Hi everyone, thank you for attending Jefferies London Healthcare Conference. My name is Kelly Shi, one of the senior biotech analysts here. In this fireside session, we are very pleased to have Mr. John Oyler, Chief Executive Officer; Mr. Aaron Rosenberg, Chief Financial Officer; and Dr. Mark Lanasa, Chief Medical Officer from BeiGene for this session. Welcome, BeiGene team. Before we dive into the commercial products and your very broad clinical pipeline, I wanted to take a step back and start with a high-level overview of BeiGene's vision: what has been going on with the company over the last 12 months, and what are the key areas to focus on for BeiGene right now, and what is the forward strategy for the company? Great, thanks. It's great to be here. I think BeiGene, when we started, had a goal of trying to transform the way drug discovery and development was done, and find a way to bring medicines more affordably and accessibly to patients all around the world. The key to doing that was really in clinical trials, because 75% of the cost of a medicine in oncology delivered to a patient is really tied up in clinical trials 90% of the time. So one of the very unique things about our company is we built this large internal global clinical development organization that's all across the world, operating in 45 countries, and we'll get to that later. But that was kind of the vision and what we were trying to do. In terms of last year, last year was an incredible year for us. We, in the third quarter, for the first time, reported revenue of over $1 billion. We had our second consecutive quarter of positive non-GAAP operating income. And in addition to that, actually had some cash flow positivity, albeit with a little working capital help. Secondly, we saw Brukinza, which is our flagship first best-in-class medicine, take the leading position in market share in first-line CLL and second-line CLL, a $12 billion global space, and become the leader in that area. We have five approvals in hematology with that asset, and that combined with our pipeline of BCL2, sonrotoclax, which has seen 1,350 patients, and a degrader, which is in the clinic and has seen over 350, we really believe we're poised to have the CLL franchise of the future by combining these and formulating these together, which helps you play through patent expertise, IRA, whatever it may be. It's really a once-in-a-lifetime opportunity, like you've seen, for example, at Gilead with HIV. From the third perspective, we have a very robust and powerful research organization, and this year we have now put nine new potential medicines in the clinic: eight in oncology, one is a degrader in INI, and Marc runs that portfolio and is very excited about what we've done in that space. Big indications and degraders, ADCs, bispecific, trispecifics. The other point that we've made is this clinical team that I talked about has now proven to have huge speed advantages. One example of that is our CDK4 program, which entered the clinic last December and has already seen data from 100 patients. We've been able to go dose cohort to dose cohort in about six and a half weeks. That's relatively unheard of in the industry, and it's because we don't have CROs, and we have this own team of ours globally that's huge and highly motivated. From the second perspective, we have ADC, B7-H4, that entered the clinic in April, has seen 30 patients again at the same patient cohort to cohort, about six and a half weeks. And in the degrader space, we have a BTK degrader that was said to be head-to-head with a second player in the class, and I think we've announced over 350 patients on study. The last time they reported a number, it was 87. They probably have over 100, but it just shows the speed at which we can execute. From the other perspective, the world has been interested in how to show you're a global company. For BeiGene, we've done two things that have been announced that we're in the process of. One is changing our name, and the future will be called BeOne Medicines. B because it's what patients want to be, be cancer-free. And the one actually has the letters ONC in it, which is our commitment to oncology and cancer patients. We'll also be changing our ticker to ONC. And the second is we're re-domiciling the company from the Cayman Islands to Switzerland. And that's a big oncology center, and we have had a presence there, our tax base is there. We've been there for a while, and it's an important place for us, so we're in the process of completing that. And lastly, we've built an $800 million biologics manufacturing facility in Princeton, which rolled out earlier this year, which will be the U.S. Supply source for our biologics and ADCs. Terrific. As a global company, could you give us an overview of your current revenue distribution across the regions, and how do you think this will evolve as your products get approved around the globe? Great. Thank you for the question, and I would say, as you've seen in our recent results, we see incredible momentum across the business in all geographies in which we operate, so as of our Q3 results, we are more than 60% of our business is between the U.S. at about 50% and Europe at about 10%, and I would say in both of those areas, we continue to have significant growth ahead of us, as to where we sit in the life cycle of particularly Brukinza. In Europe, we grew year- over- year 217%, and of course, those launches are a little behind where the U.S. was, so it's still lots of opportunity ahead of us. And I'd add, from a rest of world perspective, we're still even earlier in many of those launches if we think of significant markets like Brazil and Korea, and yet to be launched in Japan. So we really see great momentum, increased globalization, very competitive with multinationals across all therapeutic areas, and we'd expect that to continue. Great. And recently, you achieved a breakeven. Speaks to how fast the company is growing. Maybe you can walk us through your projections on the future R&D cost, or maybe like OpEx, given you actually have a pipeline growing. And also, how do you envision the company's long-term margin profile? Excellent. Thank you. So as you've seen in our recent results, we continue to deliver strong performance, but coupled with significant operating leverage. And these dual priorities of investing for growth as we move toward profitability is really important and obviously leads to sustainability for the business. And we see that operating leverage across the P&L, of course, driven by significant top line, but improved gross margin. We talked about the globalization of the business and our wholly owned assets that contribute to mixed improvements, but as well as the investments we've made to drive productivity, as you mentioned, in the investments we've made in manufacturing. We are investing in the business. We're still scaling commercial in many markets, particularly the ones that I mentioned, where we're still in early days of launch. So we're investing in that sense, and of course, we have our emerging. I'm sure we'll talk at great length about our pipeline, both our late-stage hematology assets and our early-stage solid tumor portfolio. So we will invest in R&D because clearly the opportunities are in front of us. Now, we will have some benefit of the rollover of our existing late-stage and commercial investments in the pipeline, which will ultimately roll those investments into the pipeline that's emerging. But clearly, we are a growth company, but we found the really nice balance between leveraging our growth to drive operating leverage while investing for growth. And hopefully, our pipeline will do even better than we imagined. That provides opportunity and optionality for us as we seek to optimize the business going forward. Maybe let's stay focused on Brukinza and also BTK franchise as it keeps beating expectations on sales. And the launch has been ramping up very quickly around the globe, especially following the Alpine PFS readout. And we continue to hear positive feedback from physicians from their real-world use. I'm wondering if you could share your insights on the market dynamics in CLL and what has been the new learning for the past two years and after the U.S. approval in CLL, and also what would be the key drivers for the continuous uptake for the future years? Sure, all great questions. So as we entered into that space in CLL, as you mentioned, we've run a head-to-head trial against Imbruvica. That trial was for superiority and read out positive resoundingly. And in that space, the other BTK, which is approved, Calquence, ran a head-to-head trial, which did not prove superiority. It has a hazard ratio of one and, of course, is marketed as being the same. In fact, that study was run in the subpopulation of CLL that Imbruvica doesn't do well, 17p deletion, for example. And our study was run in all populations where Imbruvica does do well, so we had a much higher hurdle. But in their study, actually, a lot of patients in the beginning had trouble tolerating Imbruvica, so came off. Their curve separated favorably in the beginning, but at 29 months, it crossed over, and by 39 months, actually, the milestone PFS for Calquence was 30%, and for Imbruvica, it was 37.5%. They stopped the study, maintaining a hazard ratio of one, but the trend was certainly not going in their favor rapidly. At the same point in time, our study had 75 patients randomized in this same subpopulation each against Imbruvica. Imbruvica performed 31% in our trial, which is worse than in their trial in this population. Why? Because of COVID. If you adjust it for COVID deaths, it's about 35%, again, consistent with their 37% number. At the same point in time, our milestone PFS, non-COVID adjusted, was 59%, and COVID adjusted is over 60%. We have a lot of conversations about how you can't look across trials because they're all different, and it's absolutely true, and we believe that, and I say all that with that caution, but seldom do those differences explain a 30% versus 59% or 60+% difference in a 39-month period. And I think that's what's really driving the rapid adoption and understanding by CLL clinicians, despite noise, despite marketing, despite other messaging, that drives patients to say, "Look, really in CLL, the bad outcome is mutating to 17p deletion. These are the hard patients. You may not know you have it, but clearly, Brukinza in this setting is the best medicine." So that's driven the success as a monotherapy. In this setting, however, people are really excited about, "What about fixed duration? What about venetoclax? What about venetoclax plus a CD20, obinutuzumab? Or even better, what about a Calquence plus venetoclax or a Calquence plus venetoclax and obinutuzumab?" This is all excitement, and we're big believers in fixed duration and that this can be a solution for patients of the future, but we actually don't believe these agents are the right agents to create that type of combination, and the data, I think, supports that. So why do we say it? The reason you don't want patients on continuous therapy for BTK is, or for any of these therapies, are they inhibit B cells? You need your B cells to fight infection. So if you're an elderly person with CLL, you don't want to be on continuous therapy because if you're not, your B cells can come back and be intact, and you won't get sick and get hospitalized and maybe die. But actually, the combinations with obinutuzumab, VO, for example, hospitalize with grade 3, grade 4 infections 18% of the patients in the first two years. And that's much higher than a single-agent BTK inhibitor. Actually, you can dose for years longer before you ever cross over to that threshold. The promise that's there is true, but with obinutuzumab, it makes it really hard because you're accelerating hospitalization and infection. From the other perspective, the hope is, "Well, can you do this with ibrutinib plus venetoclax?" Unfortunately, ibrutinib has cardiotox. In our study head-to-head, 1.8% sudden cardiac death versus zero. That's a known factor. It's labeled for 1%. People are really reluctant to use that combination. The hope was with AV, and AstraZeneca will present data at ASH. Their abstract is out. And in their abstract, in the very promising AV data, that combination has 36-month milestone PFS of 76%. Brukinza is 84 in the same time period, 76 versus 84. I mean, it's not the most exciting data that we've seen. In fact, I think it's the least attractive hazard ratio ever run in a first-line CLL study versus chemotherapy. So the promise is there. We do believe in fixed duration, but the right agents aren't there for combination. This is where our BCL2 comes in. It's designed to be more selective, it's more potent, and it's more usable, given its half-life, to prevent complications for community oncologists. From that perspective, we think that Sonro with our BTK inhibitor, Brukinza, and with our degrader, can be the future, both for fixed duration and for monotherapy and for combinations that are continuous therapy. And this is how you build a franchise. It's a really rare situation, but we're in that, and we think we can have some medicine that really is lasting and matters for patients. Brukinza launch tells you're in the winning position for the first-gen BTK inhibitor competition. We now also have non-covalent, some call it next-gen BTK, moving to a late-line trials, I mean, moving to a later phase of trials in refractory settings and also including front-line settings. You already mentioned you have a degrader and also BTK degrader and a BCL2 inhibitor building a franchise for CLL. Maybe fast forward in five years, how do you think these agents actually will be positioned across lines and based on the currently available clinical profiles and also a physician chat? Sure. I think that there's going to be physician and patient choice based on segments. There's different types of CLL patients, mutated, unmutated, 17p deletion, p53 aberrant, and it really matters which segment you're in the way you'll be treated. There will, and I think people largely believe, the majority of patients for the moment will remain on continuous monotherapy or combination therapy that's continuous, but a subsegment of those patients will be able to have fixed duration treatments, and I think this is an area in which all three of those agents have the potential to play a role. In the relapse setting, it's very clear that the degrader can handle and deal with mutations of all sorts, and so it certainly will have a role in the immediate term in that setting that is very meaningful and substantial, in addition to the potential to move up in combination for sure. Maybe quickly at ASH, what kind of data we could see from both BCL2 and degrader? Yeah. Thank you, Kelly. So we're very excited for the upcoming ASH on behalf of my colleague, Mehrdad Mobasher, who's the chief medical officer for hematology. Very happy to relay that we have 21 abstracts that we'll be presenting at ASH across these three molecules that constitute our franchise in CLL and other BCL malignancies. For sonrotoclax, we're presenting updated phase II data of the combination of sonrotoclax with Brukinza that gives us increased confidence in the ongoing phase III study for fixed duration in front-line CLL. We think those data are very compelling and are excited to share those with everybody. For the degrader, specifically, as you heard from John, we have now enrolled over 350 patients. While it's still early days in terms of data maturity, we do have enough data now that we can present the breakouts of relapsed CLL, relapsed mantle cell lymphoma, as well as other non-Hodgkin's lymphomas, and then finally, for zanubrutinib, we're also looking forward to sharing a number of different abstracts, but perhaps highlighted by the five year follow-up of Sequoia, which will show the data that John was just alluding to in terms of long-term disease control. Great. Maybe one quick question on PD-1, then we're going to move to the rest of the pipelines, CDK2/4, and also other degraders. So you recently announced a launch in esophageal carcinoma, and it will be priced at 10% lower than other anti-PD-1 therapies. Maybe walk us through your pricing strategy and give us color on the launch so far. Sure. So core to our mission and purpose as a company is to provide access to innovative medicines to patients all around the world. Consistent with that, we priced Tevimbra affordably in a way that provides access to patients in the United States, and we feel really confident that we've done so in a way that isn't a burden to the systems, but still yet operates consistent with the marketplace in which we're providing this medicine in the U.S. It is early days in terms of our launch, both in the United States and in Europe. We look forward to reporting more on performance as we progress through the balance of this year into next year. Fantastic. And Marc, you have a very busy year, and we're also going to see you at San Antonio. And so for your CDK4 inhibitor, as John mentioned, it progressed very quickly. What kind of data we could expect there? And you also have CDK2 now in your pipeline. So how do we think about the development strategy for this franchise and opportunity? Yeah. Thank you again, so we're very excited about our CDK4 molecule. Investigators are also excited about our CDK4 molecule, which is part of the reason why we've been able to progress that study so quickly, having enrolled over 100 patients in about 11 months. Now, one thing that we can't make go faster is data maturity. It simply takes a certain amount of time to understand how the safety and efficacy profiles will emerge, and therefore, what we're going to share at this year's San Antonio focuses on the monotherapy experience with a specific on safety and on PK. Nevertheless, we're very happy with how the data are emerging and think that already these early data are supportive of what the preclinical biology predicts for a CDK4 selective inhibitor over a combined CDK4/6 molecule. CDK2 is another cyclin-dependent kinase that's very important in cell cycle biology. CDK2 and cyclin E have been shown to be induced by exposure to CDK4/6. So our initial thinking is that CDK2 will be a helpful adjunct in patients and women who have been exposed to CDK4/6 inhibitors, but there's also the potential that it could also move into earlier lines of treatment in combination with CDK4. Okay. Great. Maybe moving to the protein degrader pipeline. And you have BTK, and you have EGFR and IRAK4. As mentioned in the opening remark, BeiGene's name is going to change to BeOne, including oncology, but IRAK4 is known probably for INI indications. So when we think about a pipeline strategy, is there a strong preference to oncology, but not limited to oncology, or maybe you have other thoughts you could share with us? Yeah. Look, our focus is oncology, and I think we continue to invest and grow there. And as part of the name, we want to make it clear to clinicians, patients, and patient advocacy groups at this moment that we're leaning in, we're not pulling away. I think there is a sense from patients and clinicians that the industry is pulling away from cancer right now, partially because of policy that makes it harder potentially, and partially because of the attractive results we've seen in other areas, weight loss being one of them, that are driving investment decisions in other areas. So we want to make it clear we're here, we're growing, and we're going to be here for the long term. We're fighting cancer. In addition to that, with all these great tools we have and with where science leads, there's the ability to use some of these to help out in other diseases. And that has been a small part of what we're doing, 5% to 10% of our early research, and I think it'll continue to be. And if we can have impact there too, that would be great, but the focus is oncology. Yeah. Kelly, maybe I would just comment that we're very excited about degraders as a therapeutic modality. The three that we have so far highlight the three areas where we're doing clinical work in solid tumors, hematology, and INI, but we have a number of preclinical programs and look forward to bringing more degraders forward. They're complex molecules to design and deliver. They have relatively high weight for orally bioavailable molecules, but we think that they are a powerful emerging modality. Okay. Lastly, maybe on BD front, and BeiGene has made a series of high-profile BD events. And so now with a strong balance sheet and also you already passed the break-even milestone, but you also have a very broad pipeline. So what are your thoughts now, I think, both ways on BD activities? Yeah. I mean, we're very active, and we think there's great things that other companies can do or have done better or faster than us, and we're very interested in them. We also think there's a lot of companies that either don't have the manufacturing prowess we do. In-house, we can make our own antibodies, we can make our own ADCs. That can let you move faster and more cost-effectively and more flexibly without signing a big take-or-pay contract. And then this clinical team that we've built, it moves at a speed no one can. So as I think back to my days when I'm in a smaller biotech company and I have great science that I want to get into the clinic or as early in the clinic, I'm always struggling with the manufacturing. I'm struggling with how do I run global clinical? How do I have the global regulatory conversations I need to? What should I be doing here? And then how do I execute? I think that's an area where we have a lot of value that we can add to partners, and we want to find partners from that perspective. And then I also think there's areas where we may develop science that fits well with an asset we don't have. Maybe a major company has assets that fit better with it, or maybe they have capabilities in that area that are stronger than ours, say, for example, for IRAK4. In those perspectives, we certainly entertain and have conversations with people all the time and look for the right situation. But we don't have to do anything. So we don't have to partner assets to a company that's weak in an area that it needs to be pursued or is missing capabilities to generate cash. That's a great luxury to not have to do that. We can look for great partners that can add additional value from that perspective, and that's what we're trying to do, and if we see those opportunities, there's a lot of companies that have pipeline gaps. When they do, they're willing to strike very attractive deals for partners. We certainly want to be in the room for those conversations, and that may be a good solution for both of us, so we're very active, and stay tuned. We covered a lot of areas in the short 25 minutes, probably not all, and thanks again for the team of BeiGene, or maybe I should call it BeOne, for joining us, and thanks everyone for attending. Thank you. Thank you.