BeOne Medicines AG (ONC) Earnings Call Transcript & Summary

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 presentation 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 the important highly respected external researchers and clinicians to share their insights with us. To take 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, but 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 excessively to patients all around the world. And we're striving to do that too and it's hard, but 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 is 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. But 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 thought about things very differently. From the beginning, we really wanted to change the way development is done because development accounts for 90% more or less of the cost of most oncology medicines that make it to patients. So, 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. And 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. So, 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 and we had incredible experiences there. And very, 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. Then we began in Europe and the United States 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. And 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 2 largest markets in the world, America and in China. In addition to that, we've built an incredible team in Europe. Gerwin, the gentleman with the hat, is responsible for that. And we're off trying to get our medicines BRUKINSA first to as many patients as we can there and that's been very successful too. And during this time, we've pushed for global accessibility. So even though, we've been a little company with our first product, we're approved in over 60 countries and regions around the world. And we're building out in many, many of these ourselves, so we can bring medicine the way we want to. And 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. So, we've invested very heavily in building our own biologics and small molecule capabilities that includes bispecifics and ADCs. And 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. So, 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, and 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. And with that, I would like to introduce Lai Wang, who's our Head of R&D, who is joining us remotely who is going to share a couple of thoughts on what we're doing in R&D and then we'll jump back to the room. So, 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 a special for AS 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 team in the world. The growth accelerated in the past 4 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 4 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-plus 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 cost advantage. We are one of the very few pharmaceutical companies who have the internal capability to run global Phase 3 trials. BeiGene's research has a proven track record, 3 out of our first 4 internal discount molecules are now proven and launched on the market. Today, you will hear about 3 Heme molecules, which were discovered in our research lab was to point out those molecules all come in with a strong scientific research. And also, they were getting to the clinic in very fast speed. All of them took less than 2.5 years from the establishment to getting to the clinic. About a decade ago, we started the BTK program at BeiGene. This program was initiated in 2012 based on a simple research that I will share with you in the next slide. BRUKINSA, also known as zanubrutinib and BGB-3111 is 3 solvent 111th compound made at BeiGene. It was selected as the [indiscernible] candidate in 2013 and entered the clinic in 2014. Dr. Con Tam, who is going to present our BCL2 program later was the lead PI for zanu Phase 1 program. Thank you, Con for believing zanu and its scientific research. As the clinical data emerged, we got increasing more confidence in zanu as the most efficacious and safer BTK inhibitor. However, we also understood that we had an uphill battle to fight as ibruitinib has already had a tremendous success in the field. In 2017 and 2018, 2 global Phase 3 studies were initiated to compel zanubrutinib versus ibruitinib in head-to-head fashion. In November 2019, zanu received its first approval. To date, zanu has been approved in 60-plus markets benefiting patients with B-cell malignancy around growth. The ALPINE PFS reported versus ibruitinib is certainly the highlight of its success in the past 10 years and solidifies its position as the best BTK inhibitor. About 10 years ago, as I mentioned, we started this program at BeiGene that was based on a simple experiment. We looked at ibruitinib as pharmacodynamic effect in animals, which are shown on the left. Ibruitinib had a very good BTK occupancy at 4 hours after dosing, but there was a quite a significant rebound in 3 BTK up to 12 hours, especially in disease-relevant tissues such as bone marrow, spleen and lymph nodes, suggesting BTK signaling was not completing [indiscernible] 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 of potency can potentially complete shutdown 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 dropping body was much higher than its IC50 throughout a 24-hour time period with either 160 milligram twice daily or 320 milligrams once daily dosing. For data not shown here, zanubrutinib treatment resulted in complete BTK occupancy not only in the blood but also in lymph nodes. Throughout the 24-hour time period, there's very -- there's very different and this is a very different case for ibruitinib, acalabrutinib and its major metabolite, M27. Acalabrutinib has high IC max, but it is a much weaker BTK inhibitor comparing to zanubrutinib. In addition, its short 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 ibruitinib, but not efficacy while zanu has demonstrated both. Now, 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. So, 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, a division of Hematology. I was involved in development of obinutuzumab or GAZYVA and then I led development of venetoclax, a 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. So, 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. And the hypothesis was that this will lead to increased activity and decrease 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 2 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 rate in CLL and SLL relapsed/refractory. Also, we had data in involving strong disease in a head-to-head study called ASPEN that the longer follow-up of this study that 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 4 diseases, CLL/SLL, Waldenstrom's macroglobulinemia, mantle cell lymphoma and marginal zone lymphoma. But consistent with that hypothesis that we had and the way 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 molecule models before. And with that, we continue to expand our development program. We are 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. So, I just wanted to show you what is currently ongoing in late-stage development with BRUKINSA, although on the top, you see our studies in CLL/SLL. So, it is approved in certain areas, including -- it was approved by EMA both in frontline and relapsed/refractory CLL/SLL and our PDUFA date by the U.S. FDA is January of next year. This is based on the data from 2 studies, ALPINE study, which is the head-to-head in relapsed refractory CLL/SLL as well as SEQUOIA study, which was -- which study design Ibrutinib in frontline CLL. Below that, you see our study MAHOGANY, which is our Phase 3 study in marginal zone lymphoma. We have approval in marginal zone lymphoma in different regions and this study is a confirmatory study in frontline marginal zone lymphoma. Below that, you see the bar -- the yellow bar in mantle cell lymphoma, that's the MANGROVE study. Again, we have the approval across the globe and this study will be our study, uniquely a BTK inhibitor plus rituximab for 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. And then we have the Waldenstrom's that I mentioned, the Phase 3 study ASPEN, which we have reported data from the study with those more deeper and sustainable responses in patients that were treated with zanubrutinibin in a head-to-head study versus ibrutinib. Phase 2 follicular lymphoma, I just mentioned in combination with obinutuzumab. We are very excited about the data that we saw in this combination. And all the way in the bottom, you see our plan that we are -- we have ongoing studies. Diffuse large B-cell lymphoma in combination with rituximab and lenalidomide and other combinations with rituximab. So, 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 3 oral presentations and we have 10 poster presentations. So, 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. So tonight, you will see what we will present today, and you see where we are at the end of Sunday. We have had presentations that already happened on Saturday and Sunday. So, we'll walk you through the details of those presentations. We have presentations that are pending on Monday and Tuesday and we will limit our presentation 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 we'll show with more longer follow-up. We will walk you through these data by our expert presenters and expert key opinion leaders. And as was mentioned at the end, we have a panel of internal experts from the company, executive team and also our experts and we'll answer all your questions and we ask you to hold off your questions at the end. So, you will see on Saturday, we had a couple of presentations on zanubrutinibin. For example, our MAGNOLIA study in marginal zone that again, consistently, we saw our data is better than in-class competitors and also other benchmark. And we also have data from our exciting BCL-2 inhibitor. Some of it is already presented and some of it in CLL and NHL will be presented tomorrow on Monday. And 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, and 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 o'clock Central Standard Time, so local time. And we'll -- again, we'll have executives from this company and also experts, including Dr. Brown and Dr. Shadman, who is here tonight and is also the senior author of this paper and will answer your questions about this presentation. And tonight, I'll briefly go through the data that we have put in the abstract. So again, as you know, ALPINE is a head-to-head study that studied zanubrutinib versus ibrutinib in relapsed refractory CLL/SLL. The study enrolled 652 patients enrolled in randomized one-to-one fashion between the 2 arms. And as you can see in this slide, the patient demographics and disease characteristics were well balanced between the 2 arms. And 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. And this -- you see the curve as assessed by IRC. And this clinically meaningful risk reduction in PFS was also associated with a significant -- statistically significant p-value of 0.0024. Not shown here, but we had a PFS 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 show that the superiority, zanubrutinib was across all the subgroups. I'm specifically showing one subgroup of 17p deleted and/or TP53 mutated, which is a known high-risk subgroup. And again, you see the superiority of zanubrutinib designed with a hazard ratio of 0.52, and you see the nominal p-value of 0.01 associated with this superiority of zanubrutinib. Very 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. Also important, when we think about the 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 where it's a key secondary endpoint in this study and we show that the rate of Afib/flutter was lower in zanubrutinib at 5.2% compared to 13.3% in ibrutinib arm. Specifically, when we think about adverse events that led to death, we had 0 patients in the zanubrutinib arm that had death, but we had 6 patients in the ibrutinib arm that died due to adverse event of cardiac disorders. Also, in terms of discontinuations due cardiac events, we had 1 patient with 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. So, ALPINE is the first study to show PFS superiority in a head-to-head comparison of the BTK inhibitor. So 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. Our study, 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, I want to -- 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's a professor at Fred Hutch University of Washington, in Seattle Cancer Center. His research and clinical practice is focused on high-grade lymphomas and B-cell malignancies, including CLL and he has been key in our development of both BRUKINSA and RBCL2 inhibitor. Thank you, everyone. I'll pass the podium to Dr. Shadman.

Hello. Thank you, Mehrdad, and thank you for the invitation. It's great to be part of this conversation and congratulations to the BeiGene team for the great ASH meeting. So, what I would be saying tonight -- I'm sorry, I will be covering 2 studies that are already presented and one, the study that was presented by Professor Tam and looking at the long-term efficacy and safety of zanubrutinib in patients with relapsed/refractory marginal zone lymphoma. Marginal zone lymphoma is a relatively rare Non-Hodgkin lymphoma. And especially in advanced stages is considered incurable. Patients are usually at the higher ages with comorbidities and it's important to have non-chemotherapy options as a treatment setting. So, in this is a study patients with relapsed refractory marginal zone were treated with zanubrutinib as the standard dose of 160 milligrams twice a day and treatment was continued until either progression or intolerance of the drug with the primary endpoint of overall response rate that is set by IRC. From the 68 patients who 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's also important to note that 60% of patients are 65 years old or older and 28% more than 75. So, important baseline characteristics and also different subtypes of marginal zone are listed there. And also importantly, 30% of patients have refractory disease as defined by standard criteria. Here, we see the efficacy of the drug and overall response. The response was assessed by PET scan in patients who had FDG-avid disease or by CT scan in those who did not. And as you see, the response rates are in the range of 68%, 67% and the complete response rate in quarter of patients were observed here. Just to put it in perspective, is other BTK inhibitors, the numbers, for example, with acalabrutinib from what's reported is in the 54% range with a CR rate of 16% and with ibrutinib and also at 50%, 58%, a 10% CR rate. So again, cross-trial comparison is always difficult, but this seems to be as effective or more. And the discontinuation rate prior -- so we'll cover the discontinuation rate in the upcoming slides. The different subtypes of marginal zone lymphoma are listed here. And again, the overall response rate seems to be consistent regardless of the type of marginal zone that patients have. More importantly, the variability of responses, progression-free survival and the duration of response and overall response -- 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% to 80% with very high overall survival rate as listed there in the range of 80% to 90%. So, effective treatment with very good responses with the zanubrutinib in patients with relapsed marginal zone lymphoma. Now looking at the adverse events, patients have side effects. All patients have some kind of adverse events, but Grade 3 or more that were treatment emergent 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 receive ibrutinib for marginal zone lymphoma, that DC rate was around 40% in that study with a median follow-up of 3 months. So, well tolerated drug and consistent with some of the other studies that we have with zanubrutinib in different B-cell malignancies. Most common adverse moments are shown there with basically Grade 1 and 2 in the blue collar and Grade 3 and more in the red or orange. And again, overall, consistent with low rates of adverse events. And specifically, looking at the adverse events of interest where BTK inhibitors here, we have infections, hemorrhage, cardiac side effects and secondary malignancies. And 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 and atrial fibrillation in 1.5% Grade 3 or more, and overall is 3% for Afib. In terms of Ventricular arrhythmia, another area of focus for BTK inhibitors. There was no patient who had Grade 3 or more ventricular basically, arrhythmia, 1.5% overall was reported. In terms of patients who came to the study had history of cardiovascular disorder and that's always important to note when we look at adverse events that occur on the study. So for example, here, 11% of patients had a history of Afib and 30% of patients had a history of hypertension and then we see the rate of adverse events listed there. And to, again, not unrelated to this study, but showing a pooled analysis, which was done by Professor Con Tam and basically looking at more than 1,500 patients treated with zanubrutinib compared to ibrutinib-treated patients more than 400. And here, we look at some of the AEs of interest, namely Atrial fibrillation, the difference is shown there. And for example, the numbers there was zanubrutinib -- the 6.5% versus 6.2% -- I'm sorry, the patients who came on the baseline or past medical history of Atrial fibrillation similar between the 2 groups -- I was surprised that why numbers are equal, so 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%. But then 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 arrhythmia is again an important AE that is being monitored for BTK inhibitors, significantly different between the 2. And also the hypertension rate of 14% versus 20%. So in conclusion, with the median follow-up of 28 months, zanubrutinib shows high response rate and durability of responses with overall response rate of close to 70% by both CT and PET scan in all subtypes of marginal zone this response was observed and a progression-free survival rate of 71% and an DOR, duration of response of 73% and overall response rate of 86%. And the drug was well tolerated. Hypertension, atrial fibrillation were uncommon and was comparable to the pooled analysis that was done and I briefly reviewed. And only 1 patient had major gastrointestinal hemorrhage and this patient was also on an anticoagulant at the same time and there was no new safety signal in this study. So, moving on to the next study. This is the study that looked at zanubrutinib in patients who did not tolerate acalabrutinib. An important study and as a background, we do have randomized studies comparing different BTK inhibitors, basically looking at the incidence of adverse events and with different drugs. In this study, we are looking at patients who are high risk for developing adverse events because we've already shown to have adverse events on another BTK inhibitor. So, this study started by looking at 2 cohorts patients who have ibrutinib. That cohort as is already reported and published. And what we're presenting at this meeting is cohort 2 patients who are intolerant to acalabrutinib and different histologies where basically, enrolled patients with different histologies were enrolled in this study, including CLL, mantle cell lymphoma, marginal zone lymphoma and Waldenstrom's. And basically patients who are intolerant to acalabrutinib received zanubrutinib therapy. And 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 and for progression or having adverse events. So, based on characteristics as 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 third BTK inhibitor that they have. Also, the median time on acalabrutinib or exposure to acalabrutinib before starting -- or enrolling to the study was 4.6 months and we'll see that median exposure thanks to zanubrutinib in this next slide, but this is important because some of the adverse events are -- that the incidence goes up by longer exposure, so 4.6 months. So, what this figure shows on the Y axis, you have different adverse events that patients have on acalabrutinib. And these were the reasons why patients came on this study or entered the study and received zanubrutinib. And for each event, you have different colors. When you see the blue color, it means that, that adverse event did not occur. And if it's dark blue, it means that it recurs at the lower grade. If it's yellow, it means that it's recurred at a same grade and we don't see red but red would be a higher grade AE. So in general, especially we can see that most of the adverse events on acalabrutinib either does not return zanubrutinib or they occurred at the same or lower grade. So, 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. And there was no adverse event that occurred at a higher grade. Looking at the patient level, 67% of patients did not experience any recurrence of the adverse business that they had on acalabrutinib. Also, it should be noted that few patients have the same intolerance events on both acalabrutinib and ibrutinib and these were diarrhea, atrial fibrillation and joint pain and 2 of these 3 did not have recurrence of the side effect on zanubrutinib. Again, adverse events, I would just say that there's no new safety signal and these adverse events are consistent with what we see with zanubrutinib in different studies. And in terms of serious adverse events and adverse events leading to discontinuation or interruptions and dose reductions are listed here and only 2 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 are maintained or improved over time on zanubrutinib. And again, -- so the point being that the drug continued to show efficacy in patients who had intolerance to ibrutinib. Basically, as a summary, it's an important study that in patients who have intolerant events on a second-generation BTK inhibitor that led to the discontinuation of drug can benefit from another BTK inhibitor, zanubrutinib. And most of the adverse events did not recur and patients were able to continue treatment and maintain their responses. With that, Dr. Tam will present the next study.

Thank you, Dr. Shadman. So, similar what we did with zanubrutinib, will just do a brief introduction to our exciting BCL2 inhibitor or BGB-11417. So, 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. So basically, within our research, we try to understand the real question and design molecules for that target. So this drug, our BCL-2 inhibitor also has the potential in our belief to be a best-in-class molecule. And that's given the higher potency and higher selectivity as well as shorter half-life that this drug has compared to venetoclax. But we think it will lead to improved efficacy and also improve safety of this drug. We have already started a broad clinical development with this program. You see we have studies in CLL, Non-Hodgkin's lymphoma, including Waldenstrom's macroglobulinemia, mantle cell lymphoma, marginal cell lymphoma as well as acute moderate leukemia and myelodysplastic syndrome and a subset of multiple myeloma that harbor specific translocation 1114, 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 4 different studies at Phase 1, Phase 2 studies that we have with this molecule. And 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, and we have seen higher rates of complete remission, even in the lowest dose that was tested, which was 40 milligram of 417. We have started 2 studies, 2 Phase 2 studies that have potential registration, so they have registrational intent. One of them is in relapsed refractory mantle cell lymphoma, post-BTK inhibitor treatment and the other one is in relapsed refractory CLL post-BTK inhibitor. And as we know, BCL2 inhibitors have 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. So, we are comparing RBCL2 inhibitor 417 to the established BCL2 inhibitor venetoclax. And we know that this drug has a higher target and higher potencies. On the top, you see how we are comparing our drug versus venetoclax in terms of protein inhibition. And you can see our drug is 14x more potent. And specifically, when you look at a known resistant mutation that patients develop on venetoclax or G101V, our drug has the potential to overcome that resistance. You see 57x more potent our drug compared to venetoclax. And in the bottom, you see target selectivity. And our drug is very specific to BCL2 and not inhibiting the other members of the BCL2 family. So again, like I said, very similar story to how our thinking was with zanubrutinib that we develop a very potent and very selective inhibitor of BCL2. We looked at as a PD model, we looked at as a pharmacodynamic model. We looked at the reduction of absolute lymphocyte count in CLL. So, 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. And in the middle, you see our current ramp-up. Of course, we have started with a pretty conservative ramp-up. But we looked at a 90% reduction of absolute lymphocyte count as a cut off to compare ourselves versus venetoclax. And you can see with average, we achieved 90% ALC reduction with a dose of 40 milligrams of 417 as opposed to venetoclax that achieved that level of ALC reduction with 200 milligrams. So, when you look at the milligrams to milligram, we believe we show that our drug is 5x 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 1/2 in B-cell malignancies. This is a study that we are investigating 417 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 1114, as monotherapy followed by a 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 our 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 2 study that I mentioned we have started the registrational intent post-BTK inhibitors. And below that, you see the Phase 2 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. And it's my distinct honor to present to you Dr. Con 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 Lai 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. So 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 at this late in the evening. So, I will just share my -- some of the experiences with these new drugs, BGB-11417. My personal impression is that just zanubrutinib, it really acts as backbone to the best-in-class. And as you know, venetoclax or the BCL2 inhibitor is now really a very important drug, not just in CLL and mantle cell lymphoma, but also in multiple myeloma and AML. So very, very broadly [ advisable ] category. So, this is the BGB-11417 Phase 1 versus human study. And this first presentation, we'll focus on those patients with CLL. Now, the -- because the company also has done ibrutinib in its assets and it makes sense to combine a BTK inhibitor with the BCL2 inhibitor. In this Phase 1 study, we explore not just the new drug 11417 in CLL, but also, 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 BCL2 -- BTK inhibitor zanubrutinib with the new BCL-2 inhibitor and you have a combination that is totally oral and totally in-house to the company. So, this is a study design. It's a very straightforward design. Patients are started on the low dose of the BCL2 inhibitor at 40 milligrams, which as Dr. Mobasher has shown this, it's already equivalent to a potent dose of venetoclax and the final target dose of BGB-11417 is 640 milligrams, which would be equivalent to around 3 grams of venetoclax. And the reason why we're trying to push such a high dose is because we know that resistance mechanism -- 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. So, so far, the CLL, we have dosed 50 patients, 6 patients were dosed on the monotherapy, just to prove the safety, but the majority of patients were treated in fact, in combination, we've done with ibrutinib, which is where we think the drug will ultimately end up. So, 44 patients treated in combination. This is data that was presented previously. This data will be updated at ASH this year. So, because of the 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 that you can get the most up-to-date figures. So, this is the design of monotherapy. The median follow-up in monotherapy is 11.5 months. The combination cohort data a little bit later than the monotherapy cohorts to the median follow-up for this particular report is 5.8 months. And of course, this will be updated at the ASH conference tomorrow. In terms of adverse events, this is a very busy slide. I like to emphasize with the most common side effect with venetoclax and the most feared side effect is tumor lysis syndrome. And in fact, out of the 50 patients were treated, we only saw 1 patient with tumor lysis syndrome and this is a patient who had to come off with BTK inhibitor because the progression has extremely genetically rapid progression of this disease before its first dose of BGB-11417 and this person developed biochemical tumor lysis syndrome and was controlled and continued on the drug. And to predict in the context, this is a patient with a very aggressive disease and tumor lysis syndrome is almost expected in this patient. Apart from these 1 patient, we've actually had no tumor lysis syndrome whatsoever and there's been no evidence of clinical tumor lysis syndrome, which is the most severe category. Probably the 2 most common side effect with venetoclax would be diarrhea as well as neutropenia and [indiscernible] when we first started this program, he said we will 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. And even though we were pushed the dose to a 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 was really no additional side effects that were unusual. So, you can add this drug to zanubrutinib and you get pretty much a fairly -- a very well-tolerated regimen with no unexpected new toxicities. So, this is just to just say that this will be updated tomorrow at 4:45 p.m., but my colleague, Professor Cheah and I'm sure you can see that the gist of it is a 12-month is on track. Drug regimen is doing very well with no unusual findings and we're now seeing deep responses including minimal residual negative diseases -- disease negative responses. Of course, this drug is also BCL-2 is also active in other diseases and in particular mantle cell lymphoma and Waldenstrom's. So at this meeting, we will also update the data on these 2 histologies. This is followed by my colleague, Dr. Soumerai. And you can see here, once again, that this histologies will once again have both monotherapy as well as combination with zanubrutinib. In terms of the Waldenstrom's and MCL, you can see 45 patients have been treated, 34 on monotherapy and these are patients with either NHL or Waldenstrom's and then all the combination patients received were mantle cell lymphoma. Once again, the side effects were, in fact, very benign in my view. So, there were some minor nausea, some minor fatigue. But 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 BTK inhibitors have been -- to BCL2 inhibitors have not been that good in general. In terms of the combination, adverse events, once again, just a summary that you can add zanubrutinib and you get the same side effect zanubrutinib, and there were no really unexpected toxicities when you add these drugs to zanubrutinib. This wonderful chart illustrates the histologies that were tested. Now of note, mantle cell lymphoma cohort was not at least waterfall plot and is presented separately, but you can see that the disease which did not respond as well as other 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 BCL2 inhibitor even at [ poster ] such as this. And that's not merely 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 cohorts in mantle cell combination cohort and with a very short follow-up, all these patients have had restaging scans to they have responded. We've got 55% response rate so far, so that's right on track and with the Waldenstrom's cohort, we have seen reductions in RGN, but because this drug is so mild and the patients have not been on drug for very long, we haven't had -- we haven't seen the full depth of the responses so far. So, the conclusion is essentially the drug is safe. There is no unexpected toxicity, both for dose competitive venetoclax, the side effect seems to be very manageable. With clinics, a maximum tolerated dose and the dose level reached all the way up to 640 milligrams, which, as you know, is about 3 grams of venetoclax and it's the levels of venetoclax that we got to. The side effects were low grade, the neutropenia was manageable and the responses, you need to interpreted responses in the context that for most of these diseases, you need time to reach the best responses. So, 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 heading or heading in the right direction. So quickly, just to show you 2 other presentations because lymphoma is not the only disease where BCL2 inhibitor is useful. AML is also a disease where venetoclax has found a niche. So, venetoclax is given in combination with exercising in AML. And of course, this is a natural space to explore the new BCL2 inhibitor as well in AML. This is a study design. So, patients are treated with the combination of BGB-11417 plus azacitidine in a dose-escalation fashion in patients with relapsed/refractory AML. And in terms of the -- 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. So, this is only achievable when you have a low toxic class of drug, like a BCL2 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. So, there is a high proportion of Serious and Grade 3 AEs, so that is exactly what you see when you conduct any study in relapsed/refractory AML. Importantly, the AEs is leading to discontinuation in population is relatively low at 18%. In terms of the -- this is the different cohorts you can see there were -- there was a DLT signal at 80 milligrams. The more patients were enrolled, proving that this DLT signal was not dose-limiting. And then at the moment, the doses being explored is 160 milligrams for 28-day and 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 with neutropenia and they end up neutropenia 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 rates, as you can see, exceeds 50%, which is really very encouraging because if you think about the randomized study of venetoclax and in totality, CR rate is a 37%. So, already in a Phase 1 study where we haven't really optimized the dose, we are seeing 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 bone marrow, it really tells the story. Across all the doses, we have seen a good reduction in large percentage in the bone marrow indicating this is a clearly active drug. So 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 rate so far are very encouraging and consistent with the hypothesis that a potent and optimized BCL2 inhibitor may reduce very deep responses in AML. The last disease, of course, is multiple myeloma. Now this study in multiple myeloma is restricted to those patients with a particular chromosomal abnormality translocation of 11 in 14, and that's because these patients are the ones that we know who are sensitive to venetoclax from the venetoclax studies. Once again, a very standard ramp-up is monotherapy with a plan to add dexamethasone and carfilzomib, which are standard 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 PR rate as a monotherapy, it's a single drug of 33% and an additional 8% minor response rate. So this is consistent with this drug being on target and this drug working in multiple myeloma and the next step is to combine this with other drugs as we do with venetoclax, including dexamethasone and carfilzomib. So, this is the myeloma study conclusion that the drug is tolerable in a combination of with dexamethasone that there were no and NTD reached the 640 milligrams was reached and that the toxicities were manageable. There was a particular emphasis that even on monotherapy, that those are patients who actually not only responded, but there's 1 patient who achieved a complete remission. So, the dose escalation is ongoing and they have not achieved a recommended Phase 2 dose in this study. So in aggregate, that the studies in CLL, in mantle cell lymphoma and Waldenstrom's macroglobulinemia, in AML and in multiple myeloma, the drug clearly works. The drug is clearly well-tolerated with doses achieved. We are seeing the responses expectedly as you would expect at this point in development and it's looking very promising. And in particular, I was worried that this drug would cost neutropenia given its potency, but we haven't seen any of that. So, it looks like this is -- this may be another best-in-class optimized drug for BCL2. Thank you for your attention.

Thanks, Dr. Tam. And I want to introduce another asset in our hematology pipeline, the BGB-16673 that we call it a BTK-CDAC. So CDAC stand for Chimeric Degradation Activating Compound. So basically, a protein degrader that we have developed and we are studying it in B-cell malignancies. So, 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 it 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. And in terms of treatment, it really can overcome some of the BTK inhibitor resistance mechanism and specifically, can destroy nonkinase or just capital function as well. So, this specific drug, like I mentioned, 673, if 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 2.5 years only from the program initiation to enter clinic, which we are very happy about. And the drug itself has good pharmacological property. 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 have very good oral bioavailability. So, I put a couple of panels in terms of the data that I want you to look at. On the top, you see 3 patients who were treated with our very first dose cohort of 50 milligrams, the lowest dose cohort in our first-in-human Phase 1 study. And you see a deep and rapid and sustained protein or BTK degradation that was seen. So, within 8 hours, BTK is completely destroyed and it remains sustained. It goes all the way to 1 month. And in the bottom, you see that we have studied this drug and a couple of other drugs, so basically, zanubrutinib is our own drug and LOXO-305 or pirto, which is a different BTK inhibitor. And we are showing specifically in wild-type and also in a couple of resistances that we know, all BTK inhibitors developed the resistant 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. So, we are very excited about this molecule and we continue this Phase 1 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. So, the first is how we are currently with our BTK inhibitor zanubrutinib in different diseases. So, all the way on the top, you see B-cell malignancies, but in CLL, mantle cell, marginal zone, follicular, Waldenstrom's and even diffuse large B-cell lymphoma, we have monotherapy and we have what we call it 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, I think it's 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's lymphoma. With that, I want to give the podium back to our Co-Founder and Chairman and CEO, John Oyler, to wrap up this 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. And 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 BCL2 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. And I think as we've mentioned, we're already starting -- I forget the word that Mehrdad said, I really liked it registrational -- with registrational intent, I think it was a couple of studies, but we're moving that program forward. And we're really excited about this protein degrader. And 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. And I think on the way of doing that, we've really mapped out what we think the world looks like in 5 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. And that's what we're striving to do. And 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 3 trials from that perspective. There's not many oncology companies that aren't pharmaceutical companies that have run as many Phase 3 global oncology trials as BeiGene has, and we had run none I don't know, a few years ago. So, it's really a tribute to the capabilities and the team that we have there. And that's combined with a commercial organization that is growing and strong in the 2 biggest markets and soon when Gerwin gets back to Europe with his team there and the third largest market from the European perspective. So, 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. And with that, the intention is to help a lot of cancer patients. And I think that we're well on our way to doing that. And 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 and 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. And of course, the patients that are out there from that perspective. And the rest of those that have followed us and help 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. And 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. And hopefully, every little success we have can be very impactful for a patient and impactful for their families and everyone else. So with that, I just really want to thank everyone and I think we're moving to questions. So, I think I should invite everyone up on the stage who is supposed to come up on stage and we're happy to take some questions. Thank you.

Hello, everybody. Our expert panel and I'll basically be the moderator of this Q&A channel. A couple of my colleagues are here with microphones. So, if you see a hand raised, please get the microphone quickly.

Werber from Cowen. Maybe I have a couple of questions. Maybe I'll get off to you, and you can see who ought to answer that. Maybe the first one, and I know I'm jumping the gun a little bit about BRUKINSA's ALPINE data that's coming on Tuesday. When we look at the curve, we're now 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 [indiscernible] where they came, they separated early on by year 4, so it sort of came together. That was at a high-risk population. What are you expecting in terms of exploration of those curves? Can you continue to separate it? And then maybe secondly, maybe Dr. Tam for you. When we're looking at the -- a lot of the feedback we're getting from KOLs is the dose escalation for ven and at this stage is very difficult over 4 weeks. I think here, you're actually showing an 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? And then finally, maybe, Dr. Tam, what do you want to see from a BTK degrader in terms of safety? And are you worried that's the feedback we're getting. If you're going too broad, are you going to get into some safety issues?

Maybe let Dr. Tam answer the second part of your question first. Please Tam.

Sure. So, with regards to the dose escalation and I had to do this on day in, day out. So, you're right. Venetoclax dose escalations, the pain is required for tumor lysis monitoring. There's a real advantage to BGB-11417 that I forgot to mention and that is the half-life. So, venetoclax has about a 20-hour half-life. So, it doesn't get the steady date until 5 days of therapy. Therefore, you can't actually escalate venetoclax safely and in less frequently than every 5 days. That's why it's weekly escalation. Now, when we built the BGB-11417 program, which is a very short half life, only a few hours, you can actually daily escalation, but we chose to be conservative because we wanted to -- we new is very potent and we didn't want to cause tumor lysis syndrome as if 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 test and wait for results. So, I can probably share with you that the eventual plan is to actually have a daily ramp-up of BGB-11417 in a packet, similar to, let's say, oral contraceptive pill where you take Monday to Friday in the prescribed package over about 4 to 6 weeks but hopefully, without any blood test. So, you can do that and you just paid the patient and pack it. They just follow the package and [indiscernible] from the high dose each day, and they don't require blood test. And we're currently testing the strategy to make sure it's safe, but once we think it's safe, I really think that's going to be a game changer. No blood test. You can do all at home, just escalate slowly.

Thanks, Dr. Tam. And CDAC question that he asked.

CDAC, yes. So, the middle -- zanubrutinib and possibly the, why zanubrutinib where it hit at the moment because I had session with Lai Wang and recreating [indiscernible] in the patient. So, you know that the disease, whether it's congenital absence of BTK, right in humans. So, these are guys who are born by BTK. And they are actually normal. Apart from having no B-cell, these guys are normal. They live through the 40s and 50s. They've got no other issues. So, we actually know from the congenital model where you can have not a single molecule BTK in your body and you have a normal life. So, part of the zanubrutinib strategy was to achieve a BTK inhibition as possible because we know that it's going to be safe and from the co-generative model. So, more like CDAC is I'm not worried about complete destruction of BTK, I think it's highly encouraging that even at the very, very first dose level, we're seeing complete BTK degradation and clinical responses, a bit -- while we prefer not to see, hopefully there will be no other off-target effects. I mean, the drug seems to be very clean, but only time to tell. So, I'm actually not worried about complete destruction of BTK because we know from the human congenital model that is actually very well tolerated. We 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. But based on the abstract curve that I showed, we really believe that almost 30-month follow-up is a very meaningful follow-up in the relapsed refractory setting and the subset of 17p that I showed you. And when we look at the shape of the curve, we believe this is really meaningful separation, clinically meaningful and also then we saw the statistical significance of this. But I don't know if Dr. Shadman wants to add as a senior author on that paper, if you want to add anything that we can just focus on the abstract data.

As you mentioned, the follow-up with the ALPINE is now closer to 30. So the timing is not quite -- past that 15 months. So, when you look at the preliminary results, which is now published, that was around 15 months of the concern while the discussion was like, what if you follow this, and you may need to see the cost in which did not occur. So, much longer follow-up than what is telling you.

Thank you. And I also want to mention that Dr. Lai Wang is also on the line. So, in case you have a question, please if I have an answer, speak or anybody else who have an answer to the question. I think there was a second question.

Matthew Harrison, Morgan Stanley. I guess 2 for me. So 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 considered switching versus just new patient share as you think about the agents that are available? And then the second question is somewhat similar to Yaron'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?

The first question, I'll leave it to Dr. Shadman and Dr. Tam to answer.

Yes. Well, in terms -- I mean, the question -- I mean, 2 group of patients starting with zanubrutinib available tomorrow. I have a patient who's on ibrutinib and doing well with no side effects and we'd like to expand that patient to zanubrutinib. It hasn't been the practice even with the data that we had before this meeting. But starting new patients, you need BTK inhibitors definitely, that would be -- I think this data will be practice changing and will definitely impact the choice of BTK inhibitor. But patients were doing well with no issues for years of -- I mean there's -- clinically, I don't see a reason to make that stage.

Dr. Tam, how about practice in Australia and also the rest of the world?

Similarly, the patients were doing well in ibrutinib, when you are winning a horse, you don't get off it. So, 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 study has shown very nicely that you can switch them to zanubrutinib and you will have even no recurrence of side effects or recurrence at a lower grade. So new patients, you definitely start them on zanubrutinib. I can't really think of anyone who are tolerating ibrutinib well that I will proactively switch with the exception that I am watching the cardiac signal very closely. As you know, that there is a low, but there has been a risk of sudden death with ibrutinib. We have done some analysis based upon the on the pooled clinical trials that show that zanubrutinib has a much lower incidence of ventricular fibrillation. From the ibrutinib data suggest patients who have got a history of hypertension are more likely to get that sudden death phenomenon. And I guess, as the data gathers more and more, there maybe a group of patients who have let say, [indiscernible] poorly controlled hypertension, target risk factors that may consider switching just because this is the one [indiscernible] that you can recover from. So, wake up dead, you don't wake up, you can't really recover from the side effects.

Thank you. So, I think the second part of your question was about the company's thinking about CDAC and the treatment landscape. Maybe just -- I don't know if I Lai can give -- it's a good question for Lai, if he want to answer. Lai, can you hear us?

Yes, sure. You can hear me, right?

Yes.

Okay. Yes. So, I heard a question, yes, thanks, Matt, for the question. And for BTK-CDAC there are several players out there, the front runner was a newest compound, which has the IMiD activity. I think as Mehrdad mentioned, IMiD 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 that connect with the BTK protein degradation observed at first dose level. So, we are certainly one of the front runner in this competition. We do -- with also 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 terms of the characteristics of this molecule, as Mehrdad mentioned, it's highly specific and highly potent and also has really good half-life. Right now, what you're seeing that the half-life in the connect probably is somewhere around 2 days. So, you do have some accumulation after a few days dosing. So, we do believe at that dose level we can quickly move into really the efficacy proof-of-concept stage and potentially move this into pivotal stage in a relatively quickly manner. So, I hope I addressed your question.

It's Michael Schmidt with Guggenheim. Just another question as you think about the BRUKINSA launch in the U.S. in CLL next year, obviously, the drug is already in NCCN Guidelines as a Category 1 recommendation and you do have the ALPINE data as well. I guess how should -- how does the physicians think about using BRUKINSA relative to Calquence?

Let's pass that question to Josh maybe.

[Technical Difficulty] So, we have seen some adoption. I would say there was a meaningful proportion of some use that we're getting. It's a very small proportion of the total opportunity. But what it really indicates to us is as we get approval, right, 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 the results and elevate and we cannot do that comparison, right, because that's effectively what they're going to do. We think that, that comparison bodes very well, bodes very well for zanubrutinib 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, right, mantle cell, Waldenstrom's and [Technical Difficulty] as you look for competitive uptake, maybe a proxy in mantle cell, again it's relapsed refractory mantle cell lymphoma, our approvals are based on single-arm trial. The average duration in the U.S. has maybe 1 or 2 treatment opportunities here from mantle cell. Our adoption there is on par with Calquence at this point. And that's in advance of any results [Technical Difficulty]. I think once we have the ability to sort of broaden this, we can expect really good uptake. But what's also encouraging to us is, as you look across these right patients that will be approved in, physicians ultimately want to be able to use a single BTK inhibitor, they would prefer not have to use multiple. We will have an approval within CLL, hopefully, we'll have the approval in Waldenstrom's, mantle cell, margin zone. There are 2 indications there that Calquence doesn't have. When you look across the breadth of indications, that's potentially an advantage for us as well, the ability to dose zanubrutinib with TD in addition to [Technical Difficulty] when you compare it to the other sort of concomitant medications that we can use, the ability to dose reduce, there's a number of different advantages from clinicians. So, we've heard a lot of enthusiasm for the approval. And I can say that clinical team is looking forward to expanding [Technical Difficulty]

Are there questions online?

Yes, from the line of Jill Wu from the China Merchant Bank International. Will you include PFS data in label? Have we submitted for a label update? Will we present further follow-up data? Thank you.

Thank you. So, 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 the readout will not be part of this approval. However, we are working closely in preparing the package for future submission. Any other questions online? All right. Question in the room?

Yaron Werber again from Cowen. So maybe just a follow-up. So the approval on January 20 will include the initial ALPINE data that was presented at EHA last year?

With the final analysis of ORR.

Okay. And then, Josh, can you talk about -- you just got approval in Europe? Maybe give us a little bit of a sense in the launch in CLL? Like are you launching in Austria and then Germany sort of in short order? And maybe just give us a little bit of sense if you can on how you're thinking about price in Europe?

Sure. Gerwin, you can maybe grab a mic if you'd like. Do you want to provide the update since we have Head of Europe here. Yes, go ahead.

Gerwin Winter, Head of Europe. Yes, we launched on the second day after the approval. So, we are the first region worldwide with first-line and second-line approval for CLL. And we guided on November 17 and we launched on November 18 in Germany and in Austria and we see already a nice uptick.

I think maybe some additional color to add, right, the team has worked very rapidly to secure reimbursement plus the Waldenstrom's approval. And so Gerwin, you've done a phenomenal job securing out quick reimbursement. We already reimbursed it in 10 different countries in Europe, including a positive recommendation from [ 9 ]. So, rapid market access success has been a key focus for the European team. And I think the success that we've had in Waldenstrom's bodes well for our incubation in CLL as well. So, we feel really good about our prospects in here as well.

Thank you, Josh. Maybe I'll just remind again, that the PDUFA that I mentioned is both in relapsed refractory and [indiscernible]. So, sometimes it will be based on the data from SEQUOIA. Any questions in the room. Anything online? Excellent. With that, I again wanted to thank everyone for spending this time with us. So, we really appreciate that. There are some refreshments in the room and we'll be in the room for any further questions that you might have. Thank you very much.