Good day, everyone. Welcome to BeiGene's Investor Webcast, highlighting key data from the ASH and the San Antonio Breast Cancer Symposium meetings. All lines have been placed on mute to prevent any background noise. After the speakers' remarks, there will be a question-and-answer session on BeiGene's R&D programs and the presented data. At this time, I would like to turn the call over to the company. Hello and welcome. I'm Dan Maller, Head of Investor Relations at BeiGene. With me today are Lai Wang, our Global Head of R&D, Mark Lanasa, our Chief Medical Officer for Solid Tumors, Mehrdad Mobasher, our Chief Medical Officer for Hematology, and John Oyler, our Co-Founder, Chairman, and CEO. CFO Aaron Rosenberg will also be on the line for the Q&A portion of the presentation. Before we begin, please note that you can find additional materials, including a replay of today's event and presentation, on the Investor Relations section of our website, ir.beigene.com. I would like to remind all participants that this presentation may contain forward-looking statements regarding, among other things, the company's future prospects and business strategy. Actual results may differ materially from those indicated in the forward-looking statements as a result of various factors, including those risks discussed in our most recent periodic report filed with the SEC. Please also carefully review the forward-looking statements disclaimer in the slide deck that accompanies this presentation. All information in this presentation is as of the date of this presentation, and we disclaim any obligation to update such information unless required by law. Now, turning to today's call, as outlined on Slide 4, Lai will provide opening remarks, Mark will provide an update on data presented last week on our CDK4 inhibitor program, BGB-43395, at the San Antonio Breast Cancer Symposium, as well as an update on our solid tumor pipeline progress, and Mehrdad will provide key data presented at last week's ASH conference and provide an update on our development plans for our hematology franchise. John will conclude the presentation with closing comments. We will then open the call to your questions. With that, I'll pass the call over to Lai. Lai? Thank you, Dan. Good morning, good afternoon, good evening. Thank you for joining our call from around the globe. We're here to present updates from San Antonio Breast Cancer Symposium and ASH. Before that, I would like to take a few minutes to highlight our overall strategy and the portfolio evolution. The pharmaceutical industry is known for its challenges due to three characteristics of drug development: long timelines from target identification to commercial launch, high development costs, and a low probability of success. These challenges are well known within the industry. However, is our industry effectively addressing these challenges? We believe the answer is no. Large pharmaceutical companies often over-invest in late-stage development and overpay for acquisitions for short-term revenue growth, which results in low ROI and making things even worse, frequently at the cost of sacrificing early-stage portfolio. On the other hand, small biotechs often lack certain domain expertise and financial resources, which further reduces their probability of success and limits their opportunity in success. As a new generation biotech pharma, BeiGene has a lot to offer to this industry. We believe, number one, investing significantly in discovery and early stage is crucial to organically grow a deep portfolio in the focused disease area based on our modality needs, supplemented by external innovations. Number two, clinical proof of concept is the most important value inflection point in drug development. Achieving clinical POC faster and more efficiently provides tremendous competitive advantage. BeiGene strives to be the best in executing fast POC. Mark will later provide a good example of this with our CDK4 program. With only one year in the clinic, we have dosed over 120 patients while now executing fast POC for all our programs. Number three, developing combination therapy early is critical to win in oncology. The competition in the industry heated up significantly in the past decade. For almost every target, there are many competitors. However, when you put in targets A and B together, the competition suddenly gets a whole lot less. Using our CLL portfolio as an example, we are one of the very few companies in the world who have both BTK inhibitor and BCL2 inhibitor in the clinic, not mentioning our BTK degrader. A deep pipeline provides ample opportunities for internal competition with significant advantages over combining with external assets. Number four, maintaining discipline in late-stage development is necessary as it accounts for approximately two-thirds of overall drug development costs. We should only advance transformative medicines to the late stage. Historically, the industry has over-invested in late stage to chase short-term revenue. These four principles are supported by our capabilities in two areas which really stand out. Number one, over the years, BeiGene has invested heavily in technology platforms and new drug discovery modalities, which give us the ability to make the best molecule for each target. In addition, we have established one of the largest oncology-focused discovery teams with urgency and agility. Number two, we utilize an internalized CRO-free clinical operation model, offering significant cost and speed advantages. In addition to fast POC, BeiGene now also excels in late-stage clinical trial execution. We are close to completing enrollment for our phase 3 SEQUOIA treatment-naïve CLL trial with around 640 patients in just about one year. This is a remarkable speed. This trial was conducted entirely by BeiGene staff in 20 countries over 200 sites. In addition, we believe there are many opportunities with AI and automation to improve the overall efficiency in clinical trials. With the internalized model and the significant scale, BeiGene is one of the very few companies positioned to deliver this. Next slide. One of the biggest advancements in our industry since the new millennium is our ability to make a drug with evolving new technologies. Many undruggable targets are now druggable. BeiGene has invested extensively in different technologies and platforms to improve our drugging capability. Among the 29 small molecule programs, 14 are CDAC, 14 degraders. In addition, we have three degrader programs already in the clinic: BTK, IRF4, and EGFR, positioning us as one of the leaders in the degrader space. The biology behind degrader is fascinating. In addition to destroying the scaffold function, degrader also brings additional benefits in higher potency, better selectivity, and less on target resistance compared to the traditional small molecules. We have 19 preclinical ADC programs ongoing, with half being bispecific ADCs and a new focus on novel payloads. The 13 bispecific multi-specifics are mainly focused on immune cell engagers. Next slide. Next slide, please. BeiGene began expanding its research capabilities in 2020. After three years, this investment is beginning to show results. In the past 18 months, 16 novel molecules have advanced into the clinic, with two more potentially in the next couple of weeks. This includes two degraders, three bi- or trispecifics, four ADCs, and several high-profile small molecules such as CDK4, CDK2, PRMT5, and brain-penetrant MAT2A cooperative PRMT5. With these developments, BeiGene has expanded its portfolio. For hematology, the company now has three cornerstone assets, each with multi-billion-dollar market potential. Mehrdad will share the most recent progress on them. The solid tumor portfolio has evolved from immune oncology to a more diversified pipeline with clear disease focus. In the next 12 to 24 months, many of these new molecules will have POC data readouts. The company is also working on new technologies, including iPSC-derived off-the-shelf cell therapy designed to overcome hyperimmunogenicity and the longevity issue, a proprietary TCR-like T-cell platform, and the bispecific plans. It is an exciting time for BeiGene. With that, I'm going to hand it over to Dr. Mark Lanasa, our CMO for solid tumor. Mark. Thank you, Lai, and thank you all for joining today. Next slide. So I'm just back from San Antonio, and it's been an outstanding year for our breast franchise. The backbone molecule in our breast cancer franchise is our CDK4 selective inhibitor, where we have development intent across multiple lines of therapy for women with hormone receptor-positive breast cancer when combined with estrogen deprivation therapy. We also have novel targets, CDK2, and a novel BCL2 inhibitor that we intend to combine with our CDK4 inhibitor next year to provide us a development line of sight to rational mechanisms of resistance that emerge with exposure to CDK4 or CDK4/6 inhibitors. Now, this portfolio of agents actually has applicability in gynecologic malignancies as well, with intent to develop our CDK4 in endometrial cancer, our CDK2 inhibitor in both endometrial and ovarian cancer. And importantly, we also have made great progress with our B7-H4 targeting ADC, which has development opportunities across both breast and gynecologic malignancies. Next slide. And so we have had a very successful San Antonio Breast Cancer Symposium meeting with five abstracts presented. You can see the list here, which included preclinical characterization of the CDK4 and CDK2 molecules, a trial and progress poster for CDK2, and importantly, our first clinical data disclosure for our CDK4 selective molecule, BGB-43395, which I will spend the majority of the balance of my time presenting. Next slide. And this is the abstract that was presented. As always, we want to thank the investigators, the patients, and their caregivers for their participation in this ongoing study. I will also highlight that the data cutoff date for our presentation at San Antonio was at the end of September. At that time, we had approximately 65 patients enrolled. As you just heard from Lai, we now have over 120 patients enrolled. So the data that was presented at San Antonio focused primarily on PK and safety given the relatively short period of patient follow-up. Next slide. Here you can see the study design. The study initiated with monotherapy dose escalation, and after the first three dose levels were cleared, then parallel dose escalation of combinations testing the combination of 43395 with fulvestrant and letrozole progressed. These combinations give us line of sight to future development in CDK4/6 pretreated and naive patients. For the phase 1a portion, the key study endpoints are safety and dose selection. We have not yet determined the maximum tolerated dose. Dose escalation is ongoing across all three cohorts. Key secondary endpoints include efficacy and PK. Next slide. I'll start with sharing our PK data, and what I'm showing here are the first five dose levels. On the left, you can see the concentration time plot for cycle one, day one, and on the right, you can see cycle two, day one. BGB-43395 was rapidly absorbed with a Tmax occurring approximately two hours after administration, and the observed half-life was approximately 13 hours. Exposures increased approximately dose proportionately. And importantly, while not shown here, exposures were not impacted by co-administration with either fulvestrant or letrozole. Also importantly, there were no significant differences that have been determined to date observed in different regions or across different ethnic groups as we have enrolled patients in this global phase one study. Next slide. Now I am showing the safety experience in the study. You can see again that we had a total of 65 patients enrolled across these three dose escalation cohorts. It is important to highlight that this is a late line population with a median of four to six prior lines of therapy. Importantly, the monotherapy cohort was a mixed histology cohort, while the combinations with fulvestrant and letrozole are predominantly breast cancer. When you look at the individual AEs shown towards the bottom of the slide, you can't see that the majority of women experienced GI toxicities. However, these were commonly low grade. Importantly, because this is a phase 1 study, drug was administered in a fasted state. It is our expectation that as we move into a phase where co-administration with food is allowed, that the GI toxicity will be substantially mitigated. We have also observed as we have moved from a mixed histology cohort into primarily breast cancer and into earlier lines of therapy that that has also significantly mitigated GI toxicity. Now, secondarily, what we're very excited to see are quite low rates of hematologic toxicity. Here you can see the rates of treatment-related AEs occurring in greater than 10% of the patients who were enrolled, and the rates of neutropenia are really very low indeed. It is important to caveat that, again, we have not yet selected our recommended dose for expansion. We have not determined a maximum tolerated dose, and the duration of follow-up is relatively short. Nevertheless, we're encouraged by what we're seeing in terms of hematologic toxicity that the low rates are consistent with our preclinical hypothesis of lower rates of heme tox for a CDK4 selective molecule. Next slide. Now I would like to share some data that was not included in our poster at San Antonio. Again, we have enrolled many more patients since the data cutoff for our poster, and although the data maturity is short, we actually can assess pharmacodynamic measures relatively quickly. So what you're seeing here is a pharmacodynamic assessment of activity over the first 29 days of study participation. Now, I have changed nomenclature here from dose level numbers to dose level letters. That's because the dose levels, both in terms of the absolute amount and schedule, are slightly different, but these are not substantially different from what I've shared in the PK slide. Importantly, what we have observed is that the dose levels that we are exploring most recently have substantial and sustained suppression of TK1 activity. TK1, or thymidine kinase 1, is a measure of cell cycling. The mechanism of action of a CDK4 inhibitor is inhibition of cell cycling, and therefore we're looking for a reduction in TK1 activity. What you can see is that at the higher dose, dose level B, we have a more pronounced and more substantial reduction in TK1 activity. But both of these dose levels are achieving levels of TK1 suppression that are consistent with what Pfizer has reported with palbociclib. And importantly, both of these dose levels are achieving our target of less than 20% residual activity of TK1, which we believe places these dose levels in our predicted efficacious range. And indeed, we are starting to observe clinical responses at these dose levels. Next slide. So to conclude, we believe that we have a novel, potentially best-in-class CDK4 inhibitor. BGB-43395 is a potent CDK4 selective inhibitor with a clean kinome profile. In the first year of investigation, over 120 patients have been enrolled. Put another way, over the first year of phase 1 investigation, we have enrolled one patient approximately every three days for a full year. This is tremendous operational progress, which has substantially closed the development gap with the development cycle by up to two years, and importantly, I would highlight, as you heard from Lai, that we can deploy this operational efficiency across our portfolio. This is not, shall we say, a special case. We're very happy with what we're seeing in terms of the emerging clinical data, in terms of low hematologic toxicity, the encouraging PD data, as well as the preliminary evidence of clinical efficacy, and we look forward to sharing additional study updates at medical conferences in 2025. Indeed, planning is underway to initiate phase 3 studies in both first-line and second-line hormone receptor-positive breast cancer should the emerging clinical data continue to support. Next slide. It has been a transformational year within the solid tumor organization at BeiGene, with 10 new molecular entities for solid tumors entering the clinic so far and two more poised to start before the end of the year, which has enabled us to develop deep and differentiated disease area franchises in lung, GI, and breast cancer. Upcoming milestones for our emerging breast cancer franchise include selection of doses for expansion with our CDK4 inhibitor, which we believe will happen by the end of this year, combination of our CDK2 inhibitor, which is progressing very nicely through phase 1 investigation with not only endocrine suppressive therapy, but also the CDK4 inhibitor, which will start as early as the end of the first quarter. We're starting a phase 1b study with our novel BCL2 inhibitor, which we will ultimately combine with our CDK4 in the second half of next year. And again, the B7-H4 ADC has also made outstanding progress, and we believe we will be selecting those levels for expansion in the first quarter of 2025. Thank you again for joining, and with that, I'm happy to hand over to Mehrdad. Thank you, Mark, and hello everyone and welcome. So in the next section, I'll provide a little bit of update about our presence at ASH and a brief overview of our hematology programs. Next slide, please. So BeiGene is transforming lives of all CLL patients in all segments and subsets, and in fact, all hematological malignancies with our current and future medicines. So in short, we all know about BRUKINSA or our zanubrutinib. It is the only BTK inhibitor that has shown superiority versus another BTK inhibitor. It is the leader with the broadest label of any BTK inhibitor. It's approved in 72 countries and importantly has high reimbursement and market access. And we're working on expanding the life cycle with a bunch of combinations so that this cornerstone asset can have a larger lifespan. Next is our BCL2 inhibitor, sonrotoclax. Similarly, it has the potential to be best in class with higher potency, safety, and broader usability. Now we have enrolled 1,600 patients in this program, and we have shown compelling efficacy data. This program is way into an advanced development program in pivotal stages. It was mentioned that we have initiated and advancing really well a frontline CLL study. We have fast-to-market opportunities that we are executing, and we will soon start two other phase three studies in relapse refractory CLL and mantle cell. We have differentiated opportunity in AML, MDS, and importantly, multiple myeloma. And as you heard from Mark, we have a novel BCL2 inhibitor specifically designed to be complementary and target additional B-cell malignancies. And last, briefly about our BTK degrader or BTK-CDAC. This is now the most advanced BTK degrader in the clinic. We have enrolled more than 400 patients across different B-cell malignancies in monotherapy. We see strong clinical data that you're going to see later, particularly even in BTK-resistant CLL. Combinations have started. This distinct MOA has a lot of potential that we'll talk about. With the best in class and first in class for this drug, we have a phase 2 expansion already started and a pivotal with a pivotal intent, and it has Fast Track designation, and a phase 3 is planned to start early next year. Development beyond CLL in parallel will happen for earlier lines and other B-cell malignancies. Next slide, please. So you were all at ASH, and you heard a lot of data about CLL, including data in combinations with venetoclax or fixed duration treatments or non-covalent BTK inhibitors. I think that's a testament about the importance of CLL. To your left, you see that CLL remains a significant opportunity and growing in frontline CLL, and with that, a relapse refractory population is a growing population where we need innovation indeed, and I think that can, coupled with the pipeline that we have together, really enable impact growth in our CLL leadership. To your right, you see a snapshot of what we are doing now and in the future and how we'll protect and grow our leadership in CLL. I talked about BRUKINSA. BRUKINSA is proven to be best-in-class BTK inhibitor in frontline and relapse refractory setting. As mentioned, it's the only BTK inhibitor that has shown superiority versus another BTK inhibitor. That is clear differentiation. We have long-term follow-up. We are showing highest complete remissions with this BTK monotherapy, and now we show sustained efficacy regardless of disease risk status and patient characteristics, and of course, good safety. Now we are combining a cornerstone BTK inhibitor with sonrotoclax. As an example, development of BRUKINSA plus sonrotoclax in frontline CLL can provide the best-in-disease fixed duration combination, delivering exceptional efficacy, safety, and convenience that other doublets and other fixed durations haven't been able to achieve. We'll talk about BTK degrader. With the data that we see, we can disrupt the CLL treatment paradigm as a monotherapy and combination, and we'll talk about that a little bit more. Can we move to the next slide, please? Just very briefly, these are the 21 presentations that we showed at ASH, really showcasing our commitments to continue to generate data from different resources and publish them and put them in the public forum for physicians, patients, and everyone to be aware of. I'll talk about some of the key presentations during my time. Next slide, please. Let's talk about BRUKINSA. Next slide. BRUKINSA is a next-generation BTK inhibitor that has the broadest label globally and is a leader in new patient starts in CLL. Why? These are all thinking about BRUKINSA. It was designed to be successful where other BTK inhibitors haven't been successful. That's with a greater potency, specifically, and importantly, the bioavailability that provides near-complete target occupancy in all disease-relevant tissues. With that, we took it to a bold clinical development and consistently demonstrated superior efficacy. Focusing on CLL, we have a relapse refractory study, ALPINE. In all common relapse refractory CLL, we show superiority versus ibrutinib, including the high-risk population of 17p. In our frontline study, SEQUOIA, we show that superiority of PFS is sustained, and that's regardless of patients' risk and characteristics. In terms of safety, we have shown that BRUKINSA is superior to ibrutinib in our clinical development programs in two head-to-head studies that we have shown, and also, an independent meta-analysis that was done by Mayo Clinic shows that BRUKINSA has the lowest rate of atrial fibrillation compared to ibrutinib and also acalabrutinib that was designed to address the cardiac toxicity of ibrutinib, but we see BRUKINSA is safer in that regard. We see the lowest rate of infections, including versus acalabrutinib, and importantly, lower rate of some adverse events that limit activities of daily living for patients, so compared to acalabrutinib, that has headache and GI toxicities. We have the biggest number of indications, as I mentioned, five indications, including follicular lymphoma, and BRUKINSA is the only BTK inhibitor that has follicular lymphoma approval. We have a series of phase 3 studies that will bring BRUKINSA to earlier lines and other diseases. Last but not least, it's very important for physicians and patients that we have a lot of dosing and flexibility. BRUKINSA can be given daily and twice a day and allows adjustment, flexibility, and dose reductions. We have a tablet formulation that we expect to become available in 2025. Next slide, please. Again, this is a snapshot of some of the key clinical data that we had at ASH. On the top, you see SEQUOIA, our frontline study that we presented longer-term follow-up of this study against sustained efficacy, deep responses, and good safety. In the middle, you see the results from our long-term expansion study in CLL that I'll briefly talk about. We had a rollover study, and we enrolled all our early studies, phase ones and phase twos in this study. And we have the ability to go and look at the safety and efficacy of those patients. And we've published these data at ASH, looking at patients who have been on treatment with BRUKINSA monotherapy or BRUKINSA and obinutuzumab now for more than six and a half years. And we see unprecedented CR rates in these patients. Also see efficacy sustained similarity to the pivotal trials. And most importantly, as these patients remain on treatment for a long time, safety and toxicity is acceptable. And in fact, some of the known toxicity of BRUKINSA is decreasing through time. The last presentation I would like to talk about to you is an investigator-initiated study that I'll briefly introduce to you on behalf of those authors. It's called the BOVEN Study, which is a time-limited MRD-guided therapy showing high rate of undetectable MRD rate to the point that patients were able to cease their treatments with a median of 10 cycles and acceptable safety. Next, I would like to deviate a little bit from ASH and remind all of you that the longest follow-up of a relapsed/refractory study, the ALPINE, was published in Blood in September. We see that BRUKINSA demonstrated sustained superiority versus ibrutinib in this head-to-head study now with median follow-up of 42 and a half months. That's the panel that you see on your left side. That's the ITT analysis. ALPINE was done during the COVID-19 pandemic, similar to a lot of CLL studies potentially affected by the COVID-19 pandemic. It was a global study enrolled around the globe, including in Europe and Eastern Europe. We did a sensitivity analysis to see the impact of COVID-19 on the overall study, and particularly if each arm were affected differently. As you can see in the hazard ratio, the hazard ratio was 0.66. The overall study outcome did not change. You see that we have put the 36 months and 42 months point estimates on these curves for you to become aware of how many patients are progression-free as they go 36 or 42 months on this BTK monotherapy. Next slide, please. Looking at the subset of patients with the 17p deletion or TP53, that's the high-risk feature of these patients was one of the key secondary endpoints of this study. Again, to your left, you see that in these patients, also PFS was sustained at this follow-up. Now here you see a hazard ratio of 0.51 with a nominal T-value that you see. Also, we have put the point estimates of 36 months and 42 months, and also with a hazard ratio that's very with the confidence interval that is very convincing. Similarly, we did a sensitivity analysis with COVID adjustment, and we see the effect was similar with a hazard ratio of 0.48. We see that in this population, the risk reduction is about 50% from one BTK inhibitor, BRUKINSA, to the other BTK inhibitor, ibrutinib. This is a true differentiation of this BTK inhibitor that gives us very much confidence that physicians out there that this is the best-in-class BTK inhibitor. Next slide. Another reason that these data are important and why the cross-trial comparisons are discouraged. Here we are dealing with the two very similar studies, two studies that were done head-to-head. To your left, you see a panel from the ELEVATE-RR study, reminding everybody that ELEVATE-RR study was done in patients with deletion 17p or 11q. And at the 40-month follow-up, they reported primary analysis of the study, and we haven't seen any follow-up. The hazard ratio was one, basically no difference between the two arms. The panel that you see here is only the subset of del 17p that we had seen in the supplementary of the paper. And the panel to your right is what I just showed in the previous slide. So the data from ALPINE study in 17p population. So again, you see in ELEVATE-RR, the hazard ratio in this subset is also one. Specifically, you see that in the 42-month estimate we have calculated from the paper. I looked at the estimates. You see approximately 28% in acalabrutinib, and ibrutinib is even higher at 36%. When you look at the ALPINE data, the ibrutinib is even doing very much similar to the ELEVATE-RR, but BRUKINSA is, as I mentioned, statistically significant superior to ibrutinib. So this actually shows the differentiation of BRUKINSA versus acalabrutinib looking at this cross-trial comparison. Next slide, please. Now I want to talk about the data that we showed at ASH from our SEQUOIA study. Remember that SEQUOIA study was done in frontline CLL study that were unfit to receive chemotherapy, and I've put the definition of unfit. That means high CIRS score or high age or kidney function problems, and now with median follow-up of 61 months, we see that the PFS benefit of BRUKINSA is sustained. As you can see in the blue curve on the PFS ITT, we have put the PFS estimates at 36 months, 54 months, and even at 60 months. You can see easily that the efficacy is sustained. This study was also done through the COVID pandemic. Therefore, we did a sensitivity analysis with COVID adjustment, and again, you see the similar risk reduction compared to the control arm and that the PFS data remains the same. In the bottom, you see an important finding of this longer follow-up of SEQUOIA study. The rate of CR in this study at this cutoff was 20%. This is the highest rate of complete remission of a BTK monotherapy that's seen at this level of follow-up. So many investigators, independently of us, mentioned that SEQUOIA is one of the most important presentations of ASH 2024, and it was simultaneously published at the Journal of Clinical Oncology that's available to you to see now online. Next slide, please. Thinking about safety, we presented the overall safety of this study, but we specifically are showing here what we call an exposure-adjusted incidence rate, which factors in how long these patients have been on treatment, and we have done similar analysis before. And as you can see, the numbers are the same between the BRUKINSA and BR arm. And actually confirms that the rate of hypertension, atrial fibrillation, and flutter, so these are specific adverse events of interest that were predefined for BRUKINSA, are very low, stressing about the importance of the fact that BRUKINSA is a safe treatment. Next slide, please. I also want to talk about this IIS. As I mentioned, this IIS was conducted at Massachusetts General Hospital and Memorial Sloan Kettering and sponsored by BeiGene. You have seen this data several times. It's called BOVEN study. You have seen the mantle cell lymphoma data from this particular study that now is mentioned on the NCCN guideline. And this presentation, I want to talk about the five-year follow-up of the time-limited MRD-guided treatment with ZVO, so zanubrutinib, venetoclax, and obinutuzumab. Next slide, please. Very briefly, I want to show you the safety profile of this triplet of ZVO. They show all grade adverse events, Grade 1, 2, Grade 3, and Grade 4. So overall, very safe and tolerable, very low level of high-grade AEs. You see that they did not report any Grade 5 AEs, which was very important. You see rate of neutropenia, but authors mentioned that the neutropenia was very manageable with G-CSF or drug hold to the point that they did not have any complicated neutropenia. They only reported one case of neutropenic fever. The study was also conducted during COVID-19, as you see some COVID infections, but did not lead to any complicated COVID case or any death from the COVID-19. Next slide. This is an important slide on the efficacy of this triplet. Important to mention that this study was enriched for high-risk population. They had a lot of patients that came under trial with 17p deletion, TP53 aberration, or other high-risk features of complex karyotype. You see the MRD rates. They show 96% uMRD4 in peripheral blood and 92% uMRD4 in both peripheral blood and bone marrow. But as I mentioned, it was MRD-guided treatment, meaning when the patients achieved a certain predefined stopping criteria, they were able to stop the treatment. You see with median 10 cycles of therapy, these patients were able to stop treatment. The range was only up to 12. Nobody even received 14 cycles of therapy. Very convincing and promising triplet data. Next slide, please. I mentioned at ASH, other than us, there were some important data presented. One of the data that was presented last Monday was on the AMPLIFY data. Before I briefly talk about our interpretation of AMPLIFY data, I want to mention that we really believe in the fixed duration treatment and the promise they can have for a lot of patients. AMPLIFY data did not meet the expectation. Just briefly for a reminder for those who might not know this study very well, this is a study that was done in low-risk fit treatment-naive CLL patients, meaning that they excluded patients who had del 17p or TP53 mutations at a higher serious score and had a higher score of more than six. Fit and low risk, it was an arm of AVO, an arm of AV, and the control arm was FCR/BR. I've put just an overall interpretation of how I see the data for AV and or actually both arms. Only with median of 40-month follow-up for a treatment-naive CLL patients, we see modest risk reduction versus FCR/BR that is now considered a substandard control arm. That put the 36-month PFS estimate that shows no evidence of benefit versus true current standard of care, which includes BRUKINSA or other fixed duration treatment available that are venetoclax or obinutuzumab or venetoclax or ibrutinib in the cross-trial comparisons. Thinking a little bit more about how they have reported PFS, and we'll see the curves, they do a COVID adjustment, and we see the superiority of AV versus chemotherapy is even less noticeable with COVID-19 adjustments, and you see curves converging. As one of the sensitivity that we have seen was in the unmutated IGHV patients, and you see even lower 36-month PFS estimate, which is also significantly lower compared to what we know from the standard of care. uMRD was a key secondary endpoint of this study and failed, favoring FCR/BR at 51%, and it was only 29% in AV, which is notably lower than those observed with even VI or VO in similar time points in cross-trial comparisons. With that, no claim of OS can be made as the key secondary endpoint failed and anything tested below that is not a statistically significant endpoint. In this study in general, we saw a concerning number of deaths of all causes over this short period of follow-up in a population as frontline fit, so they're supposed to do well. And when we look at the studies that are done historically, patients in frontline fit studies do a lot better than patients with frontline unfit study. AVO, it was very clear that the triplet associated with major safety concerns and increased high-risk toxicity and death. There was no benefit in this arm versus current standard of care. This is similar to what we have seen before with the IVO as well. Again, fixed treatment duration is something that we believe in. It needs to be safe and efficacious in all patients with any disease risk status, any disease characteristics, and be feasible to deliver at any clinical practice. We did not see that in AMPLIFY. In the next slide, I want to show you briefly the curves. To your left, you see this cross-trial comparison panel. You see the Sequoia data that I already showed you. To the left upper corner, reminding you that Sequoia was done in a frontline unfit CLL population. The median age in Sequoia was 70. To the right, you see the ITT population of AMPLIFY done in frontline fit CLL population of AV, AVO versus chemoimmunotherapy that we expected to see better response. The median age in this population was 61. I mentioned that we saw modest hazard ratio, but again, thinking about the control arm of FCR, this doesn't really show that this is now a new standard of care. If you look at the shape of the curves, there are several issues that we can talk about. But very briefly, you see a lot of censoring in the beginning of the curve that is consistent with a lot of FCR patients that they dropped out of the study as soon as they were enrolled on the trial, which shows this treatment was considered suboptimal for patients and physicians. You see the arms of AV and AVO are crossing. In fact, AVO is inferior, then AV becomes inferior, and then when you look at the 36-month estimate, you see that they are not that differentiating between the three arms, and the curves are getting very close, and you see a substantial amount of censoring around 36 months and after that shows this curve is relatively unstable. Below that, you see the COVID adjustment. As I mentioned, Sequoia did not have any difference with or without COVID adjustment. When you look at the AMPLIFY COVID adjustment, particularly, look at the AV versus FCR, you see the risk reduction becomes much smaller. At the 36-month follow-up, they're very close, and in fact, the curves are converging, so with that, I want to talk about sonrotoclax that we believe can deliver what is expected from a fixed treatment duration. So very briefly talking about sonrotoclax, similar to BRUKINSA, it was designed to address some unmet needs, specifically as great potency compared to venetoclax. And we know potency of a BCL2 inhibitor is really important for efficacy. It's selected for BCL2, and also very importantly, has shorter half-life compared to venetoclax. And it also doesn't have drug accumulation in peripheral blood that can also lead to better tolerability and ease of delivery at different practices. This program is now very advanced. We have enrolled more than 1,600 patients, and we no longer talk about the pre-clinical promise because all of that is delivered. We see deep and durable responses across the program in monotherapy and different combinations, but importantly, in combination with BRUKINSA, we see much better data than combinations with venetoclax. And we'll go through that, and of course, safe and feasible. We aspire to also have the broadest label of any BCL2 inhibitor with sonrotoclax, including the phase 3 CLL that was just mentioned, fixed treatment duration of BRUKINSA and sonrotoclax versus the currently standard of care globally fixed duration treatment of venetoclax and obinutuzumab. I mentioned about the ongoing fast-to-market, and I mentioned about the two studies that we are starting in relapse refractory CLL and relapse refractory mantle cell. We aspire to remove existing barriers to BCL2 inhibition. One of them is doing two head-to-head superiority studies versus global standard of care. When they read out positive, they leave no doubt that this is now the true standard of care. I talked about that frontline CLL versus venetoclax and obinutuzumab. We know that ramp-up is one of the barriers of BCL2 inhibitors. Our current ramp-up is already differentiated in the phase 3 study and has less lab checks and not very late lab checks. And the next day allows us to have this drug to be used by a wide range of physicians. Also important to know, a further ramp-up optimization study is now open and ongoing. This is after alignment with health authorities to start a study that continues to optimize ramp-up of sonrotoclax in a wide range of diseases since we have seen no tumor lysis syndrome. Again, I want to talk about BeiGene's leadership. This drug expands our leadership in CLL that we have already established. We'll go to acute myeloid leukemia, which is an area of unmet need. Specifically in multiple myeloma, we can be the first drug approved with translocation 11-14 in combination with dexamethasone, and we are starting it in early 2025, while some other combinations are already ongoing. Next slide, please. These are the three abstracts that we showed at ASH. The first one is the oral follow-up update of our phase 2 study of doublet of sonrotoclax and zanubrutinib that I'll talk about later. And we showed a trial progress poster of the treatment-naive CLL and also one of our fast-to-market opportunities in Waldenström's macroglobulinemia. Remember that venetoclax doesn't have a label there. So let's talk about our frontline CLL study. Next slide, please. Just briefly reminding you of the design of this study. This one-on-one study is a sophisticated study design that was designed to answer several important questions on the dose and combinations that we wanted to do with sonrotoclax. Here, I want you to focus on what is bolded in green. That is the expansion in treatment-naive CLL. We took the two doses of 160 milligrams and 320 milligrams to an expansion after we did our dose finding, which we showed all the doses were safe. And now with the median follow-up range of 19.4 months, we are presenting the updated data. Next slide, please. This is the baseline characteristics. This is an ongoing study. I just want to show you that this study also enrolls young and old patients, patients up to 84 years old, patients with high-risk features of 17p, TP53, complex karyotype. So a true population of frontline CLL. Next slide. Very importantly, constantly hearing from our investigators and here showing in this slide, this doublet has been very safe and tolerable. The AE profile that you see broken down by 160 and 320 overall is very safe and tolerable. You mostly see low-grade and transient adverse events. Some things that are important to point out: we have had zero tumor lysis syndrome, no lab tumor lysis syndrome, no clinical tumor lysis syndrome. One line that you see on the top is neutropenia. Investigators are telling us neutropenia is transient with some drug hold or G-CSF. They recover and they can continue to take the rest of the treatment, and in fact led to no higher rates of grade 3 and higher infection and no neutropenic fever. This study was also done during the COVID-19 pandemic, and we did not see any complication of COVID-19 or COVID-19 death. In fact, no adverse events leading to death. Next slide, please. At ASH, we showed a 100% overall response rate in our doublet with 320 milligrams, and also CRs is something that we haven't seen in AMPLIFY. Here in this slide, I want to show you that we see high and early rates of uMRD4 with a doublet of sonrotoclax and zanubrutinib that deepens from the week 24 to week 48, so about six months to one year. An early version of this slide really gave us the confidence that this doublet is really differentiating than any venetoclax combination. Now with this large dataset, we see that. Just look at the part that is highlighted in red. These are the 53 patients that we also showed the efficacy. 91% of them are uMRD4 by flow cytometry. We have had no patients who converted from uMRD4 to MRD-positive going from week 24 to week 48. That is very promising for us. The yellow that you see up there is NA. That means if the sample was missing or if the lab test had an issue. On the right, I added a table from AMPLIFY to remind you what you saw at AMPLIFY. That was very different than what you saw here. You see the three arms of AMPLIFY listed, AV, AVO, and FCR/BR, and the two time points that they put in their ITT population that are their key secondary endpoint and the end of treatment. Key secondary endpoint was a time that they tested MRD and failed. You see the MRD rate with AV with the doublet was 26%. At the end of treatment was 34%, and that the follow-up point that they showed was even going down. Similarly, 66% for triplets and 51% in chemotherapy and slightly going up. I want to summarize that the mid-treatment, the month 6 and month 12 MRD rates that we are seeing here is higher than any venetoclax combination that we have seen, particularly this uMRD compares very favorably to what we see with AV, AVO, and chemo at similar time points. Next slide, please. This is a PFS curve. It is very self-evident. 19 months follow-up, we have had only one single primary progression. That was on our 160 milligram cohort. One patient developed Richter's transformation. With a median of 19.3 months, we have had no primary progression on our 320 milligram dose, which is our dose that we call it recommended phase 2 dose. So if you show the next slide, please, this is now the study that we are conducting. It's called sonrotoclax. So let's show TN CLL. It's the only phase 3 trial that is showing a BTK inhibitor and a BCL2 inhibitor, both BeiGene drugs, sonrotoclax and zanubrutinib versus venetoclax and obinutuzumab, globally approved fixed treatment duration standard of care. That is a very high bar. And the study is designed for superiority of PFS. You see the study design, primary endpoints and superiority of PFS. The secondary endpoint is MRD rate and, of course, safety. With that, I want to move to the next slide that shows you that we have a very deep and data-gated development plan for sonrotoclax. We're aspiring and we are delivering a potentially broadest label for any BCL2 inhibitor. For the phase 2s and phase 1s, for the majority of them I've talked about, I want to guide your attention to that phase 1, 2 that we call it ramp-up optimization. That study is now started. You can see it on ClinicalTrials.gov. We continue to optimize our ramp-up in CLL and in other diseases. Our phase 3 relapse refractory mantle cell study is about to start. Below the line, you are seeing some other studies that we are planning. An important one is a relapse refractory CLL study. As leaders in CLL, we believe in the role of anti-CD20s. But as you saw, we don't need that for our doublet. So we are putting the CLL CD20 in the relapse setting, and I think there is a need for that. We are designing our Waldenström frontline study that will convert the potential accelerated approval and also the studies that were mentioned in AML and in multiple myeloma. Next slide, please. Last, I want to talk about our novel BTK degrader. Like I mentioned, we have BTK degrader. Our BTK degrader is the most advanced hematology degrader in the clinic and can be the first and best in class. Just very briefly about our platform, BeiGene's degrader is a novel MOA that degrades the protein, can be more potent than inhibitors, can overcome and, in fact, obviate emergence of resistance mechanisms and our degrader platform was truly optimized for safety and efficacy before we rolled it out to clinic. Just briefly about BTK degrader. Our BTK degraders in the pre-clinical model, we showed that it degrades a variety of mutations of BTK and wild type, and now we see it in clinic. Importantly, we have shown data for blood-brain barrier penetration. Our drug doesn't have immune activity. We know that some BTK degraders have that and led to some toxicity. It's important to know what BTK degrader can do. BTK degrader can displace BTK inhibitors, particularly non-covalent BTK degraders. Talking about our striking clinical data that I'll talk about, now we have enrolled 400 patients across 14 countries in a variety of B-cell malignancies, including BTK-resistant CLL patients. Overall, we see rapid improvement of disease status, including how patients feel. Cytopenias are very rapid to resolve. We see deep responses, including complete remissions in CLL, Richter's transformation, which is an aggressive disease. We show data in indolent non-Hodgkin lymphoma, and the deepest response that's typically seen in Waldenström VGPRs. And these responses are durable in this very heavily pretreated population of patients with BTK mutations. Safety is promising, appears to be similar to second-generation BTK inhibitors, and actually supports use in the earlier lines. So what we are doing in terms of our robust clinical program, we already have a phase 2 with potential pivotal intent open in relapse refractory CLL. We have shown strong data with this. We have fast-track designation from the U.S. FDA, and we are starting the confirmatory study in 2025. I'll show later that the study has other expansions. We have started the study that we call it a platform study, meaning that we can have several combinations in different sub-studies with our BTK degrader. That includes our internal assets, including sonrotoclax and some other assets. I'll show it later. And we are planning an aggressive development plan to early lines of therapy and other diseases, including frontline CLL and second line. Again, I want to talk about the leadership of BeiGene. The fact that we are so advanced with this molecule is really a testament to how BeiGene can deliver drug development, particularly in B-cell malignancies. When we are done with these studies that we'll talk about, it will really, truly expand and enhance our leadership in CLL. We have launched opportunities in diseases that we haven't been in. We're thinking about chemo-free follicular lymphoma and actually in aggressive lymphomas like Richter's transformation or large B-cell lymphomas. Next slide, please. These are the three presentations that I will talk about, all of them. We have two orals in CLL and Waldenström and one poster in follicular lymphoma and marginal zone. Next slide, please. This is the overall design of our phase I, II study, Cadence 101. And you see that it has several dose escalations, 1A, 1B, 2, 1C. And in the bottom, you see that we have pre-planned some expansions, that some of them, for example, relapsed/refractory CLL and mantle cell are already open. And in Waldenström, we are about to open. So I'll not show it again, but in the future presentations, this is the design I want you to remember. And the data that we are showing is mostly from the dose escalations of these indications, per indication. Next slide. Starting with our CLL data. This study enrolled relapsed/refractory CLL patients, and you see the baseline characteristics. Again, you see patients' median age was 70, as old as 91 years old. And you see in the red box to your left, this is probably the highest risk patient population in a CLL study that I've seen, with 66% having TP53 or 17P and 50% having complex karyotype. To the right, you see that we tested patients for BTK mutations, then 30% had BTK mutations. We had patients with PLCG2 mutations. And below, we list the prior lines of therapy. The median was four, and we had patients up to 10 prior lines of therapy. And we had patients, a vast majority of covalent BTK or non-covalent. And we list the double. They had covalent and BCL2 and triplet, that covalent, non-covalent, and BCL2, and also a vast majority came off of their BTK inhibitor because of a progression. Next slide, please. Safety of this BTK degrader, overall, we believe is very safe and tolerable. You see all great. You see Grade 3 and higher. We have not seen atrial fibrillation in CLL. We have reported before that we see lab abnormalities of amylase and lipase. As we have said before, this is just a lab finding because we have been checking per our protocol in a phase 1 study. They are transient. They're all in the first couple of cycles. No patient had clinical findings of abdominal pain or pancreatitis. Patients and physicians are not concerned about that. We have had two cases of hemorrhage. You see a Grade 1 subarachnoid hemorrhage and a subdural hemorrhage. You see rates of neutropenia. In fact, recall that recovery of cytopenia is one of the features of this drug, and we have very fast recovery of cytopenias. In fact, we showed graphs at the ASH presentation that I'm not talking about. But I want to show you that in CLL patients, in these heavily pretreated patients, majority of them had chemo and all, with very weak bone marrow reserve, we only had one case of febrile neutropenia. And that was in the context of COVID-19 and diarrhea. Next slide, please. Important to look at efficacy in CLL. We saw high ORR across our doses, including our lowest doses all the way. So you see that I've highlighted the 200 milligram, the overall response rate, and disease control is 94% in these heavily pretreated patients. We have reported two CRs. One of them is at our low dose of 100 milligram, and none of the BTK degraders or even BTK inhibitors at early follow-ups of 10 months have seen data like this. I'm not going to go through all the poor risk features, but we see efficacy among all poor risk features. Next slide. At the presentation, we showed durability, including swim lanes and this PFS curve. Also, at the same session, we heard the data from the BRUIN study, the BRUIN 321 study. When you see these two PFS curves across trial comparison, you see that the PFS estimates from our study favor pirtobrutinib. Pirtobrutinib data, this was the final analysis. They have cutoff data, and we see that at this final analysis, the median PFS is 14 months. That follow-up is shorter than theirs, but the shape of the curves is very telling. In the bottom, I've put patients' characteristics. Median prior therapy was higher than ours. Double-exposed was higher. And as I mentioned, the majority of our patients discontinued due to PD that was higher than pirtobrutinib study. Next slide. At the request of investigators, we also put data from our Richter's transformation. We see very promising activity in this high-risk, high-grade risk transformation. This is the worst outcome of a CLL patient when they progress. They convert basically a disease to an aggressive disease. You also see we had 14 patients enrolled, 12 patients efficacy evaluable. You see responses are durable, including a CR in Richter's transformation, including a patient who had never been able to have a meaningful response to proceed to an allotransplant. This is a key finding of the CLL and Richter's transformation. Next slide. I want to show you some data from our Waldenström data. Similarly, heavily pretreated patient population, older population up to 81 years old, up to 11 lines. All of them had covalent BTK inhibitors, the vast majority chemo, non-covalent BCL2 inhibitor, and next slide shows really important efficacy. 94% of our patients, so basically everybody who enrolled on the trial, all patients have achieved the disease control, including a quarter of patients who have that deep responses of VGPR, and we slice it by all mutations of high-risk features, and you see similar responses in all high-risk features. An important next slide feature of Waldenström is IgM. It's a PD marker of IgM, and to your left, you see our curve from our phase II study, and you see a rapid reduction with a very steep curve of IgM reduction in all of our patients. There was one patient that you see is going up. That patient had a drug hold. No mutation was identified and progressed. To the right, as a cross-trial comparison, I've put the Waldenström data that the Nurix company presented at IWWM in October. You can actually compare the angle, how steep some of the curves are in ours. There appears to be more flat. You see they've gone to a dose of 800 milligram. Our doses are not shown, but we see the steep curves in all doses. It seems that only in the higher doses, they can have steeper curves. We heard that in their CLL, 600 milligram is also a dose that they are taking to expansion. Next. Very briefly on the two doses of follicular studies of follicular lymphoma and marginal zone lymphoma, we also saw high responses and complete remissions. Again, you see remissions and complete remissions and overall responses in all diseases. Next slide. With the totality of data that we have seen in these 400 patient studies, we have been thinking. And now that we saw the BRUIN 321 study, additionally, a phase II study of our BTK degrader, head-to-head versus pirtobrutinib, is planned to study. You see that it's going to be previously untreated patients with CLL with at least one prior line of therapy, simple randomized 1:1 to degrader, or PIRTO. And the primary endpoint will be PFS superiority. Next slide. Next slide. This is the overall clinical development plan. I've mentioned phase I that has several expansions. I've mentioned a couple of phase II pivotal expansions that are opened. Platform study is already open. We are enrolling patients in combination of degrader and sonrotoclax, degrader and zanubrutinib. And soon, we will start enrolling degrader with bispecifics in a wide range of B-cell malignancies. And the two phase III's in CLL in the bottom are mentioned. Next slide. I mentioned that we are leaders in CLL and building on the leadership that we have developed with BRUKINSA with our assets now and in the future. We think our portfolio allows us to maintain and grow our leadership in CLL. We'll provide options across the entire patient's journey. To your right, you see how we think about our diseases and our agents. In relapsed refractory CLL, we have BRUKINSA now. Then fixed duration of BRUKINSA and sonrotoclax in front line. There are some BRUKINSA combinations, important IISs that are ongoing. We work with some of the most important cooperative groups. We are taking our BTK degrader to front line as monotherapy and combination. Similarly, in relapse, it's important to have options. We are working on BTK degrader as monotherapy, as I mentioned. We are working on the fixed duration of sonrotoclax and anti-CD20, and also the sonrotoclax and degrader. So the circle that you see is really truly showing how our leadership is growing as we combine BTK degrader with sonrotoclax and more combinations. And as degrader comes, and I think the overall leadership of BeiGene for all patients and addressing their unmet need is growing. Last slide is showing how we see the evolution of our company. We have cemented ourselves as leaders in CLL. We are growing our leadership with the two assets that I mentioned. We are expanding our indications on patient AML myeloma, high-risk diseases, Richter's, and large B-cell lymphoma. And most importantly, we are maximizing our impact, impact on patient outcomes, and of course, significant market opportunities. Thanks for your attention. And I'll invite our CEO and chairman of the board, John Oyler. Thanks so much, Mehrdad. As you folks can see, Lai, Mark, and Mehrdad haven't been up to much this year. It's been an easy year for them. Really, we're just spectacularly excited. And I wanted to provide a little bit of context because there's a lot to absorb in this hour or so. Can we jump to the next slide, please? You know, I'm going to talk a little bit about our sustainable leadership in CLL and hematology. And then I'm going to jump to what's happening on the solid tumor side. I think it's important for us to kind of provide context for you folks because there's so much going on, and that's hard in the context of the company. To me, for CLL and hematology leadership, there's basically been, I think, three major questions that have come up. You know, one is, what's going to happen with fixed-duration regimens in the U.S.? How's it going to affect this $12 billion-plus CLL market? The second question, I think, is, where is PIRTO going to ultimately fall in the treatment paradigm? And you know, is that a risk even to BRUKINSA in first line? And I think the third question which comes up is, look, you have Sonrotoclax and you have the CDAC, and the data is really compelling, and they're definitely going to help patients. But how's IRA or patent expiry and price pressure for Calquence then going to create, you know, for these programs? And what does that mean for the long-term economics of the programs and for BeiGene? So I think those are very good and fair questions. And I want to address them all in the context of, you know, what we've learned over the course of the last couple of months. I think, first of all, in fixed duration, as Mehrdad said, we're a huge believer. This is the best of patients. But what do we want in a fixed duration? We want a deep response that's MRD negative so that we have confidence to stop treatment. And then we want a safe regimen. And we want to see patients, once you stop treatment for a period of time, to not progress. I think as we look at the AMPLIFY data, it definitely represents a step forward for treatment, but it's not the best solution for patients even today. When you look at the 36-month PFS that is reported, COVID adjusted or not, the numbers are notably numerically worse than previous historic controls. And in what I believe is a clinically meaningful way. You know, why is that the case? You know, is it something strange about the study? Well, we can see very meaningfully lower MRD rates. This was the secondary endpoint, and it was not met, and it was actually resoundingly favorable for chemo. Not surprising that the PFS matches that. And then when we look at this, this is still early data. The data represented, you know, has patients at this time point only 21 months off of therapy, but 24% of the patients have already progressed. And if you look at the curve, it's early, and it continues to have a downward slope. So what's it going to look like in a year or two years? We don't know. It's premature. From the second perspective, I think as you look at the zanubrutinib data, you know, this study that is, you know, now nearly fully enrolled really has the potential to deliver what people were looking for. When you look at does this have a deep response, the MRD data, it's there better than we've seen before. When you look at where we are with respect to safety and usability, it has that early data. This is not because of, you know, random trial. It's because of purposeful design. These molecules were designed to be better, to be safer, to be more efficacious, and have the correct PK characteristics to enable that. And I think that's what we're seeing at this point in time. Secondly, if we jump to, you know, how pirtobrutinib is going to fall into this paradigm, this is, you know, a great promise of medicine. And there's a lot of patients that still relapse. And whatever you see on these PFS curves, that's a great clinical center. The real-world data is not as good. There's still tremendous unmet medical need in CLL. And pirto had the promise to be an important medicine after a covalent BTK failure. Unfortunately, that data deteriorated from 22 months to 14 months in the latest data readout. And as we look at our BTK CDAC, this is probably, you know, one of the biggest and most impressive surprises that we've seen in a long time. The data is extremely compelling. And I think as we've mentioned, we're going to move forward with a head-to-head trial for pirto. Again, why? We strongly see the BTK degradation offering real mechanistic advantages over non-covalent BTK inhibition. And we can talk about why, but it's purposeful design. It is not unexpected, but it's actually better as it translates into human than even we would have hoped for. This is really compelling, and we're really excited about the potential for patients here. The third point about how do you protect yourself in the long run? We're all worried about small molecules with price deterioration of competitive products. The underwhelming AMPLIFY data really provides much lower hurdles, and it gives us the ability to show real separation for BRUKINSA monotherapy, for sonrotoclax in combination, even for the BTK CDAC from a Calquence then. This is not the only study. I think as you go back and look at ELEVATE-RR, you look at our ALPINE study. Again, in those studies, this is not the first time it appears that a Calquence may be no better or even numerically worse than Imbruvica. So I think that really, you look at the data, we have much, much more confidence in our ability to maintain pricing over the long term as we get to know and understand this better. And the second point is we really do have the ability to put these three tremendous medicines together in unique combinations that will enable us to provide additional mitigation through IRA and through patent expiry and really build a franchise as you've seen companies like Gilead do in the past. On the early solid tumor portfolio, again, there's just major progress. You look at the very compelling potential for huge blockbuster medicines that we're putting in the clinic. This is a very exciting set of, you know, programs that we believe have great promise and are early. They're not that far behind, or they're not behind at all, but have best-in-class features. There's numerous readouts coming in the next 12 months, even more in the next 18. And we're really, really excited and believe this is one of the best, if not the best, early solid tumor pipelines in the industry. Secondly, it's built in a way that we have combination potential to build franchise in lung, breast, and GI. And we think this provides us the opportunity to do that just as you see we're doing in HEME. And lastly, with the CDK4 inhibitor program that's been shown, this is really incredible early data. And the execution of enrolling 120 patients in less than a year, companies just don't do this. This is why BeiGene has built its own internal 3,600-person global clinical operations organization, which is a force to be reckoned with in the industry. And as we've said, we're planning the phase III that's underway. So with that said, as you think about these products, you know, as you look at the studies that are reading out, the biggest thing I can encourage you to do is look at the data. You'll hear a lot of qualifications around why the data didn't look as good as it should, but just look at the data. Our studies were run in the heart of COVID right on top of the AMPLIFY study. There's really no difference. You'll hear they're European enrolling, Eastern Europe. So were we. The data is there. Look at the data. It tells the story. And that's all we ask. If you look at it and see it, you can understand how these three medicines are really the future of CLL. Thank you so much, and we're happy to take questions. If you'd like to ask a question, please use the raise hand icon, which can be found at the bottom of the webinar application. When you are called on, please unmute your line and ask your question. We will now take a minute for the queue to assemble. Our first question will come from Rennie Benjamin with JMP Securities. Your line is now open. Hey, good afternoon. Good morning, everyone. And thanks for taking the questions. Thank you very much for this data update. I guess I have two questions. One on the solid tumor franchise and one HEME. On the solid tumor side, as you evaluate, you know, the data, we saw some, you know, really good safety data. But as we're thinking about efficacy, you know, when might we see efficacy data? What kind of efficacy data would you need to hit for, you know, for you to move forward with the franchise, kind of, you know, make that go/no-go decision? And what kind of efficacy would you like to see in combination? Because I'd like, I think, Mark, you can correct me if I'm wrong, that ultimately, you know, CDK4 inhibitor would be used in combination in the, you know, at least with breast cancer moving forward. And I think just on the HEME side from Mehrdad, if you could just help me understand a little bit more about, you know, as I think about the degrader, you did the cross-trial comparisons to other degraders. I guess I'd love to understand a little bit more about how it compares to, you know, maybe a small molecule like venetoclax. Do you have any sort of early data regarding resistance mutations and whether or not that, you know, the claim that degraders might be able to prevent or obviate resistance mechanisms, you know, is actually taking place? Thanks. Thank you, Rennie. Mehrdad, okay, if I start? Thank you very much for the question. I think that for efficacy data, it's important to recall that the mechanism here is not cytotoxic, and responses can take some period of time to emerge. Therefore, we think realistically, we're going to need four to six months of patient follow-up to have a good estimate of response rate, let alone durability, which is also going to be important. We, as you said, do not have intent for monotherapy development in breast cancer, that the hormone suppressive therapy is a necessary component of the regimen. I think now that we have seen data for both palbociclib as well as abemaciclib in post-CDK4/6 treated patients, we have a fairly clear idea of what the benchmark is, both in terms of response rate and durability that we're looking for as we accumulate this data. As I alluded to before, we haven't made a formal decision or yet, but it is absolutely our intent to share efficacy data at a major medical conference in 2025. Maybe I'll take the CDAC question. As I mentioned, you know, we have shown that the degrader is optimized to be, you know, best in class. It degrades the mutations as it's supposed to do. In our data set, we have checked for the mutations of BTK and PLCG2. A vast majority of patients were enrolled on trial after that progression or received BCL2 inhibitor. They're responding to our drug after a BCL2 inhibitor, which is majority of them are venetoclax. We haven't tested for BCL2 mutations. That's something that we are going to do in the batches. It was the most important part to put the BCL2, sorry, the BTK mutations up. But as we combine the two, sonrotoclax plus BTK degrader, that's something that we'll definitely look at, and that study is ongoing now. Maybe I'll just add a comment on the mechanism, why degrader has less resistance. Degrader does not require strong target binding compared to a small molecule inhibitor because this is a catalytic reaction. Once you have some binding to the target, degrader will catalyze this ubiquitination and leading to the protein degradation. So we have done quite extensive in vitro mutagenesis to look for degrader-induced resistance compared to the small molecule inhibitor, which requires constant binding. Degrader actually is the best way in terms of preventing the resistance because it does not need a whole lot of target binding. Got it. Let me just follow up real quick. The head-to-head study with pirtobrutinib, is that presumably going to be a pivotal trial that, you know, that's being conducted and could be used for registration, or is it a study that, you know, ultimately leads to further, you know, sort of more registrational type studies? It's aimed to be a phase III head-to-head trial aimed for registration. Excellent. Thanks very much for taking the question. Our next question will come from Jess Fye with J.P. Morgan. Please go ahead. G reat. Hey, guys, can you hear me okay? Yes. Great. I have a couple on this EK4, two on safety, two on efficacy. First, can you talk about the neutropenia and decreased neutrophil counts described on this EK4 poster? And, you know, if we want to think about what% of patients had either one of those, what's the right way to think about it? Like, is it a function of different reporting terms where we should sum them? Or alternatively, are all of the patients with neutropenia also captured under those with decreased neutrophil counts so we can think of the neutropenia rate as a subset of decreased neutrophils and we don't need to add them up? The second one on safety, can you elaborate a little bit on the GI side effects and the reasons you expect those to move lower? Can you, maybe, I don't know if it's possible for both of these talk about kind of what rates you have seen at those doses where you're achieving the target of less than 20% residual TK1 activity? So we have a better sense of kind of like what the profile might be at the go forward doses. And then on efficacy, what's the right bar to think about for efficacy for the CDK4? Is Pfizer CDK4 the right product to look to? And if not, why not? And I know we, you know, only had two months median follow-up as of San Antonio. How much follow-up do you need to report on initial efficacy data? Thank you. Thank you very much, Jess. Hopefully, I will keep all of this front of mind. So in the poster, we present both treatment emergent AEs as well as treatment-related AEs, which is why the numbers are slightly different. It's just one of the challenges of CTCAE that when reporting low neutrophil counts, it can be reported in two ways. My understanding is that if you simply sum the neutropenia and low neutrophil count, there will be a little bit of double counting. So the true rate in terms of treatment emergent is a little bit higher than the larger number, but not as large as the sum of the two. Nevertheless, again, we're quite happy with what we're seeing in terms of rates of neutropenia, that the majority of those rates are, the majority of those events are low grade. For the GI toxicity, the most notable has been diarrhea. This has to date not been strongly dose associated. We're not seeing dramatically different rates at higher doses compared to lower doses. We do think that co-administration with food, particularly food that has some fat in it, is likely to mitigate this. Diarrhea is a relatively common side effect. Low-grade diarrhea is a relatively common side effect of CDK4/6 inhibitors. The investigators that we were speaking with at San Antonio were saying that they're comfortable managing this. Indeed, our study investigators have been saying that, again, this is familiar and it's not leading to dose interruptions or down dosing. Certainly, we want to maximally mitigate it to improve the patient experience. Insofar as what are we looking for efficacy, I think in an ideal situation, we would have, say, six months of follow-up so that we could provide confirmed response rates. We will have a view of emerging efficacy earlier than that. As I mentioned, we do have benchmarks now for what to expect for both the TRBO as well as the approved CDK4/6 inhibitors in front line, as well as in later line in CDK4/6 pretreated patients. So that will be our benchmark for moving forward with registrational opportunities in both front line and second line. Our next question will come from Yaron Werber from Cowen. Please go ahead. Yes. Hi. Thanks for doing this. This is really useful. So I got a couple of questions on the BCL2 inhibitor program. The first one, I think, Mehrdad, you mentioned that you're planning on literally starting the phase I dose ramp study. Can you give us a little bit of a sense of how that study is going to run and what you're trying to do? The current escalation is actually nine weeks, right? So it's actually slower, but easier than then. So are you thinking that this is going to be even less monitoring, maybe moving it outpatient or shortening that nine-week escalation? And then secondly, as you're thinking about maybe time to market, you mentioned that next year we're going to get some of that data in potentially, I think it was Waldenström's and maybe relapsed refractory CLL in the first half of the year. I'm sorry, the MCL and CLL. Is that going to be the registrational path? Can you file based on those phase III data, or would you even file based on Waldenström's or the phase II? Thank you. Thanks, Yaron. So the simple answer to your first question is all of it. So you're right. We have a longer ramp up because it was a potent BCL2 inhibitor. We went slower and with lower doses, particularly in front line CLL. That's something we could afford. And with that, you know, we have less lab checks. We don't have the late lab checks. So that's already a lot easier for patients and physicians. Thinking about the venetoclax, it's not necessarily the ramp up that is a barrier. It's the back and forth and the lab checks and the late lab checks. So that program already is differentiated compared to venetoclax. The study that we have actually already started works on what we call it optimizing. And the aim is all you mentioned, shorten it, less labs, less back and forth, and allows a lot of flexibility. It's very nice to design that allows a lot of flexibility and across all the diseases to continue to optimize this ramp up. And if it is done well and have a good number of patients, it has the potential to be in the label. In terms of the fast-to-market opportunities versus the phase III, the first phase III, of course, the fast-to-market studies are data dependent and discussions with health authorities. We'll keep you all posted when and if they decide that we're going to file them. But those studies are doing really well. Our next question will come from Clara Dong with Jefferies. Please go ahead. Hi, this is Clara for Kelly. Thanks for taking our question. So we have one question on CDK4. Recently, we saw CDK4 and six inhibitors showing improved PFS benefit in HR positive and HER2 positive breast cancer. And we were wondering whether you plan to explore opportunity in this population as well and whether this population is incorporated in the planned phase III study. And maybe another high-level question, you know, as you have a very broad pipeline across tumor types and many also move into clinics this year, wondering whether it's reasonable to expect some preliminary data from some of them or what are the data readouts investors should focus on in 2025? Thank you. Thank you very much, Clara. The data readouts, so many of the molecules that we're highlighting as the high potential molecules, whether it's PRMT5, the EGFR degrader, entered the clinic in the second half of the year. So earliest potential data disclosure would be in the second half of next year. We have made good progress for both CDK2 and B7-H4, as I mentioned, and are hopeful that we'll be able to share some data for those programs in 2025. And I'm sorry, could you go back to the first, remind me of the first part of your question about CDK4? Yeah, absolutely. So we saw at the San Antonio Breast Cancer Symposium was just CDK, yeah, HER2 HR-positive that we saw, you know, CDK4 and six inhibitor with improved PFS benefit in HR-positive and HER2-positive. So like just wondering what's your plan to explore the opportunity in this population and, you know, whether this population is incorporated in your planned phase III study? Yeah, thank you for the reminder. So we saw the Patina trial at San Antonio. I think it's fair to say that it has been suspected, but it is wonderful for patients. It has now been proven that the addition of a CDK4/6 inhibitor to patients with dual positive, HR positive, and HER2 positive breast cancer adds substantial benefit as measured by progression-free survival. So we certainly were excited to see that. We would think about including that in the overall development plan for our CDK4 selective inhibitor. That said, that's likely a separate phase III study. That would not be something that we could easily fold into the planned front line study because the control arm is different. Those patients would require ongoing HER2 targeting therapy. Thank you. Our next question comes from Yigal Nochomovitz from Citigroup. Please go ahead. Hi everyone. Can you hear me okay? Yes. Hello? Yes, we can hear you. Very, very comprehensive review here. This is really helpful. My question is on the whole AMPLIFY situation. So I guess just to put it simply, you know, help us understand what you've done and how you've designed your fixed dose study in front line that may or should avoid, you know, some of the pitfalls that Mehrdad nicely articulated with the AMPLIFY, which we just saw last weekend in San Diego. Thank you. Sure. Thanks. So maybe again, on AMPLIFY, the overall outcome was suboptimal. They didn't really show the efficacy that we wanted to show in the front line fit patients in this patient, you know, compared to a chemoimmunotherapy. So the design that you saw, first of all, we have enough data that gave us the confidence to start fixed duration treatments. Our phase II data shows 92% MRD negativity. That is what you want to see. You want to see patients in deep, deep responses so that you can cease their treatments, right? In AMPLIFY, in AV, you saw that they had a really lower limit of uMRD. The other thing for this, any double or any data to be really a standard of care, it has to have the relevant control arm. We are using VO, which is fixed duration. We know it has a high rate of MRD, has long-term follow-up, and good PFS data. We have set this study to a high bar. This study is being conducted globally at some of the best centers, best cooperative groups, the U.K. cooperative groups that did the VAI study, the French cooperative group, German. We have really quality sites. Part of, I think, the conduct of AMPLIFY, we talked about patient dropouts because of control arm that's suboptimal, increased deaths. Our IDMC is closely watching the safety of ongoing study. Okay, thanks. And then just sort of, I'd throw in another couple points from that perspective. You know, look, I think part of what we were trying to say is, you know, you're going to hear a lot of stories about why, despite the data being unimpressive, there's not an issue with it. But in reality, that's not a lot of those issues, if you actually look at the data, you know, whether it's, you know, this was enrolled during COVID, all of our studies were enrolled during COVID, right on top of it. All of our studies were enrolled in Europe and in Eastern Europe too. And you don't see, you know, poor data as a result of that. I think that, you know, I don't think that our view is there's a study conduct issue there. I think it's just the data is what the data is. I think that's what we were trying to convey. And our data will be what our data will be. And we're very, very confident in it. It has always looked different than this. And we think it will continue to look different than this. Okay. Thanks, John. And then, Mehrdad, just kind of one more in the little bit more in the weeds, I guess. You know, we also look at the AML space. And there's sort of a philosophical shift from MRD4 to MRD6, meaning moving from flow detection to, you know, to PCR, I believe, which is even more sensitive. Is that something that you're looking at as well? I'm just curious where that stands in the CLL development world. So in the CLL, we are using NGS, which is an FDA-approved test for our pivotal study. In other studies, we use MRD too in our myeloma study. I know that we are, we know that myeloma is not an approvable endpoint. In the expansion that we have with dexamethasone and sonrotoclax, we're using MRD as well. Okay. Then for Mark, obviously, a lot going on on the solid tumor front, to say the least. And, you know, we noticed you recently in-licensed, I believe, a PRMT5. So I was just curious there. Sorry. And MAT2A, you in-licensed. You have the PRMT5. So I was just curious there with respect to, you know, thinking about how you prioritize on R&D. Obviously, you have a really strong innovation engine. But in this particular instance, you decided it may be more prudent to go with an external asset. Just curious if you could expand a little bit on that. Thanks. Maybe I would ask Lai to comment a bit on that insofar as how we're thinking about internal delivery versus looking at external molecules. Suffice to say, for my role, we're extremely excited to have both PRMT5 and MAT2A in-house. We think that this could be a very impactful combination. Yeah, thanks, Mark. And also thanks for the question. In terms of the MTAP deleted population, this is really of great interest to BeiGene. This patient population counts for pretty much about one out of seven patients. It's a huge segment. You have seen the data from IDEAYA about their MAT2A. This particular MAT2A, while in-licensed from CSPC, has greater potency and also has a very interesting feature, which does have brain penetration. We think this can complement extremely well with our brain penetrable PRMT5 inhibitor we already have in the pipeline. The MAT2A PRMT5 in the preclinical setting has shown wonderful synergy with each other. With that, you know, we actually, to be completely transparent, we actually do have an internal MAT2A program ongoing, but it's behind this one. We always keep our eye open in terms of external innovation. If there are right opportunities for us to grab, we definitely won't hesitate to get on that to help us to really accelerate. Also, I think this is part of BeiGene's key strategy is to do combination of it. I think everyone will agree oncology is a very complicated disease. You do need a combination. Probably one drug wouldn't be able to cure all the patients. The combination is really the winning recipe. We're trying to identify the right combination part of our pipeline assets. Great. Thanks very much. Our next question will come from Yige Guo from Guggenheim. Hey, good morning. Thank you very much for providing the comprehensive update. And thank you for taking our questions. I guess two quick ones from us. One on CDK4/6, sorry, one on the CDK4 inhibitor and one on the BTK degrader. For the CDK4, Mark, you mentioned this TK1 PD biomarker. Just wondering, have you observed that dose-dependent PD activity and what level of TK1 reduction or inhibition will give you confidence on a potential meaningful clinical activity? And on the BTK degrader, very interesting data, cross-trial comparison data between the degrader and the pivotal ibrutinib. I was just curious if there's any mechanistic explanation or maybe preclinical data that can explain the, you know, superior PFS, but more or less comparable ORR or response rate. Thank you very much. Thank you for the question. So I'll mention very briefly that the TK1 data that we share today is very, very new data, just emerging in the last few weeks. So we do not have a lot of clinical maturity associated with an early PD biomarker. That said, yes, we do see a dose dependency, a pretty clear association between patient exposure and pharmacodynamic activity. The target level that we're trying to achieve in combination is less than 20%. We have already achieved that, and we have not yet reached our maximum tolerated dose. So we're quite encouraged by the fact that we're seeing the combination of low hematologic toxicity, good pharmacodynamic activity, and we're still going and exploring the higher end of the dose range. So we're optimistic in so far as how things are shaping up. As I mentioned, we are in what we anticipate to be our target efficacious range. Indeed, we are beginning to see unconfirmed partial responses. But again, we'd like to have more durability of follow-up to give a sense of, or more maturity of follow-up to give a sense of both what is our aggregate response rate at a larger patient population, as well as the duration of any potential responses. Yeah, maybe I can take the degrader question. As I mentioned during the presentation, BeiGene probably now have one of the broadest degrader programs in the industry. While we are doing more degrader programs, we learned a lot about how degrader works. As also to another question we just answered previously, which is about degrader preventing resistance. It's a fascinating biology because degrader does not require strong binding to the target. You can really, with even a weak binding, you can induce the target degradation. We have seen in the preclinical setting, compared degrader to the inhibitors, you definitely have advantage in terms of preventing resistance. Whether this is exactly the reason behind our early data seems like we have a better PFS compared to, let's say, pivotal, as you pointed out, ORR might look similar, but it seems like the response is more durable. We still needed the clinical data to ultimately tell that. But I think that can be a reasonable explanation for that. Thank you very much. There are no further questions at this time. I will now pass back to John Oyler for closing remarks. Hey, so I just wanted to thank everyone for participating in our call. We look forward to seeing you all at J.P. Morgan. I think, as you know, we've said, with Aaron Rosenberg as our new Chief Financial Officer, you know, we're going to begin to have a call on a regular basis from an earnings perspective. Partially, that reflects the maturity of our company. The second reason is no one has any questions for him in this meeting, so he wants a chance to say hi. But we will see you at JPM. We want to wish all of you thanks for your support and your interest. We do believe that we have the ability to be a truly transformational and highly impactful oncology company. We're well on our way to doing that, and we appreciate your time and energy and support in helping us do that. Best to you and your families for the holiday, and wish you a healthy and happy 2025. Thank you.