BeOne Medicines AG (ONC) Earnings Call Transcript & Summary

Good afternoon and good evening. This is Howard Liang. I'm the CFO and Chief Strategy Officer of BeiGene. Welcome to our ALPINE Results and the EHA 2021 Update Zoom Webinar. I'd like to first thank everyone for taking time out of your busy schedule to join us, especially those joining us from Asia in the late night. We're very excited to provide you with the latest results of the ALPINE study, which, as many of you know, is our head-to-head Phase III study comparing BRUKINSA to ibrutinib in relapsed refractory CLL patients. The data were just presented by Professor Hillmen at the -- principal investigator of the study, at the Presidential Symposium of EHA about 45 minutes ago. Next slide. During this call, Professor Hillmen will recap the ALPINE presentation at EHA. After that, Professor Jennifer Brown from Dana-Farber and Harvard Medical School will provide perspectives of the results. This will be followed by an overview of the BRUKINSA development program by Dr. Jane Huang, the CMO of Hematology at Beijing; and our CEO, John Oyler, will close the prepared remarks with some takeaways before we take questions from our analysts. [Operator Instructions] As a reminder, today's call will be recorded. Next slide. Before we get into the presentation, I need to remind everyone that we'll be making forward-looking statements. Our business carries certain risks. Some of these are discussed in our filings with the SEC and Hong Kong Stock Exchange. So please see those filings for a discussion of the business and the risks. At this point, I'd like to ask Dr. Jane Huang to introduce Professor Hillmen. Jane?

Thanks, Howard. Professor Hillmen, on the next slide, is the of lead PI of the ALPINE trial and Professor of Experimental Hematology and an Honorary Consultant Hematologist at Leeds. He's a renowned expert in CLL and PNH. I'd like to now turn it over to Professor Hillmen to walk you through the results of the ALPINE trial.

Thank you, Jane, and thanks for the invitation to speak and to go over the results of the trial, which I've just presented at EHA as Howard said. Next slide. Okay. So this is the abstract title in the co-authors from the Presidential Symposium. So first of all, I think it's notable that a late [indiscernible] got into Presidential Symposium I think is very significant. Next slide. Okay. So in terms of the treatment of chronic lymphocytic leukemia, this is really being transformed by the advent of effective targeted therapies, particularly to the B-cell receptor, the first of which was the first-generation Bruton's tyrosine kinase, zanubrutinib. Zanubrutinib is an irreversible, potent, next-generation BTK inhibitor designed to maximize the BTK occupancy, but also to minimize off-target inhibition of TEC and EGFR-family kinases. And the hypothesis behind this study was that zanubrutinib would hopefully minimize toxicity related to the ibrutinib off-target inhibition kinases and shows a little bit of the PK may improve efficacy outcomes by covering the target better. Next slide. So this slide shows the pharmacokinetics of the 2 drugs in the study. So zanubrutinib is given at the dose of 160 mg twice a day. And you can see here the PK in relation to the IC50 was is 0.5 nanomolar for zanubrutinib. And you can see that the team at the top level, the IC50 is well covered by zanubrutinib. In contrast, ibrutinib was given as a once daily dose 420 mg [indiscernible] for CLL the IC50 for BTK is 1.5 nanomolar, and for the majority of the time for probably about 18 to 24 hours of the day, the PK of ibrutinib is below the IC50 for BTK. So just to define that the target is covered more effectively with zanubrutinib from PK perspective. Next slide. The ALPINE study is a randomized Phase III trial in patients with relapsed/refractory CLL, and we plan to [indiscernible] patients -- we actually recruited 652 patients. The key inclusion criteria here. So relapsed/refractory CLL had at least 1 prior systemic therapy for CLL and measurable disease on the CT or MR. Exclusion was transform disease, prior treatment with BTK inhibitors or treatment with BTK antagonist such as a warfarin. Patients were randomized in a one-to-one fashion, and stratified by a graphical location whether refractory to the last treatment and the presence or absence of 17p or a presence of a TP53 mutation. Next side. The endpoints of the trial is shown here. So the primary endpoint was overall response rate defined as partial or complete remission as was assessed by the investigator. This was [indiscernible] noninferiority followed by superiority. Key secondary endpoints were the atrial fibrillation of any grade; overall response rate by the IRC, [indiscernible] PFS and overall survival; time to treatment failure; partial response as we see with B-cell receptor inhibitors initially; patient-reported outcomes; and safety. And the data presented with the preplanned interim analysis and the first data, which was 400 and -- when the first 415 patients had at least 12 months post randomization show the efficacy and the safety analysis. Next slide. This is the abstract diagram of the -- what happened to the patient. The 415 patients were randomized between zanubrutinib 207 and ibrutinib. The median follow-up announced in just over 15 months. You can see that in the zanubrutinib arm, the [indiscernible] 87.4% of the patients or 181 remained on treatment. And in contrast 75.5% of patients on the ibrutinib arm remaining on treatment. And you can see that the progressive disease [indiscernible] patients for ibrutinib was the reason for discontinuation as opposed to -- for zanubrutinib and AE is 27 compared to 16. Next slide. This is the patient characteristics. You can see the trials, as you might expect well balanced. Median age was 67, which is very typical for relapsed trials of this nature [indiscernible] we see in CLL [indiscernible] is 1, but there's a big range, as you can see, the prior therapies were -- chemotherapy was balanced. And you can see the key marker of 17p of TP53, which is a classification variable. So 18 point -- sorry 19.8% versus 18.3% well balanced [indiscernible] as shown below. Next slide. This is the primary endpoint of the trial. So it's investigation assessment of overall response showing that 78.3% of patients responded to zanubrutinib compared to 62.5% to ibrutinib. This is statistically significant with a p-value of 0.0006 and the hazard ratio, obviously, in favor of zanubrutinib. Next slide. And if you include the [indiscernible] so the lymphocytosis, the overall response rate was at 88.4% versus 81.3%. The FDA mandated that the primary endpoint should be just PLs and CLs. Next slide. Yes. So the overall response rate for the 17p patients was [indiscernible] trial was 83% for zanubrutinib and 53.8% for ibrutinib. Next slide. And in terms of the IRC, the overall response rate was again inferior 76.3% compared to 64.4%. The -- this is obviously concordant with the investigator assessment of response shown here. Next slide. This shows the key patient subgroups. And if the spot is to the right of the line in favor of zanubrutinib in terms of response. If you move to the left, it would favor ibrutinib. And you can see it across all subgroups within the trial: age, gender, stage, presence or absence of TP53 favors zanubrutinib overall as well overall response. So there's no particular group of patients that stand out that it benefits patients across the board. Next slide. A key secondary endpoint is the progression-free survival. It's the progression-free survival by investigator assessment. Between the 2 arms, obviously, red is the zanubrutinib curve, which is superior to ibrutinib. The 12-month [indiscernible] progression-free survival rate was 94.9%, where zanubrutinib was 84%. With ibrutinib ratio of 0.4 and a p-value of 0.0007, obviously, a meaningful difference. This is the median follow-up of 14 months in both arms. Next slide. The overall survival is obviously relatively short follow-up in the trial, but there's no significant difference between the 2 arms to date. The 12-month time point, there were 11 deaths in the zanubrutinib arm and 19 in the ibrutinib arm which totals 97% survival compared to 92.7%. This is not significant, but hazard ratio is 0.54. Next slide. Considering the safety assessments. Any great AEs, of course, are seeing the vast majority of patients in all of these trials. In terms of grade 3 or higher or serious AEs, there's no difference in any way in straight through higher AEs, slightly lower serious AEs in the zanubrutinib arm and slightly lower fatal AEs, AE 12. And if you look at the AEs leading to treatment discontinuation was just 7.8% for zanubrutinib versus 13% for ibrutinib, consistent with the most [indiscernible] and improved safety profile. Next slide. As is all the AEs greater than 10% in either arm [indiscernible] AEs is slightly higher [indiscernible] with zanubrutinib, which did not translate into a higher infection rate. More arthralgia which is one of the [indiscernible] ibrutinib -- in the ibrutinib arm 14% versus 9.3%. No difference to date in the hypertension rate. Slightly higher instance of cough with zanubrutinib compared to ibrutinib. Next slide. And in terms of AEs of special interest, these the ones that are selected for by the patents team of ibrutinib. The rate of cardiac disorders [indiscernible] early grade is significantly higher [indiscernible] 25% as opposed to 13.7% and versus grade 3 at 6.8% versus 2.5%. In terms of atrial fibrillation, which is a major [indiscernible] with ibrutinib, this is significantly lower at 2.5% versus 10.1% for ibrutinib. No difference in the hemorrhage or hypertension, as I mentioned before, slightly higher rates are shown here. Next slide. This is the cumulative event rate for atrial fibrillation in the trial. Again, red is -- sorry, blue is ibrutinib. So you see a continuous increase in AF [indiscernible] with ibrutinib up to 10.1% just around 15 months of follow-up, as opposed to just 2.5% in patients on the zanubrutinib arm of the trial, which obviously significant with a p-value of 0.0014. Next slide. So the conclusion is that this present analysis of the randomized ALPINE study in relapsed CLL shows zanubrutinib was superior and in terms of overall response rate by investigator assessment, PFS and a lower rate of atrial fibrillation [indiscernible] zanubrutinib in this randomized trial. And certainly, this data support the use of a more selective BTK inhibition, both in terms of efficacy and safety. Next slide. I'll just -- [indiscernible] investigation is obviously an international study. So there are many investigators from many countries around the world. So thanks, Jane.

Yes. Thank you. I now have the pleasure to introduce Dr. Jennifer Brown. Dr. Brown is the Director of the CLL Center at the Dana-Farber and a Professor of Medicine at Harvard. She's a leading hematologist specializing in CLL and is on the steering committees of both our ALPINE and [indiscernible] studies. She is here today to give her perspective on BTK therapies in CLL. Jennifer?

Thank you very much, Jane. Next slide, please. So I know that we're all aware that BTK inhibitor therapy has really transformed the treatment of CLL. And ibrutinib, of course, is the first-in-class BTK inhibitor. It's profoundly effective as we've seen in multiple randomized trials. But I would argue that it's not very tolerable, particularly as a continuous therapy. These are data from the RESONATE-2 study with a median follow-up of 60 months, 5 years. And the progression-free survival in the ibrutinib arm is 70%, which is obviously quite excellent, but there's a 41% discontinuation rate, primarily due to adverse events of various types. And we know that with single-agent BTK inhibitor continuous therapy is required to maintain benefit so that discontinuation will lead to failure. Next slide. The real-world data around ibrutinib has suggested even higher discontinuations. In this retrospective analysis of over 600 patients, the discontinuation rate was 40% in a median of about 8 months. In frontline CLL, the most common causes included arthralgia, atrial fibrillation and rash. While in relapsed refractory CLL, causes including atrial fibrillation, infection, pneumonitis, bleeding and diarrhea. And again, the median time to discontinuation is quite short before patients could really derive the maximal benefit from the therapy. Next slide. In the same study, the median progression-free survival for the cohort was 3 years, which is significantly less than we've seen in randomized trials. So you have seen that these early discontinuations translated into reduced clinical benefit as we might expect. Next slide. Cardiovascular toxicity, in particular, continues to be an ongoing and increasing concern with ibrutinib. Atrial fibrillation was first noticed in the RESONATE study, and since then has been a signal that has been frequently observed, and our group reported the first case series of ventricular arrhythmias and sudden deaths in the setting of ibrutinib. This is an analysis from the WHO VigiBase, which is a reporting database for drug adverse events. And this analysis was led by [indiscernible] group. But you can see here that it's not just atrial fibrillation and supraventricular arrhythmias that are increased with ibrutinib nor ventricular arrhythmias, so those are increased fivefold. There are also events of heart failure, conduction disorders, CNS ischemic events and hypertension that are all increased. And we saw at ASH this last year several presentations around the incidence of hypertension in patients maintained on ibrutinib over 3, 4 and 5 years and that this was rising to on the order of 75% of patients. Next slide. So in this context, I think we're all particularly interested in the next-generation BTK inhibitors, including zanubrutinib, which is shown here. It has equal potency or a higher potency against BTK compared to ibrutinib, but markedly reduced off-target effects against EGFR kinases, ITK kinases, JAK3 or HER2. Next slide. Some of the data that I think is particularly distinguished zanubrutinib, even prior to the current data, I wanted to highlight. And these include the initial report of a randomized trial comparing zanubrutinib to ibrutinib, this 1 in Waldenstrom, the ASPEN trial. And the adverse event profile in this randomized trial, I thought, was quite striking, where with a median of 19 months follow-up, the incidence of atrial fibrillation with ibrutinib was 15%, but only 2% was anabrutinib. And there were trends to reductions in hypertension, edema and contusion as well. Neutropenia was somewhat increased compared to ibrutinib, but did not translate into infections, as you can see that pneumonia is reduced to zanubrutinib despite the neutropenia. Discontinuation adverse events were also reduced. Next slide. Another clearly distinguishing data set comes from SEQUOIA, which as you know, is the randomized registration trial in frontline. But here, I'm going to talk about Cohort 2, which is a prospectively enrolled cohort of patients with dilution 17p treated with zanubrutinib. This cohort enrolled 109 patients and is the largest experience of frontline dilution 17P patients treated with BTK inhibitors that we have. Next slide. These data were updated at this past ASH with a median follow-up of a little under 2 years. And the 18-month progression-free survival in this high-risk group was 91% with an overall survival of 95%. And in general, zanubrutinib has been very well tolerated in this high-risk patient population. Next slide. And so what caught my attention, particularly in terms of the results of ALPINE. Well, the rate of patients coming off therapy for adverse events, 11% was zanubrutinib compared to 24% with ibrutinib. So -- or excuse me, that's off therapy in general. So reduced by more than 50%, addressing this issue of discontinuation, which is a big problem with ibrutinib. And then discontinuations for adverse events were also reduced. The atrial fibrillation rate was notably low at 2.5% with zanubrutinib versus 10% with ibrutinib. The overall response rate in the dilution 17P group also caught my attention and 83% was zanubrutinib versus 54% with ibrutinib. Ultimately, of course, we are interested in whether that translates into a difference in progression-free survival or not. And then the progression-free survival data are also intriguing, suggesting that zanubrutinib had a 95% 12-month progression-free survival compared to 84% with ibrutinib. So this is a potentially quite significant difference in favor of zanubrutinib, obviously. And then there's also a trend in the overall survival data. Next slide. So ALPINE together with prior data demonstrate significantly improved tolerability of zanubrutinib compared to ibrutinib and very encouraging activity in dilution 17P, where, in fact, we have the largest data set in frontline 17P with any BTK inhibitor. And then the improved 12-month PFS with a favorable overall survival trend compared ibrutinib is very intriguing. And I think we'll be extremely interested in how that continues to develop with further follow-up. But very exciting data for zanubrutinib. Thank you.

Thank you, Dr. Brown. So I'm Dr. Jane Huang, the Chief Medical Officer of Hematology at BeiGene, and I'll be going over the BRUKINSA program more broadly and providing updates and new data that we're presenting at EHA. On the next slide, you can see that the data that you've just seen by -- presented by Dr. Hillmen is some of the most compelling data that BeiGene has reported to date. The fact that outside readout superior only corroborates what we at BeiGene have believed all along that we have a potentially best-in-class treatment for patients, and this is why we are the only ones to have conducted 2 large head-to-head Phase III trials against ibrutinib. ALPINE, however, is part of a broader development program, including over 10 indications. This slide shows you the multiple different B-cell malignancies where we have over 2,000 patients treated with zanubrutinib in our studies that have been conducted in more than 15 countries. On the next slide, before walking you through the additional data, I wanted to show you again our PK slide, which depicts the mechanistic rationale for why we believe zanubrutinib is differentiated. Our preclinical hypothesis was that maximizing BTK in addition is critical because new BTK protein is continually synthesized by malignant cells. Also, we felt that selectivity and exposure advantages lean forward qualitative advantages relative to ibrutinib in both disease response as well as improvement in regards to safety and tolerability. Zanubrutinib was designed to not only be more selective, but to maintain its therapeutic concentrations across the complete duration of the dosing interval. And you can see on this slide that zanubrutinib has more time above the IC50. And while there are limitations to cross trial comparisons, it's approximately 10x more potent than acalabrutinib and its metabolite in the peripheral blood. This higher exposure is particularly important so that you have the ability to penetrate the deeper compartments such as bone marrow and lymph nodes. This preclinical hypothesis has been supported by our clinical experience to date, and we see favorable and sustained responses, which I will show you in the next 5 slides across multiple tumor types. This quality of response has not been replicated in the historical data set with other BTKs. On the next slide, I'm going to show you our AUO 3 global Phase I/II data, where we have data on 101 relapsed/refractory patients who have been followed for more than 3 years with a median follow-up of 39.4 months. Here, you can see a landmark PFS of 83% at 3 years. And despite this long follow-up, the AFib/flutter rate remains only at 5.8% and patients continue to do very, very well. On the next slide, in ASPEN, which Dr. Brown already reviewed with you, this was our first head-to-head study that we previously reported on and the preclinical hypothesis was translated into differentiated safety and efficacy over ibrutinib. While the steady narrowly missed its statistical significance for the [ IRCSF ] superiority for VGPR, over time, the data continue to mature and responses continue to improve in favor of zanubrutinib. I also wanted to point out that we have a 27% VGPR rate in the very difficult-to-treat MYD88 wild type, and this has also continued to improve over time. On the bottom panel, you can also see graphically the differentiation from ibrutinib in atrial fibrillation, and these differences continue to widen with more follow-up. Turning to the next slide and the third tumor type mantle cell lymphoma. Our data presented at EHA demonstrate continued high progression-free survival rates, median progression-free survival of 33 months. While there are limitations to cross-trial comparisons, the reported median progression-free survival with the other BTKs range from 13 to 22 months, supporting the robustness of our current data. Another newer data set on the next slide from Magnolia is shown on this -- here. These patients had marginal zone lymphoma, and we've recently filed this data with the FDA and received priority review. At a median study follow-up of 15.7 months, our ORR is high at 68% with a CR of 26% and responses were observed in all marginal zones subtypes. The PFS rate is 82.5% at 15 months with a safety profile that is consistent with all of the safety data that we have reported to date. On the next slide, the last study I'm going to show you today really demonstrates not only the efficacy of zanubrutinib, but how well zanubrutinib is tolerated. In this poster, Dr. [ Shadman ] reports on the 48 patients who switched to zanubrutinib after having intolerable adverse events on ibrutinib or acalabrutinib. On zanubrutinib, 75% percent of the events that cause patients to discontinue ibrutinib or acalabrutinib did not recur. And additionally, even though we did not require progression prior to coming on study, 90% of patients had their response deepen or remain controlled, and 89% of patients remain on trial at this time. On the next slide, I finally wanted to highlight what Dr. Brown and Dr. Hillmen have reported, serious cardiac side effects have occurred with ibrutinib. And based on this analysis, which is adjusted for time, you can see the relative difference in AFib/flutter between zanubrutinib and ibrutinib. This statistically significant difference was demonstrated in both the ALPINE and ASPEN studies, which, despite the different follow-up time, are remarkably consistent, we expect this difference to persist. So on the next slide, finally, the underlying hypothesis that sustained target occupancy may produce meaningful improvement in efficacy and safety are validated by the data we showed today and BRUKINSA's efficacy and safety profile that has been consistently demonstrated across multiple tumor types. ALPINE is the second Phase III study to demonstrate the superior cardiac profile of zanubrutinib versus ibrutinib. And additionally, ALPINE is the only study to have proven superiority over ibrutinib in response rates, has improved landmark PFS and favorable overall survival trends. This is consistent with our ASPEN experience in Waldenstrom's and is corroborated with the additional clinical data from longer-term follow-up in mantle cell lymphoma and the high overall response seen in marginal zone lymphoma. Overall, on the next slide, our broad program has enabled us to file more than 30 applications globally for mantle cell lymphoma, marginal zone lymphoma and Waldenstrom's. As we prepare to move forward with potential filings in CLL, we are anticipating that the SEQUOIA results will be available as early as the second half of 2021, and we're excited to discuss both ALPINE and SEQUOIA with their regulators. Also this year, BRUKINSA's development program will continue to expand with the anticipated completion of enrollment in our follicular lymphoma trial, ROSEWOOD, with results from multiple head-to-head trials against ibrutinib and potential indications across multiple malignancies, BRUKINSA is well positioned to deliver on its promise to become the best-in-class BTK inhibitor. I'd like to now turn this over to our CEO, John Oyler.

Thank you, Jane. I'm John Oyler. I'm BeiGene's CEO, and I'd like to provide some final thoughts before we move on. Let me first speak about BRUKINSA. The data that we've had the privilege to present to you today is, I believe, the most important data that the company has produced to date. As Jane mentioned, we're not surprised by the results. It's consistent with the totality of the clinical data that we've reported from BRUKINSA's broad and deep development program. It's consistent with our hypothesis from the inception of the program that a molecule providing more complete and sustained BTK inhibition across disease compartments would be better equipped to fight the cancer that it faced. ALPINE's data is mature for the first year, and itself, the data speaks to the differences and outcomes during a first year of treatment. The context and wealth of data across multiple indications with other long-term follow-up, specifically in the CLL population to which Jane referred and shared a slide, which had a 39-month medium follow-up are -- make us quite confident in our original and initial hypothesis. ALPINE is unique with its efficacy results and safety results. BRUKINSA and the development program support our enthusiasm for our unique capabilities and reasons here. And some of the things we want to point out include the following: BRUKINSA is the only BTK that has been in head-to-head studies against ibrutinib in 2 indications. We're the only second-generation BTK that's filed in marginal zone and Waldenstrom's. We're the only BTK with BID and QD dosing flexibility and are usable with [ PPIs ]. We also are priced not at a premium despite our hypothesis -- and we are committed to not increasing the cost of treatment despite having what we believe is a superior profile. Second-generation medicines have already been taking share from ibrutinib, which is a feat that many people were skeptical could ever happen. This has largely been historically due to perceived safety differences, but we're hopeful that this new data related to efficacy could increase this trend over time. BRUKINSA is being developed on a worldwide basis for a broad set of indications. It's the subject of 10 pivotal studies. It's approved in 3 indications in multiple geographies, including 2 of the world's biggest pharmaceutical markets. And it's the subject of over 30 applications, as Jane said, covering the EU in more than 20 countries outside of the U.S. and China. This is part of BeiGene's commitment to bring its medicines as broadly across the world as we can. And we're not resting on our laurels here as BRUKINSA is the cornerstone of our hematology franchise that includes other potentially best-in-class assets like our BCL-2 inhibitor, which we've had early data also this year's EHA meeting. I do want to speak, again, to the confidence that we have in BRUKINSA. We have run 2 head-to-head trials. That's not a feat for the weak of hearts. In both, we did not design trials to go after the hard-to-treat populations that we know ibrutinib struggles in. Actually, in the Waldenstrom's study, we pulled out a separate cohort of the hard-to-treat mighty 88 patients. We went after the ones where ibrutinib performs well. And in the CLL study, again, this is a broad allcomers, it's not just the dilution 17 population. We picked high hurdles, and we ran those studies as broadly as we could, and we really like the data that we're seeing. I think I will jump to the next slide and kind of sum up in conclusion. I'd just leave you with a few takeaways. The first is we do believe that the data supports our belief that BRUKINSA can be a best-in-class medicine in the BTK inhibitor class full stock. We're developing the medicine broadly and across indications that other second-generation BTKs are not. And we're planning to make the medicine available very broadly around the globe, that's important to who we are. The portfolio of commercial products at BeiGene is strong with 7 approved medicines now and we have 5 more that are filed. BeiGene is delivering on our mission to bring better medicines to more patients more affordably across the globe. And with that, I'd really like to thank our esteemed guest speakers, Dr. Hillmen and Dr. Brown, and I'd like to thank everyone very much for their time and attention. And with that, I'd like to turn the call back to Craig for instructions on how to participate in the Q&A session.

Thank you, John. [Operator Instructions] Our first question comes from the line of Yaron Werber.

Here we go. Congrats on the data. So I have a couple of questions. Maybe Dr. Brown, for you, if you can help put some of this in perspective. Calquence has been running the RR-ELEVATE study. They've shown data at ASCO. They also hit the AFib, but actually in all -- across all levels they have a benefit over IMBRUVICA, but not on Grade 3. They actually have more AFib than IMBRUVICA for some reason. How do you explain that? And then secondly, how do you compare now BRUKINSA, which is not approved, hopefully will be approved soon for CLL, versus Calquence, both are better than IMBRUVICA and which one do you choose?

Great. Of course, this is the big question now, right? I would not -- with atrial fibrillation, we don't concern ourselves too much with grades. I tend to look at atrial fibrillation all grade as the primary point of concern. So the ELEVATE relapsed/refractory study did meet its endpoint in terms of showing reduction in atrial fibrillation and the cumulative incidence of atrial fibrillation was reduced. That study had a different patient population, a much longer follow-up at this point. So it really can't be directly compared in any way. What I would say is that I think that the potential efficacy data that we're seeing with zanubrutinib in relation to ibrutinib is quite interesting and exciting and that is not something that we appear to have seen with ELEVATE relapse/refractory where noninferiority was seen. But again, the patient populations are different. And the follow-up is also very different. So we're going to need more time with that. In terms of tolerability, I think that some of the data that Jane showed about patients who have come off ibrutinib and acalabrutinib being able to tolerate zanubrutinib is consistent with my personal experience that zanubrutinib is extremely well tolerated, probably the best of the BTK inhibitors, and that is a potential advantage as well as the potential for improved efficacy that, that will -- that we see here in this data and that we may see additionally over time.

All right. Looks like our next question is coming from the line of Matthew Harrison. Please state your affiliation.

Matthew Harrison with Morgan Stanley. I was hoping you could comment on efficacy broadly. And I guess there's 2 parts here. One, can you comment on how important it is to have seen a difference in IRC versus investigator assessments? And then maybe more importantly, as you look at the PFS curve and the separation there, how do you think that's going to influence your view on which drug to pick either for subpopulations or all of your refractory CLL patients?

So I -- should I start?

Yes, please, Dr. Hillmen.

I was feeling it. Well, first of all, I think the overall difference between the IRC and investigator is not particularly relevant. And I think we, as clinicians, look more at the survival outcomes, progression-free and overall survival differences, which obviously are not subject to that extent to our investigator differences. And I think that's the compelling difference in this trial. Just to cover both the safety side, first of all, I think both the ELEVATE-RR and the ALPINE study show that the second generation BTK are better tolerated than ibrutinib and Jennifer mentioned it in her talk, I think the ventricular arrhythmia -- atrial fibrillations are a nuisance, but the ventricular arrhythmias and sudden death that were seen and reported in ibrutinib-treated patients in a number of trials in small numbers have not been seen with zanubrutinib, but were seen in the ALPINE study. I think that's a really important difference. In terms of the choice of the therapy. I think Jennifer also mentioned that this is the first interim analysis for the trial. So we're going to get more mature data going forward. But I think there are advantages to zanubrutinib over [indiscernible] ibrutinib. I don't think that there will be a switch in therapy from the first generation to next-generation BTK inhibitors.

Yes. I would agree completely with Pete. And there's a question in the chat as to whether there's sufficient differentiation for zanubrutinib, second generation to take over from ibrutinib. And as someone who has used a lot of all these drugs, the differentiation is dramatic, which I'm sure Pete will agree with, certainly from a tolerability standpoint.

Well, certainly and also for PK is quite notable, isn't it? So actually covering the target throughout the duration of the treatment of the 24-hour treatment cycle is possibly important. That might be the explanation for the difference in outcomes. It will be interesting to see with the [indiscernible] on the whole 652 patents when they're sort of unveiled.

Okay. It looks like our next question comes from the line of Ziyi Chen. Please state your affiliation.

Sure. This is Ziyi Chen from Goldman Sachs. Very exciting data from the EHA presentation. So first of all, I would like to understand a bit more about with this exciting data from ALPINE, how would you position zanubrutinib in competition with [indiscernible] because I think the market consensus used to be you're going to be primary targeting ibrutinib-intolerant patients, but it sounds like now company with this kind of very impressive data, you are going to be more aggressive in terms of marketing strategy. So being a bit more proactive in competing with zanubrutinib and [indiscernible] in the all comer patient type of a strategy. And also secondly, I think Dr. Brown also mentioned about in the real world, there's more than 40% of the patients actually intolerant to ibrutinib and actually [indiscernible] as being pretty limited. I'm trying to get a sense that data is more based on the Caucasian population, Western population or what about the intolerability of zanubrutinib -- sorry, of the ibrutinib in Asian population [indiscernible] population. Any sense on the data on that? Still also like 40% of patients cannot tolerate that? Or it's going to be given higher or smaller percentage? Trying to understand better on that.

I can comment on the efficacy question. I don't know [indiscernible] our strategy, but I think the data would support going for the whole population of patients with reduction disease on the basis of ALPINE. Compared to the [indiscernible] trial, it was a broader population of patients, as John said. So any [indiscernible] patient was eligible for ALPINE and across all the risk groups, the advantages [indiscernible] ibrutinib. So I think on the data we have to date and with the other studies, it's a justifiable comment that there is more [indiscernible] more effective, driven by ibrutinib, which is also a very good drug. And I go back to saying the same point. I mean the severe cardiac abnormality [indiscernible] so I think it would go [indiscernible] let's say we'll have hopefully CLL from the SEQUOIA study soon in the second half of this year, which, again, hopefully, I'll be confident with [indiscernible] population. In terms of the Caucasian versus non-Caucasian, I don't have any personal experience [indiscernible] any data to suggest the difference.

Yes. And the only thing I would add to that really is that in Asia, particularly in China, the ibrutinib efficacy is substantially lower in their randomized Phase III trial and what we've seen in our -- with zanubrutinib in our Asian China-specific trial. So their overall response rate is a lot lower.

All right. Our next question comes from the line of Andrew Berens. Please state your affiliation.

Andrew Berens, SVB Leerink. Congrats on the data. I know it's somewhat speculative at this early juncture. But with a head-to-head statistic difference in AFib versus IMBRUVICA, how could the label possibly reflect this? I know Calquence has a warning for AFib in their label, but I was just wondering what are the possibilities for your label to reflect these data?

We usually don't speculate on the regulatory discussions. We will be engaging with them and as we proceed with the filing and label negotiations, of course, we are hopeful to see this data in the clinical trial's section.

Thanks. There was a question earlier around the overall marketing strategy and how we might position based on this data. So maybe just a quick comment on that. If we consider the development program that we have put in place, as John went through earlier and Jane covered, we have multiple head-to-head trials against ibrutinib. The hypothesis around zanubrutinib has always been that it has the potential to be a best-in-class product. And so certainly, our aspiration is for zanubrutinib to become the standard of care BTK inhibitor. Now in the U.S. currently, were indicated in relapsed B cell lymphoma only with filings pending currently for Waldenstroms and for marginal zone. But we've seen strong quarter-over-quarter growth in spite of the fact that we don't have head-to-head results were already about of new patient starts in mantle cell. If you look at the overall conversion and mantle cell as a proxy perhaps for where we can anticipate second-generation use might do in advance of these head-to-head results, it's already at about 60% in mantle cell. And so as we look to achieve our labels, provide clinicians with the ability to use zanubrutinib beyond simply the mantle cell, which for the average clinician, is about maybe 1 to 2 treatment opportunities at most per year, with the ability to use this across multiple more indications, we do anticipate an expansion of use and only with the results of ALPINE, hopefully, the pending results from SEQUOIA we do anticipate that we'll be able to compete for overall use. So I think there was a comment made around positioning as an option for intolerant patients. That's certainly not the way that we view this medicine, we view it as a drug that has the potential for emerging as the standard of care a BTK inhibitor, right?

And the only other thing there I wanted to add is we are pursuing labels in multiple different indications that the -- some of the other BTKs don't have like marginal zone lymphoma and Waldenstrom's.

Andy, your mic shows live to me. Did you have a follow-up? Or if not, we'll move on. Okay. Let's move on to the line of Yang Huang. Please state your affiliation and remember to unmute yourself.

Yes. This is Yang Huang from Crédit Suisse. My first question is for Dr. Hillmen and Dr. Brown. So suppose we are going to continue to see efficacy difference between zanubrutinib and ibrutinib. And once it gets approved in our [ CAR ] so how do you 2 are going to consider prescribe zanubrutinib compared to ibrutinib? That's my first question. And my second question is for BeiGene management team is that we understand that you are going to have BCL-2 data sometime maybe at ASH. So from what you have to see and what's the confidence level to support that you think you have a best-in-class BCL-2? And I also want to understand if we are going to see positive data from BTK plus BCL-2 in the Phase III because that's going to be kind of a shorter treatment? And then probably a safety concern for ibrutinib will be maybe smaller and under that kind of situation, how do you position zanubrutinib versus ibrutinib in terms of safety differentiation?

Jane, could you start?

Thank you. So if the efficacy difference continues between zanubrutinib and ibrutinib, particularly with an exist on progression-free survival, in addition to the better tolerability, I think it will take over. I will certainly use it as my preferred BTK inhibitor. In fact, even just with similar efficacy and improved tolerability and from a physician standpoint, it doesn't make any sense to use the drug that has toxicities that could cause harm to the patient and then switch later, it makes a lot more sense to start with the drug that doesn't cause the toxicities at the beginning. And then if there's an efficacy difference on top of it, it really, from my perspective, it seems quite obvious that we would use zanubrutinib.

Yes. Just to add to that, I think the treatment in CLL is to move to [indiscernible], it's already happened largely in North America and in the U.K. and globally [indiscernible] so chemotherapy will disappear. And we know that in frontline patients, progressive disease through targeted therapies is relatively uncommon, and the biggest problem is the tolerability. So having an efficacy advantage in relapsed/refractory is obviously a strong point. But it's the tolerability that the big difference in terms of frontline, which will be merged to the patient, of course, is going to be can the patients stay on the treatment? And having the side effects that we see with our ibrutinib, particularly things like atrial fibrillation requiring arthralgia, all those symptoms are very difficult if the patient drug indefinitely. And so I think there are significant advantages to reduce in terms of reducing toxicity in the frontline setting, which will translate to better efficacy over time. So I think in terms of ibrutinib I think that's a given in my mind. So then the question is what was -- what about [indiscernible], well, I think zanubrutinib is best tolerated in terms of PPI is an issue for many of our patients with acalabrutinib. And I don't -- they are both well-tolerated drugs. So I think it's probably the PK and the coverage of the target that will make the difference. So we're seeing better efficacy for zanubrutinib or ibrutinib, but not for acal or ibrutinib, then clearly, we're going to lean towards more effective drug.

Yang, I show your mic is open. Did you want to come back with a follow-up? I'm sorry, Jane, did you have a follow-up comment?

No, I was just going to answer the question. There was a question embedded in there, I think at the end, about our BCL-2 inhibitor and the studies in development. And actually, there is a poster here on our preliminary data on 11417, which is our BCL-2 inhibitor.

And I can just make a comment about that in terms of BCL-2 inhibitors as I've been leading the U.K. group for a long time and we need another BCL-2 inhibitor to allow us to do the combinations that we need to do. And so I think that will be a very valuable addition, so we're waiting for that [indiscernible] open the trial, I think, in our centers. So that's one of the things we're waiting for, for some time.

Yes. This is -- maybe I'll also add a comment on our BCL-2. I think the early data as well as the PK -- specially PK data is very consistent with what we have predicted about how BCL-2 and it's probably the most potent BCL-2 at this moment in the clinic, whether this eventually translate into the better efficacy, better safety, we're actually highly, highly selective compared to. But whether this is a best-in-class BCL-2 then need the clinical data to demonstrate that. In addition to that, I just want to mention there are multiple trials has been planned for BCL-2 in addition to the current Phase I, we're working on additional Phase I studies in AML as well as in multiple myeloma.

And Craig, if I could jump in for 1 second. The last question was about what happens when you have BCL-2 combinations? Does the toxicity matter? I think that this CLL study itself, there's just 15 months follow-up, you have a lead-in with a BTK inhibitor. And from that perspective, the difference that shows up just in the short period of time and AF and some of the other toxicity to us, we think, will be meaningful even so when you look at combination solutions in the future. And ultimately, if we can get the shorter duration of treatment, that's the home run. That's what we're all trying for patients. So hopefully, that's going to work. And hopefully, in the short term, while we get to that, it's something that can be a safer solution for patients. Thank you.

Okay. Our next question will come from the line of Yige Guo, and remember to state your affiliation.

This is Yige Guo on for Michael Schmidt with Guggenheim. Congrats on the ALPINE data. We have 2 questions. The first 1 is on the trial of the ALPINE trial design. Can you help us understand how do you determine the timing of interim analysis, meaning why do you specifically select 15 months of median follow-up for ORR analysis? And when will we see the final analysis. The second question on a bigger picture. Can you help us understand the positioning of BRUKINSA relative to other approaches targeting BTK such as reversible kinase inhibitors or protein degraders?

Yes. This was a prespecified analysis. If you recall, we did increase the sample size several years ago in order to give us more power for the progression-free survival analysis. But this was the preplanned original timing of when we were going to look at ALPINE after the first 400 patients had been enrolled.

[indiscernible] from our previous studies, Jane, the -- it takes about 6 to 12 months to see the first [ announcable ] response to BTK inhibition. So it's a minimum of 12 months is a reasonable time point [indiscernible] earlier that you're going to have a lot of [indiscernible] cytosis, which hopefully the FDA will not go to count as a response. So I think 12 months is a reasonable cut-off for assessing overall.

And related to the question about the BTK protein [indiscernible] we're fully aware of that, and we are actually very much interested in this space. So that will be a different action to inhibit BTK, the first generation, the second generation, the reversible BTK inhibitor or the kinase activity, while protein [indiscernible] remove -- eliminate the protein from the cells. So mechanism of action will be different. However, it will still need to be binding to the BTK protein. What kind of resistant [indiscernible] will emerge with all different type of the BTK inhibitor that will be very interesting to look into in the future. We have a lot of interesting space and stay tuned.

Thanks. There appears to be no more questions in the queue. But just a couple of questions sent over the chat. The first question for SEQUOIA, how relevant will the data be given BR, bendamustine plus Rituxan is not a standard of care anymore. I believe this appears to be a regulatory angle, so maybe Jane or Li, if you could address that?

Yes. We started the study back in 2016. And of course, BR at that time was a relevant comparator. And there's usually no issues in evolution or with regulatory agencies when you have started the study with a relevant comparator. But perhaps Dr. Hillmen and Dr. Brown may want to comment on the significance of the results when we see them.

I can -- yes. I mean in terms of a regulatory study, most of the -- I think all of the regulatory studies that have been done so far have been against [indiscernible] as a frontline trial. So actually, BR is a better therapy than the studies that have been performed. And so I'm sure that's assuming positive results but it will be meaningful. Only now we designed trials without a chemotherapy arm in frontline CLL.

We do have the alliance data with ibrutinib, ibrutinib rituximab versus BR that provides something of a comparison, but we'll primarily be interested, of course, in the zanubrutinib results.

The next question is when can we expect filing of SEQUOIA and ALPINE? So since it's the time I'll start the -- we've said that -- so obviously, we have the ALPINE results, certainly from the interim analysis and the SEQUOIA study, we have said that the results could be as early as this year. So with this data, we'll discuss with the relevant regulatory authorities on potential filings. So stay tuned on that. So I think that concludes our Q&A session. I'd like to really thank everyone for joining us, especially Dr. -- Professor Hillmen and Professor Brown. We hope that you can feel our excitement in these results. And our progress, we'll be releasing our Q2 2021 financial results in the upcoming weeks. We look forward to providing you with an update on our performance. So thanks, again. Good day, and good night.