients had refractory disease as defined by standard criteria. Here we see the efficacy of the drug and overall response. The response was assessed by either PET scan in patients who had FDG-avid disease or by CT scan in those who did not. As you see, the response rates are at the range of 68%, 67%, the complete response rates in a quarter of patients were observed here. Just to put it in perspective, is other BTK inhibitors, the numbers, for example, with acalabrutinib from what is reported is in the 54% range with a CR rate of 16%, with ibrutinib in also at 58% with 10% CR rate. Again, cross-trial comparison is always difficult, this seems to be as effective or more. We will cover the discontinuation rate in the upcoming slide. The different subtypes of marginal zone lymphoma are listed here. Again, the overall response rate seems to be consistent regardless of the type of marginal zone that patients have. More importantly, the durability of responses, progression-free survival, and the duration of response and overall survival are listed here, ranging from 65% to a higher 70% and 77% in some subtypes in terms of progression-free survival and duration of response in the range of 75%-80%, with very high overall survival rates as listed there in the range of 80%-90%. Effective treatment with durable responses with zanubrutinib in patients with relapsed marginal zone lymphoma. Now looking at the adverse events, patients had side effects. All patients had some kind of adverse event, Grade 3 or more, that where treatment emergence were observed in 48% of patients. The adverse events that led to discontinuation happened in 7% of patients. Just again, to put it in perspective, a small study from University of Pennsylvania, patients who received ibrutinib for marginal zone lymphoma, the DC rate was around 40% in that study with a median follow-up of three months. Well-tolerated drug and consistent with some of the other studies that we have with zanubrutinib in different B-cell malignancies. Most common adverse events are shown there with basically Grade 1 and 2s in the blue color and Grade 3 and more in the red or orange. Again, overall consistent with low rates of adverse events. Specifically looking at the adverse events of interest for BTK inhibitors, here we have infections, hemorrhage, cardiac side effects, and secondary malignancies. As you see, hemorrhage Grade 3 or more is only shown and observed in 1.5% of patients. Hypertension, an important side effect that we closely monitor with BTK inhibitors, Grade 3 or more was only reported in 3% of patients. AFib, atrial fibrillation, in 1.5% Grade 3 or more, and overall it's 3% for AFib. In terms of ventricular arrhythmias, another area of focus for BTK inhibitors, there was no patient who had Grade 3 or more ventricular, basically, the arrhythmia in 1.5% overall was reported. In terms of patients who came to this study had history of cardiovascular disorder, and that's always important to note when we look at adverse events that occur on this study. For example, here 11% of patients had a history of AFib, and 30% of patients had history of hypertension. We see the rate of adverse events listed there. Again, unrelated to this study, but showing the pooled analysis, which was done by Professor Han Tam, basically looking at more than 1,500 patients treated with zanubrutinib compared to ibrutinib-treated patients, more than 400. Here we look at some of the AEs of interest, namely atrial fibrillation. The difference is shown there. For example, with the numbers there for zanubrutinib Let me see here. 6.5% versus 6.2%. I'm sorry. The patients who came on the baseline or past medical history of atrial fibrillation is similar between the two groups. I was surprised at why numbers are equal. 6.5% and 6.2%. This is past medical history, patients coming with a history of atrial fibrillation and also history of hypertension in 43% versus 48%. In adverse events after treatment with zanubrutinib or ibrutinib, as you see, there's a significant difference with 3.9% with zanubrutinib and 14.2% with ibrutinib, and these differences were significant based on the statistical analysis. More importantly, ventricular arrhythmias, again, an important AE that is being monitored for BTK inhibitors, significantly different between the two. Also the hypertension rate of 14% versus 20%. In conclusion, with a median follow-up of 28 months, zanubrutinib showed high response rates and durability of responses with overall response rate of close to 70% by both CT and PET scans. In all subtypes of marginal zone, this response was observed and a progression-free survival rate of 71% and a DOR or duration of response of 73% and an overall response rate of 86%. The drug was well-tolerated. Hypertension, atrial fibrillation were uncommon. It was comparable to the pooled analysis that was done and I briefly reviewed. Only one patient had major gastrointestinal hemorrhage, and this patient was also on an anticoagulant at the same time. There was no new safety signal in this study. Moving on to the next study. This is the study that looked at zanubrutinib in patients who did not tolerate acalabrutinib. An important study, just as a background, we do have randomized studies comparing different BTK inhibitors, basically looking at the incidence of adverse events and with the different drugs. In this study, we are looking at patients who are high risk for developing adverse events because they already shown to have adverse events on another BTK inhibitor. This study started by looking at 2 cohorts, patients who had ibrutinib. That cohort is already reported and published. What we're presenting at this meeting is cohort 2 patients who were intolerant to acalabrutinib. Patients with different histologies were enrolled in this study, including CLL, mantle cell lymphoma, marginal zone lymphoma, and Waldenstrom's. Basically, patients who were intolerant to acalabrutinib received the zanubrutinib therapy. In this study, we actually had the choice of going with the BID dosing and also once-a-day dosing, and the schedule was otherwise consistent with other studies, treatment until progression or having adverse events. Baseline characteristics are shown here. I'm not going to read them. I think one important point to mention here is that some of these patients were also on ibrutinib before going on acalabrutinib, so zanubrutinib was the third BTK inhibitor that they had. Also, the median time on acalabrutinib or exposure to acalabrutinib before starting or enrolling to this study was 4.6 months. We'll see the median exposure time to zanubrutinib in this next slide. This is important because some of the adverse events are that the incidence goes up by longer exposure, 4.6 months. What this figure shows on the Y-axis, you have different adverse events that patients had on acalabrutinib, and these were the reasons why patients came on this study or entered this study and received zanubrutinib. For each event, you have different colors. When you see the blue color, it means that that adverse event did not occur. If it's dark blue, it means that it occurred at a lower grade. If it's yellow, it means that it occurred at the same grade. We don't see red, but red would be a higher grade AE. In general, just visually, we can see that most of the adverse events on acalabrutinib either did not recur in zanubrutinib, or they occurred at the same or a lower grade. To basically summarize some of the important points from that figure in terms of just looking at the event, 75% of intolerant events on acalabrutinib did not recur in zanubrutinib. There was no adverse event that occurred at a higher grade. Next, looking at the patient level, 67% of patients did not experience any recurrence of the adverse events that they had on acalabrutinib. It also should be noted that few patients had the same intolerance events on both acalabrutinib and ibrutinib, and these were diarrhea, atrial fibrillation, and joint pain. Two of these three did not have recurrence of the side effects on zanubrutinib. Adverse events, I would just say that there's no new safety signal, these adverse events are consistent with what we see with zanubrutinib in different studies. In terms of serious adverse events and adverse events leading to discontinuation or interruptions and dose reductions are listed here, only two patients stopped treatment because of adverse events. The drug was, in terms of we showed the safety profile and the fact that patients could continue on treatment. The efficacy was also promising. Remember, I did not mention that these patients, when they entered the study, some of them did not have measurable disease, but the responses were maintained or improved over time on zanubrutinib. The point being that the drug continued to show efficacy in patients who had intolerance to ibrutinib. As a summary, it's an important study in that in patients who have intolerance events on a second-generation BTK inhibitor that led to the discontinuation of drug can benefit from another BTK inhibitor, zanubrutinib, most of the adverse events did not recur, and patients were able to continue treatment and maintain their responses. With that, I believe Dr. Campbell will present the next study. Dr. Shadman. Similar to what we did with zanubrutinib, we'll just do a brief introduction to our exciting BCL-2 inhibitor or BGB-11417. I will just walk through a couple of characteristics of this molecule, and you will see that the story is very similar to what we did with zanubrutinib. Within our research, we try to understand the real question and design molecules for that target. This drug, our BCL-2 inhibitor, also has the potential, in our belief, to be a best-in-class molecule. That's given the higher potency and higher selectivity, as well as shorter half-life that this drug has compared to venetoclax. We think it will lead to improved efficacy and also improved safety of this drug. We have already started a broad clinical development with this program. You see we have studies in CLL, non-Hodgkin lymphoma, including Waldenström macroglobulinemia, mantle cell lymphoma, marginal zone lymphoma, as well as acute myeloid leukemia and myelodysplastic syndrome, and a subset of multiple myeloma that harbor a specific translocation 11;14, that makes this subset very susceptible to BCL-2 inhibition. This is one of our early molecules, but not very early. We have already enrolled more than 300 patients across four different studies that are phase II studies that we have with this molecule, so far, we have not shown any safety signal of concern. We do have encouraging efficacy data accumulating, and you will see some of the data that will be presented later. Just an example, we are seeing some deep and durable responses in CLL as we are still in dose escalation. We do need more follow-up in some of our higher doses, but we are very encouraged with the efficacy that we are seeing. Similarly, in AML, we are combining a drug with azacitidine, we are seeing higher rates of complete remission, even in the lowest dose that was tested, which was 40 milligrams of 4-1-7. We have started two phase II studies that have potential registration. They have registrational intent. One of them is in relapsed/refractory mantle cell lymphoma, post-BTK inhibitor treatment, the other one is in relapsed/refractory CLL, post-BTK inhibitor. As we know, BCL-2 inhibitors have a really large, broad registrational potential that BeiGene is aggressively looking and designing studies that we're hopeful that soon we can present to you. I just wanted to talk very briefly about a couple of characteristics of the molecule that I showed in the previous slide. We are comparing our BCL-2 inhibitor, 4-1-7, to the established BCL-2 inhibitor, venetoclax. We know that this drug has a higher target and higher potency. On the top, you see how we are comparing our drug versus venetoclax in terms of protein inhibition, you can see our drug is 14 times more potent. Specifically, when you look at a known resistance mutation that patients develop on venetoclax, or G101V, our drug has the potential to overcome that resistance. You see 57 times more potent our drug compared to venetoclax. In the bottom, you see target selectivity, our drug is very specific to BCL-2 and not inhibiting the other members of the BCL-2 family. Again, like I said, very similar story to how our thinking was with zanubrutinib, that we developed a very potent and a very selective inhibitor of BCL-2. We looked at the PD model. We looked at the pharmacodynamic model. We looked at the reduction of absolute lymphocyte count in CLL. All the way to your left, you see venetoclax. Of course, venetoclax has a ramp-up starting from 20 to 50 to 100 to 200. In the middle, you see our current ramp-up. Of course, we have started with a pretty conservative ramp-up. We looked at a 90% reduction of absolute lymphocyte count as a cutoff to compare ourselves versus venetoclax. You can see with our drug, we achieved the 90% ALC reduction with dose of 40 milligrams of 4-1-7, as opposed to venetoclax that achieved that level of ALC reduction with 200 milligrams. When you look at the milligrams to milligram, we believe we show that our drug is five times more potent compared to venetoclax. This is a development program that we have put together. All the way on the top, you see our phase I/II in B-cell malignancy. This is a study that we are investigating 4-1-7 as monotherapy and in a staggered way in combination with zanubrutinib in CLL and NHL. Below that, you see our study in multiple myeloma. As I mentioned, we are investigating the drug in a subset of multiple myeloma that harbors translocation 11;14 as monotherapy, followed by combination with dexamethasone and ultimately combined with proteasome inhibitor carfilzomib. Below that in orange, you see our study in myeloid malignancies, AML and MDS. We are investigating a drug both in relapsed/refractory setting and frontline setting in combination with azacitidine. In blue, you see the line in mantle cell lymphoma. That's the phase II study that I mentioned we have started with registrational intent, post-BTK inhibitors. Below that, you see the phase II study that is ongoing in CLL/SLL in patients who have already been treated and progressed through BTK inhibitors. With that, we will move on to presenting some of the highlights of the data that we are presenting at ASH this year. It's my distinct honor to present to you Dr. Khan Tam, who really doesn't need any introduction. You see that he's a professor of hematology at Monash University in Australia. It was mentioned earlier by Ly that he played a crucial and pivotal role in development of zanubrutinib. In fact, he has treated the very first patient in the first-in-human study that we did with zanubrutinib. One thing that I think I should highlight that he has published 259 peer-reviewed manuscripts, and he's one of the editors of Blood Advances. With that, I'll pass on the podium to Dr. Tam. Thank you, Dr. Tam. Thank you for your invitation and thanks for sticking with us this late in the evening. I will just share some of the experiences with this new drug, BGB-11417. My personal impression is that, just like zanubrutinib, it really has the backbone to be the best in class. As you know, venetoclax or the BCL-2 inhibitor is now really a very important drug, not just in CLL and mantle cell lymphoma, but also in multiple myeloma and AML, very broadly applicable category. This is the BGB-11417 phase I first-in-human study. This first presentation will focus on those patients with CLL. Now, because the company also has zanubrutinib in its assets, it makes sense to combine a BTK inhibitor with the BCL-2 inhibitor. In this phase I study, we explore not just the new drug 11417 in CLL, but also exploring this drug in combination with zanubrutinib, because ultimately we think that the best use of this drug will be, in fact, by combining the best BTK inhibitor, zanubrutinib, with the new BCL-2 inhibitor and to have a combination that is totally oral and totally in-house to the company. This is a study design. It's a very straightforward design. Patients are started on a low dose of the BCL-2 inhibitor at 40 milligrams, which, as Dr. Mobasher has shown you, is already equivalent to a potent dose of venetoclax. The final target dose of BGB-11417 is 640 milligrams, which would be equivalent to around three grams of venetoclax. The reason why we're trying to push such a high dose is because we know that resistance mutations are a problem with venetoclax, and hopefully by achieving a high dose, we can inhibit those resistant mutations and prevent the emergence of other mutations. Far, with CLL, we have dosed 50 patients. six patients were dosed on the monotherapy just to prove the safety, but the majority of patients were treated, in fact, in combination with zanubrutinib, which is where we think the drug will ultimately end up. 44 patients treated in combination. This is data that was presented previously. This data will be updated at ASH this year. Because of embargo, we're not able to show you the updated data. I will talk through the gist of it, but I encourage you to actually attend the conference so you can get the most up-to-date figures. This is the design. Monotherapy, the median follow-up of monotherapy is 11.5 months. The combination cohort started a little bit later than the monotherapy cohort. The median follow-up for this particular report is five point eight months. Of course, this will be updated at the ASH conference tomorrow. In terms of adverse events, this is a very busy slide. I'd like to emphasize that the most common side effect with venetoclax and the most feared side effect is tumor lysis syndrome. In fact, out of the 50 patients we've treated, we only saw one patient with tumor lysis syndrome, and this is a patient who had to come off his BTK inhibitor because of progression. He had extremely genetically rapid progression of his disease before his first dose of BGB-11417, and this person developed biochemical tumor lysis syndrome and was controlled and continued on the drug. To put this into context, this is a patient with very aggressive disease and tumor lysis syndrome is almost expected in this patient. Apart from this one patient, we've actually had no tumor lysis syndrome whatsoever. There's been no evidence of clinical tumor lysis syndrome, which is the most severe category. Probably the two most common side effects with venetoclax would be diarrhea as well as neutropenia. Part of my fear when we first started, or part of my worry when we first started this program, is that we would get quite severe GI toxicity and neutropenia, and I'm very glad to tell you that we have in fact seen almost none of that. The GI tolerance has been excellent for the dose that we've been given. Even though we've pushed the dose to much higher dose than venetoclax ever achieved, the neutropenia rates have actually been really quite low. With the combination therapy, we saw all the side effects that we expect of zanubrutinib, and there were really no additional side effects that were unusual. You can add this drug to zanubrutinib, and you get pretty much a very well-tolerated regimen with no unexpected new toxicities. This is just to say that this will be updated tomorrow at 4:45 P.M. by my colleague, Professor Chia. I'm sure you can see the gist of it is that 12 months data track. The regimen is doing very well with no unusual findings. We're now seeing deep responses, including minimal residual disease and negative disease-negative responses. Of course, this drug is also BCL-2, it is also active in other diseases and in particular mantle cell lymphoma and Waldenström's. At this meeting, we will also update the data on these two histologies. Reported by my colleague, Dr. Semrai. You can see here once again that in this histology, once again, have both monotherapy as well as combinations with ibrutinib. In terms of the Waldenström's and MCL, as you can see, 45 patients have been treated, 34 on monotherapy, and these are patients with either NHL or Waldenström's. All the combination patients received were mantle cell lymphoma. Once again, the side effects were, in fact, very benign, in my view. There was some minor nausea, some minor fatigue. Given the doses of drugs that we've been using, my personal impression is that the side effects are actually more benign than venetoclax at the same doses. As you can see, so far, 25 patients of this cohort have discontinued treatment, predominantly for progressive disease, but these were in patients with diffuse large B-cell lymphoma, where the response to BCL-2 inhibitors has not been all that good in general. In terms of the combination adverse events, once again, the summary is that you can add this with ibrutinib, and you get the same side effects as on ibrutinib, and there were no really unexpected toxicities when you add these drugs to ibrutinib. This waterfall plot illustrates the histologies that were tested. Now, of note, the mantle cell lymphoma cohort was not on this waterfall plot and is presented separately. You can see that the disease which did not respond as well with yellow, and that's diffuse large B-cell lymphoma. Diffuse large B-cell lymphoma in refractory state typically does not respond well to BCL-2 inhibitor, even a potent one such as this, and that's not really an unexpected finding. However, you can see that there is some response in green in follicular lymphoma and in marginal zone lymphoma in purple, which is the expected histology to respond. They do respond well. In terms of the sensitive cohort, in a mantle cell combination cohort and with very short follow-ups, and not all of these patients have had restaging scans to prove that they have responded, we've got 65% response rate so far, so that's right on track. Same with the Waldenström's cohort, we have seen reductions in IgM. Because this drug is so new and the patients have not been on drug for very long, we haven't seen the full depth of the responses so far. The conclusion is essentially the drug is safe. There is no unexpected toxicity, dose for dose compared with venetoclax. The side effects seem to be very manageable. We couldn't find a maximum tolerated dose, and the dose level reached all the way up to 640 milligrams, which as you know, is about three grams of venetoclax, and that is the level that venetoclax never got to. The side effects were low grade. The neutropenia was manageable. You need to interpret the responses in the context that for most of these diseases, you need time to reach the best responses. We're taking a snapshot at a very early time point, and from what I can see in my patients, the responses are exactly as I expect, that they are all heading in the right direction. Quickly, just to show you two other presentations, because lymphoma is not the only disease where BCL-2 inhibitor is useful. AML is also a disease where venetoclax has found a niche. venetoclax is given in combination with azacitidine in AML, and of course, this is a natural space to explore the new BCL-2 inhibitor as well in AML. This is a study design, patients are treated with a combination of BGB-11417 plus azacitidine in a dose escalation session in patients with relapsed refractory AML. And based on characteristics, this is a very typical group of patients with relapsed refractory AML. In fact, it's probably a bit more adverse than usual. You can see that we actually treated patients up to the age of 91 years old in this trial. This is only achievable when you have a low toxic class of drugs like a BCL-2 inhibitor. In terms of the AEs, remembering that these are patients with acute myeloid leukemia who enter the study with a severely compromised bone marrow, the AEs are really, there's nothing unexpected there at all. There is a high proportion of serious and grade 3 AEs, but that is exactly what you see when you conduct any study in relapsed refractory AML. Importantly, the AEs leading to discontinuation in this whole population is relatively low at 18%. These are the different cohorts. You can see there was a DLT signal at 80 mg. The more patients were enrolled, proving that this DLT signal was not dose-limiting. At the moment, the dose that's being explored is 160 mg for 28 days in 28-day cycles. These are the side effects. Now, as I said, these are patients with acute myeloid leukemia, so neutropenia is almost expected in these patients. They come in neutropenic and they end up neutropenic on the drug. But if you look at the other side effects such as infection and pneumonia, all those rates are actually very low, and remembering that this trial included patients up to the age of 91 years. The complete remission rate so far, if you consider all the patients in total, the CR rate, as you can see, exceeds 50%, which is really very encouraging because if you think about the randomized study of venetoclax and ibrutinib, the CR rate is in the order of 37%. Already in a phase I study where we haven't really optimized the dose, we're seeing a CR rate that is historically higher than that was reported historically for venetoclax. And I think that if you look at the blast percentage in the bone marrow, this really tells the story. Across all the doses, we have seen a good reduction in blast percentage in the bone marrow, indicating that this is a clearly active drug. The conclusion was that it is generally well-tolerated in patients with AML, really about as well-tolerated as you can hope it can be. The side effects are essentially those that were expected when you perform any study in an AML population, and the response rates so far are very encouraging and consistent with the hypothesis that a potent and optimized BCL-2 inhibitor may produce very deep responses in AML. The last disease, of course, is multiple myeloma. This study in multiple myeloma is restricted to those patients with a particular chromosomal abnormality, translocation of 11 and 14, and that's because these patients are the ones that we know who are sensitive to venetoclax in the venetoclax studies. Once again, a very standard ramp up in monotherapy with a plan to add dexamethasone and carfilzomib which are standard regimen drugs in myeloma once we have the dose optimized. Early-stage data so far, but you can see that the side effects are really quite benign up to the current dose level of 640 milligrams. In terms of disease responses, once again, this is very early, but you can see that across all the patients that we have a CR rate as a monotherapy, so single drug, of 33% and additional 8% minor response rate. This is consistent with this drug being on target, this is this drug working in multiple myeloma, and the next step is to combine it with other drugs as we do with venetoclax including dexamethasone and carfilzomib. This is the myeloma study conclusion that the drug is tolerable in a combination of dexamethasone, that there were no MTD reached, the 640 milligrams was reached, and that the toxicities were manageable. There was a particular emphasis that even on monotherapy, that there was a patient who actually not only responded, but there's one patient who achieved a complete remission. The dose escalation is ongoing, and they have not achieved a recommended phase II dose in this study. In aggregate, that these studies in CLL, in mantle cell lymphoma, in Waldenström macroglobulinemia, in AML, and in multiple myeloma, the drug clearly works. The drug is clearly well-tolerated through the doses achieved. We are seeing the responses exactly as you would expect at this point in development. It's looking very promising. In particular, I was worried that this drug would cause severe neutropenia given its potency, but we haven't seen any of that. It looks like this may be another best-in-class optimized drug for BCL-2. Thanks for your attention. Thanks, Sam. I want to introduce another asset in our hematology pipeline, the BGB-16673 that we call it a BTK CDAC. CDAC stands for Chimeric Degradation Activating Compound, so basically a protein degrader that we have developed, and we are studying it in B-cell malignancies. Protein degraders are basically targeting BTK as an important new class of drugs because it's approaching BTK and BTK inhibition with a different mechanism. The reason that we are approaching this degrader is that we think it's a new mechanism that will actually, based on the experience and expertise that we have developed in BTK inhibition, it really adds on to what we have done already. In terms of treatment, it really can overcome some of the BTK inhibitor resistance mechanisms and specifically can destroy non-kinase or this scaffold function as well. This specific drug, like I mentioned, 673, we call it, is our first protein degrader. There are a couple of important points to highlight about this drug. First of all, it took us two and a half years only from the program initiation to enter clinic, which we are very happy about. The drug itself has good pharmacological properties. A differentiator between this drug and another in class molecule, which is in the clinic, is that this drug doesn't have IMiD activity which will ultimately lead into improved safety. Again, similar to some other drugs that we have already talked about, it's highly potent and selective and has very good oral bioavailability. I put a couple of panels in terms of the data that I want you to look at. On the top, you see three patients who were treated with our very first dose cohort of 50 milligrams, the lowest dose cohort in our first-in-human phase I study. You see a deep and rapid and sustained protein or BTK degradation that was seen. Within 8 hours, BTK is completely destroyed, and it remains sustained. It goes all the way to one month. In the bottom, you see that we have studied this drug and a couple of other drugs. Basically, zanubrutinib, our own drug, and LOXO-305, or pirto, which is a different BTK inhibitor. We are showing specifically in wild type and also in a couple of resistances that we know all BTK inhibitors have developed resistance to when they have this mutation, or a specific mutation that's relevant to pirto. We see that this drug can overcome that resistance mechanism. We are very excited about this molecule and we continue this phase I study, and we are hopeful that soon we can report more clinical data from this study. With that, I want to talk a little bit about how we are putting all these drugs together and how we are approaching our overall pipeline. The first is how we are currently with our BTK inhibitor zanubrutinib in different diseases. All the way on the top, you see B-cell malignancies, as in CLL, mantle cell, marginal zone, follicular, Waldenström's, and even diffuse large B-cell lymphoma. We have monotherapy and we have what we call rational combos, both with external assets and also our own assets that you will see. But in the near future, BCL-2 inhibitor will actually get us into a lot of these diseases that we were studying before, basically building on our leadership in B-cell malignancies and also get us to new disease indications, the myeloid, AML, MDS, and multiple myeloma. In terms of our BTK CDAC, like I mentioned, it's being currently assessed in a series of B-cell malignancies, but of course, we will down the line think about combining them with our own drugs and also some external rational combinations. We didn't really talk about our IO assets, but we are studying our immuno-oncology assets in diffuse large B-cell lymphoma, and also we have presence in classical Hodgkin lymphoma. With that, I want to give the podium back to our Co-Founder and Chairman and CEO, John Oyler, to wrap up the session. Great. Thank you so much, all the presenters, for the great presentations. I just want to make a couple points. I think that this has been made. I think we have a really exciting and growing hematology platform. I think you've heard a bit about BRUKINSA. From the beginning, this was designed for great efficacy. We thought there was an opportunity, and we pursued that. I think that as you've seen, there's a very broad development program. We've taken a bold approach. I think we've tried to follow the science and run the right studies, and that's risky, but in this case, the risk certainly has paid off because BRUKINSA is a wonderful asset. I think that as we committed as a company when we began, we're going to really try to get this as broadly available as we can. Again, I really thank the team for the extra time and effort they put in to really expand this program to 60-plus markets as quickly as a company that was growing. You've heard a little bit about the BCL-2 inhibitor, and again, we think that this is a similar story to the one we've heard before. It's got the potential really to be something compelling and different, and we're excited about that. I think as we've mentioned, we're already starting, I forget the words that Mehrdad said, I really liked it, registrational, with registrational intent, I think it was a couple studies. We're moving that program forward, and we're really excited about this protein degrader. This is an area in which the company is working very heavily, not just in hematology, but also on the solid tumor side. The other points I want to leave you with is I think BeiGene from the beginning has been a little different company. We really are committed to trying to find ways to do things differently, really trying to make medicine more broadly accessible and affordable to patients. I think on the way of doing that, we've really mapped out what we think the world looks like in five years and what we need to do as an organization to get there, and what strategic capabilities we need to build to really become one of the most impactful companies in the world in oncology. That's what we're striving to do. I think in that perspective, we've built an incredible research team. It's not a one-trick pony. You can see what else is coming. I think that we've built this unique clinical development team that's largely CRO-free all across the world that has been very, very effective in running a broad number of phase III trials from that perspective. There's not many oncology companies that aren't pharmaceutical companies that have run as many phase III global oncology trials as BeiGene has. We had run none, I don't know, a few years ago. It's really a tribute to the capabilities and the team that we have there. That's combined with a commercial organization that is growing and strong in the two biggest markets, and soon, when Gerwyn gets back to Europe with his team there, in the third-largest market from the European perspective. We're really building that, and again, we've invested heavily for our own manufacturing so we can move fast, we can be flexible, and we can control our costs. With that, the intention is to help a lot of cancer patients. I think that we're well on our way to doing that. Again, I want to thank, incredibly, the BeiGene team. I want to thank our families who support us and put up with us when we put in a little extra time and energy. I want to thank the collaborators that we have, who really have inspired us and help us direct and drive this program in the best way possible. Of course, the patients that are out there from that perspective, the rest of those that have followed us and helped us get to where we are today. Fighting cancer isn't something that an individual can do easily alone. They need a lot of support. Fighting cancer isn't something that a company can do alone. We need a lot of support, and we all need to work together because it's a terrible thing we're trying to fight. Hopefully, every little success we have can be very impactful for a patient and impactful for their families and everyone else. With that, I just really want to thank everyone, and I think we're moving to questions. I think I should invite everyone up on the stage who's supposed to come up on stage, and we're happy to take some questions. Thank you. You know everybody. Our expert panel, and I'll basically be the moderator of this Q&A panel. A couple of my colleagues are here with microphones, so if you see a hand raised, please give the microphone. Here, please. Orville from Cowen. Maybe I have a couple of questions. Maybe I'll kick it off to you, and you can see who ought to answer them. Maybe the first one, and I know I'm jumping the gun a little bit, but BRUKINSA's ALPINE data that's coming on Tuesday. When we look at the curves, we're now at 26 months. I think you're going to be updating it. It's probably going to be close to 30, I think, when we're actually going to see more mature data. When you're looking at the separation in PFS, and we compare that to the studies from Calquence, where they separated early on and by year four or so, they sort of came together, and that was in a high-risk population. What are you expecting in terms of separation of those curves? Can you continue separated? Maybe secondly, maybe Dr. Tam to you. A lot of the feedback we're getting from KOLs is the dose escalation for ven and the BTK is very difficult over 4 weeks. I think here you're actually showing it early on. You're getting to trough at that 40 by 5 weeks or 6 weeks, and then you go lower. You expedite that a little bit. Finally, maybe Dr. Tam, what do you want to see from the BTK degrader in terms of safety? And are you worried that the feedback we're getting, if you're going too broad, are you going to get into some safety issues? Thank you. Maybe I'll let Dr. Tam answer the second part of your question first. Please, Con. Sure. With regards to the dose escalation, and I had to do this day in, day out. You're right. venetoclax dose escalation, the pain is required for tumor lysis monitoring. There's a real advantage to BGB-11407 that I forgot to mention, and that is the half-life. venetoclax has about a 20-hour half-life. It doesn't get to steady state until five days of therapy. Therefore, you can't actually escalate venetoclax safely any less frequently than every five days. That's why it's weekly escalation. Now, when we built the BGB-11407 program, which has a very short half-life, only a few hours, you can actually do daily escalation. We chose to be conservative because we knew it's very potent, and we didn't want to cause tumor lysis syndrome, at least in the early stage. If you think about what the most painful thing about dose escalation is, it's a blood test. It's having to do blood tests and wait for results. I can pretty share with you that the eventual plan is to actually have a daily ramp-up of BGB-11407 in a packet similar to, let's say, an oral contraceptive pill, where you take Monday to Friday, then Monday to Friday in a prescribed packet over about a 4 to 6 week period, but hopefully without any blood test. If you can do that, and you give the patient a packet, they just follow the packet every day and take an higher dose each day, and they don't need required blood tests. We're currently testing the strategy to make sure it's safe. Once we think it's safe, I really think that's going to be a game changer. No blood test. You can do it all at home, just escalate slowly. Thanks, Con. I think there's a question. There's a question. CDAC question that you have. CDAC, yeah. Yeah. When we looked at zanubrutinib, and part of the reason why zanubrutinib got to where it is at the moment because I had a slight obsession, with Lai Wang in recreating Bruton's agammaglobulinemia in the patient. You know that the disease where there's congenital absence of BTK, right? In humans. These are boys who are born without BTK, and they are actually normal. Apart from having no B cells, these guys are normal. They live till their 40s and 50s. They've got no other issues. We actually know from the congenital model where you can have not a single molecule of BTK in your body, and you have a normal life. Part of the zanubrutinib strategy was to achieve as deep BTK inhibition as possible because we know that it's going to be safe, from the congenital model. More or less what we see from the CDAC is I'm not worried about complete destruction of BTK. I think it's highly encouraging that even at the very first dose level, we're seeing complete BTK degradation and clinical responses. What we would prefer not to see is, hopefully, there'll be no other off-target effects. I mean, the drug seems to be very clean, but only time will tell. I'm actually not worried about complete destruction of BTK because we know from the human congenital model that it's actually very well-tolerated. You don't need BTK. Again, like I mentioned before, I really invite all of you to come to the late breaker session and the similar panel and discussion that we'll have after that. Based on the abstract curve that I showed, we really believe that almost 30 months follow-up is a very meaningful follow-up in the relapsed refractory setting and the subset of 17p that I showed you. When we look at the shape of the curve, we believe this is really meaningful separation, clinically meaningful, and also then you saw the statistical significance of it. I don't know if Dr. Shadman wants to add as a senior author on that paper, want to add anything that we can just focus on the abstract data. Months. As you mentioned, the follow-up with ALPINE is now closer to 30, so that timing is not quite past that 15 months. When we looked at the preliminary result, which is now published, that was around 15 months where the concern was or the discussion was like, what if you follow this and you may see the crossing, which did not occur. Much longer follow-up than published studies. Thank you. I also want to mention that Dr. Lai Wang is also on the line, so in case, Lai, you have a question, please, if you have an answer, speak up or anybody else who has an answer to the question. I think there was a second question. I can't There we go. Yeah. Matthew Harrison, Morgan Stanley. I guess two for me. One just for the physicians as we think about BRUKINSA getting the CLL label and being available, could you just talk about, are there any patient subgroups that you might consider switching or actively consider switching versus just new patient share as you think about the agents that are available? Then the second question is somewhat similar to Ron's, it's just on BTK degraders. Just as you as a company think about the landscape of other degraders, what do you think are the sort of key differentiating factors for your drug? Thanks. The first question, I'll leave it to Dr. Shadman and Dr. Tam to answer. Well, I mean the question, two group of patients starting with we have zanubrutinib available tomorrow. If I have a patient who's on ibrutinib and doing well with no side effects and would I switch that patient to zanubrutinib? It hasn't been the practice, even with the data that we had before this meeting. Starting new patients who need BTK inhibitor, definitely that would be I think this data will be practice changing and will definitely impact the choice of BTK inhibitor. Patients who are doing well with no issues for years, I mean, clinically, I don't see a reason to make that switch. Dr. Tam, how about practice in Australia and also the rest of the world? Similarly, the patients who are doing well on ibrutinib, when you're winning horse, you don't get off it. We tend to keep them on ibrutinib unless there's a problem. Of course, we know that if there are intolerance issues, including atrial fibrillation, Dr. Shadman's study has shown very nicely that you can switch them to zanubrutinib, and you will have either no recurrence of the side effect or recurrence at a lower grade. New patients, we definitely start them on zanubrutinib. I can't really think of anyone who are tolerating the ibrutinib well that I would proactively switch, with the exception that I am watching the cardiac signal very closely. As you know that there is a low but devastating risk of sudden death with ibrutinib. We have done some analysis based on the pooled clinical trials that show that zanubrutinib has a much lower incidence of ventricular tachycardia and fibrillation. From the ibrutinib data suggest patients who have got a history of hypertension are more likely to get that sudden death phenomenon. I guess as the data gathers more and more, there may be a group of patients who have, let's say, cardiomegaly, poorly controlled hypertension, cardiac risk factors that may consider switching just because this is the one complication that you can't recover from. If you wake up dead, you don't wake up. You can't really recover from that side effect. Thank you. I think the second part of your question was about the company's thinking about CDAC and then treatment landscape. I don't know if Lai can hear us. That would be a good question for Lai, if he want to answer. Lai, can you hear us? Sure. You can hear me, right? Yes. Okay. I heard the question. Thanks, Matt, for the question. For BTK, see that there are several player out there. The frontrunner was the newest compound, which has the immune activity. I think as Madan mentioned, immune activity might not really help with the BTK protein degradation activity, which might add additional toxicity. We do believe BGB-16673 has now have at least the mechanism proof of concept in the clinic with the BTK protein degradation observed at 1 dose level. We're certainly one of the frontrunner in this competition. With our extensive experience now in the BTK field, in the B-cell malignancy field, we do believe we can also move this molecule pretty quickly. In term of the characteristics of this molecule, as Madan mentioned, it's highly specific and highly potent, and also has really good half-life. Right now, what you're seeing, the half-life in the clinic probably is somewhere around two days, so you do have some accumulation after few days on dosing. We do believe at that dose level, we can quickly move into really the efficacy proof concept stage and potentially move this into pivotal stage in a relatively quickly manner. I hope I addressed your question. Questions at the back. Go ahead. Hey, it's Michael Schmidt with Guggenheim. Just another question. As we think about the BRUKINSA launch in the U.S. in CLL next year, obviously the drug is already in NCCN guidelines as Category 1 recommendation, and you have the ALPINE data as well. I guess how do the physicians think about using BRUKINSA relative to Calquence? Let's ask that question to Josh, maybe. Just based on some discussions. What we've seen since then has been Other questions online? We have seen some adoption. I would say to all, it's a meaningful proportion of some of the use that we're getting. It's a very small proportion of the total opportunity. What it really indicates to us is as we get approval, there's a significant opportunity to rapidly drive utilization. As it relates to acalabrutinib, what physicians are going to do is compare the results from ALPINE to the results from ELEVATE-TN. We cannot do that comparison, but that's effectively what they're going to do. We think that comparison bodes very well for venetoclax as they think about the patients that they would use it in. What we've also been experiencing is we've had good uptake in our approved indications, mantle cell, Waldenström's, and marginal zone lymphoma. As you look for competitive uptake as a proxy in mantle cell, again, it's really attractive in mantle cell lymphoma. Our approvals are based on single arm trials. The average clinician in the U.S. has maybe one or two treatment opportunities a year for mantle cell. Our adoption there is on par with Calquence at this point. Again, in advance of any results, we're doing very well in Waldenström's as well. I think once we have the ability to sort of broaden use, we can expect really good uptake. What's also encouraging for us is as you look across all the various patients that we'll be approved in, physicians ultimately want to be able to use a single BTK inhibitor. They would prefer not to have to use multiple. We will have an approval within CLL, hopefully. We'll have the approval in Waldenström's and mantle cell and marginal zone. There are two indications there that acalabrutinib does not have. When you look across the breadth of indications, that's potentially an advantage for us as well. The ability to dose acalabrutinib twice a day in addition to the once a day is significant when you compare it to the other sort of concomitant medications that we can be used, the ability to dose reduce. There's a number of different advantages from Clariation. We've heard a lot of enthusiasm for the approval, and I can say that clinical teams looking forward to expanding these categories. Josh. Other questions in the room? Are there questions online? Yes. From the line of Jill Wu from the China Merchants Bank International. Will you include PFS data in the label? Have we submitted for label update? Will we present further follow-up data? Thank you. Thank you. Maybe I'll take that question in terms of, I assume the filing is about the U.S. filing. The PDUFA date that I mentioned in January is based on the data that we had already submitted to the FDA, so the sNDA that we already had pending with the FDA, so this late-breaking data that we are showing, the late-breaking event to us with this readout will not be part of this approval. However, we are working closely in preparing the package for future submissions. Any other questions online? All right. Question in the room? Yaron Werber again from Cowen. Maybe just to follow up, the approval on January 20th will include the initial ALPINE data that was presented at EHA last year? With the final analysis of ORR. Okay. Yes. Josh, can you talk about, you just got approval in Europe. Maybe give us a little bit of a sense on the launch in CLL. Are you launching in Austria and then Germany sort of in short order? Maybe just give us a little bit of sense, if you can, on how you're thinking about price in Europe. Sure. Gowri, you can maybe grab a mic if you'd like. Do you want to provide the update since we have the head of Europe here? Yeah, go ahead. Gavin Winter, Head of Europe. We launched on the second day after the approval. We are the first region worldwide with first-line and second-line approval for CLL. We got it on November 17, we launched on November 18 in Germany and in Austria, we see already a nice uptick. I think maybe some additional color to add is the team has worked very rampantly to secure reimbursement for both the Waldenström's approval and Gowri and his team did a phenomenal job securing, I would say, quick reimbursement. We're already reimbursed in 10 different countries in Europe, including a positive recommendation from nine. Rapid market access success has been a key focus for the European team, I think the success that we've had in Waldenström's bodes well for our ambition in CLL as well. We feel really good about our prospects in Europe. Maybe I'll just remind again that the approval that I mentioned is both in relapsed/refractory and first line. Sometimes we'll be based on the data from the coding. Any other questions in the room? Anything online? No. Excellent. With that, I again wanted to thank everyone for spending this time with us. We really appreciate that. There's some refreshments in the room, we'll be in the room for any further questions that you might have. Thank you very much.