BeOne Medicines AG ($ONC)

All right. Thank you, everyone, for joining this session. My name is Linhai Zhao, I'm the China biotech analyst. Today, with great privilege, we have the opportunity to host the management from BeOne Medicines. On the further right of the stage, we have Aaron Rosenberg, the CFO, and Mark Lanasa, the CMO, joining this fireside chat. So welcome. And I think BeOne Medicine has shown very exciting data at ASCO this year, and investors have been highly anticipating some exciting news from our solid tumor pipeline. Besides that, we have done extremely well for our hematology pipeline. BRUKINSA is by far #1 BTK inhibitors globally, and we are continuing to see exciting clinical progress from our BCL2 inhibitors and the BTK degraders.

So I think the first question, I think, would be about our [indiscernible] strategy. You've taken a very disciplined data-driven approach to prioritizing the pipeline with the 5 highlighted cornerstone programs for solid tumor, as well as a few deprioritized programs that you shared at the quarterly results. What is the go versus no-go bar for the clinical data? What is your vision on the solid tumor franchise over the next 5 years?

Thank you, Linhai, and thank you very much for having us present this morning. So yes, we have brought a lot of molecules into the clinic, and it is our aspiration to bring additional internally discovered as well as some partner molecules into the clinic. Through this, we have been very disciplined in our early phase approach. We think that this is critically important in allowing us to progress a large portfolio as a midsized organization. So put simply, when a molecule is coming to the clinic, the teams are asked what would a differentiated medicine look like for the target patient population in development. And that is something that is expected of the teams at the time of the first-in-human study. And by understanding what a differentiated medicine would look like we're able to establish clear go/no-go criteria. If the programs are meeting those criteria, then great, we'll look to expand those programs. And we've highlighted 5 programs that have met those criteria and are on track to a Phase III study start. We highlighted 3 of them at the recent ASCO. But we also announced that there were other programs that we have stopped because they weren't meeting those criteria. And these include some programs that we had previously highlighted based upon previously -- based on very strong preclinical data. So we think that that disciplined approach is really critically important to be able to progress and prioritize a broad pipeline of innovative molecules.

Yes. Can you be a little bit more particular [indiscernible] with examples? I know that differentiation or differentiated medicine can look very differently [indiscernible]. We have very different requirements when we are talking about different indications or different molecules.

So ultimately, it comes down to what is the target population for development. Since we recently disclosed some data, I can make a few examples. So for example, for CDK4, what we were excited about with that molecule is really strong efficacy data with a response rate of approximately 70% across 2 different cohorts. We feel that that's clearly differentiated from what the CDK4/6 molecules deliver at a range of, say, 50% to 55% in a frontline patient population. So that hits our go criteria in combination with favorable PK and safety and whatnot. And then for GPC3, where our target patient population was hepatocellular carcinoma, there the molecule exceeded our go criteria with a response rate of 30% and a very clean safety profile. So for both of those molecules, we have confidence that they not only deserve to go to Phase III, but can eventually be impactful medicines. We'll have a similar conversation about PRMT5 in the second half of the year. And again, we're applying that same lens to all of the molecules that we bring into the clinic, our [ Cat6AB ] that we started in last December, again, what does a differentiated molecule looks like in later-line breast cancer?

Yes. I think we're all very excited about the ASCO readout, but we can definitely discuss deeper about that later. I want to briefly touch about our pipeline or the clinical pipeline targets we mentioned of the target of -- to deliver 8 to 10 NMEs per year. How do you maintain the speed without sacrificing quality and clinical decision-making? And more particularly, with China being increasingly recognized as an innovation source, how would you describe BeOne's strategy to leverage China innovation given that we are targeting to deliver this amount of NMEs per year?

So what's really important to understand is that our internally delivered development work is global by its nature, that we are the leading sponsor of early phase research in Australia, we're the leading sponsor of early phase research in South Korea. And therefore, we're not only moving quickly, but we're moving quickly globally. And this enables us to generate data that, again, enables us to have those go/no-go criteria. But also by having global patient data, we can have confidence that the data does not have significant determinations based upon ethnicity or region and that it will meet the needs of global regulatory agencies. We recognize that there are a lot of exciting molecules that are emerging from China as well as other global regions. Our BD approach is fundamentally global. But what we look at, again, our development model by being global in its nature, we think that that has substantial advantages over other, shall we say, regional models.

Yes. I think that's really well said. And given our global footprint, we're able to identify and seek opportunities for business development in all the geographies in which we operate. We've done excellent investments in business development with innovation that's been sourced from China. Our B7-H4 is an example of that. We recently announced a very interesting deal in the [ IO ] space for a trispecific with a company called [ HH Bio ] that emanated out of China. But we've done deals globally as well in all the geographies. So ultimately, our clinical development organization is global first, and that puts us in a really strong position relative to competition to really deliver quality with speed to ensure that these innovations get to patients as fast as possible.

Yes. One quick follow-up on that I think is worth saying, part of BeOne's highlight on the clinical execution, and I think in more recent presentations, BeOne has been highlighting what they call the global development superhighway, right? How should we understand this competitive edge compared to other global pharmaceutical companies, especially that we are seeing more global MNCs; they are getting deals with China biopharmas that include early-stage integrations, which the biopharma -- the China biopharma companies could also be very quick in terms of getting the clinical proof-of-concept data?

Yes. So I recognize the importance and the intent of the question. Yes, what I would highlight really is the global nature of our development organization. So it's important to understand that we have fully internal development capabilities across clinical development and clinical operations, statistics, regulatory and so on. But we also have in-house manufacturing, and we run our studies globally. So yes, there may be some molecules that are able to generate limited data sets within a specific region. But when those molecules are partnered, there's always a certain amount of work that goes into the transition to the partner. And then often there will have to be a duplication of earlier data sets to ensure the generalizability of those data sets. So any speed that might have been captured through a single-region approach is then lost through the process of re-globalization. For our CDK4 molecule, we went from the global first patient dosed to our global first Phase III patient dose in only 30 months. We believe we're going to replicate that for B7-H4. Our [ GPC341bB ] will be shorter than that. So we really believe that we're industry-leading in speed, not only from Phase I to Phase III, but then also from readout to submission and so on.

Sure. And I want to briefly touch on most recent earnings performance. I think it's another beat strong quarter, and we also raised our full year '26 guidance. If we're looking a little bit more in detail, we can see that for the full year of '26 guidance, for the EBIT level, was upgraded from $750 million to $850 million for the full year. And if we consider that in 1Q, the EBIT level was $250 million, that is more than 1/4 of the full year guidance. How should we understand the numbers here? And particularly, does the guidance leave room for higher R&D spending for the rest of the 3 quarters? And how do you balance the spending in both selling, R&D while maintaining the continuous operating leverage?

That's great, and thanks for the question. I think we've talked for a long time about our intent to run the business both as a growth organization, but also is one that does it so in a sustainable way. And sustainability is ultimately translating that growth to margin expansion and ultimately, and most importantly, free cash generation. And I think you see those kinetics in action in our Q1 results. We feel very comfortable with the current year that enabled us to raise, as you said, our guidance on revenue by $100 million the range, to $6.3 billion to $6.5 billion on the top line. And that translated to a bottom line improvement of $50 million across the range to $800 million to $850 million on a GAAP operating income basis. As you said, Q1 was quite strong in terms of its income generation. We did affirm our OpEx guide for the year. And I think that reflects our continued investment in our core capital allocation priorities. That's continuing to drive and invest in our commercial businesses that are driving profitable growth and as well as our clinical opportunities. And you saw the great data at ASCO. I'm sure we'll spend some time talking about that, as Mark alluded to earlier. And obviously, that was investment that we've contemplated in our full year guide in terms of OpEx, and that's what translates to the guidance that we updated with our Q1 results.

Sure. And I think if we talk about the earnings, we -- one thing that we have to talk about is BRUKINSA. And especially, we're talking about BRUKINSA is entering, is already becoming the global #1, right? It's capturing more than 35% shares globally. And a natural question is, what is the room for growth further? And specifically, we've seen that for the EU part, it currently accounts for roughly 1/4 of U.S. sales. How do you see the potential in the EU market versus the U.S. market?

No, thank you for the question. We're very pleased with the performance for BRUKINSA. As you said, BRUKINSA became the #1 BTKI, that eclipsed the curve toward the second half of 2025 globally, we had done so earlier in the United States. And that's really behind strong performance in all the geographies in which we operate. We've talked historically, you were touching a bit on geographic mix, we've talked historically that our European business as an example was a little later in its launch trajectory than the United States. And important, rest of world markets or even earlier than that in terms of their launch trajectory. And you see that in the results, where the United States grew in the mid-30% range, high 20s on a volume basis. Our European BRUKINSA was more like 60%. There's some FX in there, but still very strong demand generated growth. And our rest of world markets doubled in Q1. So I think that reflects the launch life cycle of the brand. So we do see continued opportunity in all of our geographies to continue to drive demand through new patient share. And of course, the geographies that are a little earlier in their life cycle have higher growth rates. As we get bigger, obviously, growth rates in their percentage terms, those will naturally come down. But we'll continue to drive new patient starts driven behind the differentiated clinical data for BRUKINSA. At ASCO, we shared another update to our [ SEQUOIA ] data, going to [indiscernible] that unprecedented PFS at 72% over that time period. And really that's noncomparable as you look at the other medicines in the class in terms of its absolute PFS over that long of a time period. And ultimately, that's what's translating to utilization in the marketplace.

Sure. I do want to have one question specifically for sonrotoclax because we are seeing recently the good news from this drug approved in China followed by the approved in U.S. We have seen very strong conviction on this drug with -- in terms of both better tolerability and extremely encouraging high and durable and deep responses. How do you see like the early product launch, especially how do we see the -- how do we expect to get this drug in terms of the near-term launch? And based on the China performances or the China observations, what has been the early physician feedback on this drug?

So maybe I'll start. So my understanding from Amit, our CMO for hematology, is that the prescriber feedback in China has been very positive, both in terms of efficacy as measured by MRD rates as well as the safety profile and the tolerability by patients, compared to what prescribers have experienced with other molecules in the class. That said, I would say that this is similar to the feedback we've received on the development side, the CELESTIAL 301 study, our fixed-duration therapy in frontline CLL, the investigators who have been using sonrotoclax in an investigational sets are also providing positive feedback on their experience. So we're very excited about the potential for our novel BCL-2 inhibitor.

And then with BEQALZI, our brand name, obviously the first indication that's been approved in the United States is in the relapsed/refractory MCL setting. And that's a pretty narrow indication. We're very excited to get this differentiated medicine in the hands of prescribers and patients. There's significant unmet need in this relapse-refractory MCL setting, and it's a great opportunity to gain experience. Obviously, the larger opportunity that you referenced is with our zanubrutinib plus sonrotoclax fixed-dose combination in the frontline in CLL. That CELESTIAL 301 study is fully enrolled. Obviously, the data will have to play out. So in the short term, we've talked about the opportunity being fairly immaterial in the very short run. Obviously, as we continue to get this in the marketplace, we'll serve those patients in the relapsed/refractory MCL setting, and look forward to the larger market opportunity. And as you said, we're really encouraged by the data as you think about a fixed-dose combination, the potential to have the kind of deep durable responses that this combination could bring with what we hope is efficacy and a safety profile that's comparable to continuous use BRUKINSA. Time will tell, right, across all -- as BRUKINSA has generated such a robust data set in the short, medium and long term. And ultimately, as you think about BRUKINSA the differentiation in terms of efficacy, [ and that SEQUOIA ] data that I mentioned, we had a really nice chart on this in our Q1 results, is really from that year 3 to year 6 time period where you really see BRUKINSA standing with significant and durable PFS across that time period. And when you look at the other in-class competition as well as existing then based fixed dose treatments, that's typically where you see the drop-off. So we're really encouraged about our fixed-dose combination. Look forward to bringing the initial data set, and we hope it will be an important solution for patients. In the meantime, BRUKINSA has demonstrated significant durability and really unprecedented durability and it's serving patients today.

Cool. And switching gears to our ASCO data. The CDK4 inhibitors, I think there are a lot of excitement about the early ORR. And we've also seen a very dose-dependent way of safety, tolerability. Can you talk a little bit more about dose selection? You chose 400 mg over 240 mg for the dosage? And how would you expect the ORR with mature follow-up? I'm aware that for the CDK4 inhibitors, the longer the maturity, you're actually going to see an increase in ORR. How do you want to comment on maturity data?

So the -- thank you for the question. For CDK4, the maturity of the data that we presented at ASCO, the median time of follow-up or the median time on treatment was approximately 9 months. Interestingly, we do observe late emerging responses. We had 2 patients that were relatively recently detected unconfirmed responses. So these were late emerging responses. Now that said, I wouldn't want to create a notion that we think our response rate is going to continue to climb and climb and climb from there. We're really pleased with what we have seen in terms of the response rate. And as I mentioned before, we think that it is differentiated from what one would expect from the CDK4/6 inhibitors. And that gives us confidence to move into our Phase III study.

Yes. I do want to make sure that we talk about the tolerability profile. And we're talking about the CDK4/6 versus CDK4. I think naturally, there is a trade-off between the human toxicity versus the GI toxicity. Based on our communication with physicians, how should we think about this potential trade-off with the CDK4/6 selectivity? And particularly, what is the bar for GI toxicity to be considered as accessible based on physicians' feedback? And can you share a bit more on the mitigation tactics that we have been explored for the GI tox?

Great. Again, thank you for the question. There's really 2 components there. The first relates to the heme tox safety profile. So with CDK4/6 inhibitors, it turns out that the majority of the hematologic toxicity is driven by CDK6 inhibition. And indeed, that was the core hypothesis of the molecule. By having greater 4 versus 6 selectivity, that we could drive deeper and more sustained inhibition of CDK4, which drives antitumor efficacy. That is now reflected in the high response rate, while mitigating the associated hematologic toxicity. At the investor event that we had at ASCO, I shared our selectivity data. And indeed, we have the most selective 4 versus 6 inhibitor with approximately 35 -- fold for versus 6 selectivity in a preclinical cellular assay. That has pulled through in our view based on mechanism to an unprecedented heme tolerability profile, that across 240 and 400 milligrams, we only had a single Grade 3 event and no Grade 3 heme tox events at 400 milligrams. We have had the feedback sometimes that patients don't experience hematologic toxicity. But the reality is that hem tox is the leading cause of dose reductions for the 4/6 inhibitors, and therefore, they are important. I also tried to make the point that heme tox also prohibits some combinations, and we think that there are a whole group of combinations that are available to us through having this more favorable safety profile. Now in terms of the patient experience, the GI tolerability is also very important. What we shared in our poster was that in the fasted state, our rate of any-grade diarrhea approached 90%, and we had perhaps a 10% rate of Grade 2, Grade 3 events. However, in a small cohort of patients who had co-administration of food, that that event rate dropped substantially to 50%. And importantly, all of those events were Grade 1. The feedback we've had from investigators is that Grade 1 diarrhea is essentially very manageable. There are many successful medicines that have a moderate rate of Grade 1 diarrhea, and that's straightforward for most oncologists to manage in their daily practice. So we're very pleased to mitigate those Grade 2/Grade 3 events, which are the events that tend to lead to [indiscernible] -- I apologize, so your last question [indiscernible] dose selection. But suffice to say, when we look at the cohorts of 240 and 400 , the response rates were quite similar. But when we do our more detailed exposure response analysis where we look at not just the dose level but actually drug exposure, we found that the 400 optimized our characteristics, both in terms of efficacy and safety. We have confidence given the favorable efficacy and safety profile that, for those patients who do require a dose reduction, that they will be reducing to a very efficacious dose, if they do require dose reduction in the Phase III study. And importantly, the study is now active. We have taken that 400-milligram dose selection to global regulatory authorities who have essentially endorsed that choice and agree that 400 is an appropriate dose to take into a registrational study.

Yes. That's very important to know, especially we've -- quite a lot of feedback saying that currently the regulators, they prefer like lower dosage versus higher doses if the higher doses doesn't show meaningfully improvement.

We're absolutely aligned with the feedback of FDA's Project Optimist to move towards the lowest efficacious dose, right? We think that it's really important in terms of the overall patient experience. We and others absolutely focus and we focus our discussion primarily on efficacy, but when you look at what constitutes a successful medicine, the patient experience vis-a-vis tolerability is also extremely important.

Yes. So a little brief follow-up on the mitigations. You mentioned the co-administration with food can effectively mitigate the GI toxicity. How are we integrating that into our Phase III protocols?

So the Phase III will require that patients take the drug with food. There's a couple-of-hour window and there's many medicines [indiscernible] not, shall we say, problematic or burdensome to the patient [indiscernible] a significant improvement in tolerability, medical management of low-grade diarrhea is quite straightforward, using antidiarrheals. And that said, we continue to look to mitigate this further with, for example, in the Phase I study, we're now enrolling a cohort that's going to take primary prophylaxis with antidiarrheals and understand that impact. That's something that we can look to integrate into the protocol if need be. Again, we're very comfortable with where we are, understanding that it's a small cohort and we'll be enrolling more patients to give us greater confidence in that initial observation.

Yes. Great. And for the GPC3, you mentioned that it's kind of reached beyond your -- way beyond the go versus no-go bar. And we've seen that this molecule was not highlighted as much as the other programs previously, but it was brought up more recently highlighting the very encouraging clinical profile where we see that the Phase I data at ASCO showed very nice controlled safety profile overall with only single-digit percentage of Grade 3 TRAUAs, and more particularly, for 4-1BB related liver toxicities, we've also seen very nice control. So what is the plan for the registrational trials in both the first line and second line plus?

Yes. Thank you. And we're extremely excited about our GPC3 4-1BB is where we have increasing confidence -- I have increasing confidence that this will be a clinically breakthrough molecule for patients with hepatocellular carcinoma. For context at ASCO, the EMBRAVE-251 study was presented in that study. The current standard of care, the control arm delivered a response rate of 5%, and what we just demonstrated was that our molecule has a response rate of 30%. And importantly, it delivers a response rate of 30% actually with a better safety profile than the currently available TKIs. So we think that this is really potentially a big step forward. There are other GPC3 targeting mechanisms such as CAR T cells or ADCs, but this is a patient population that tends to have substantial comorbidities related to liver cirrhosis. And frankly, those modalities are not well tolerated. So we really think that we are uniquely positioned in this later-line setting with a very safe and efficacious molecule. We intend to have development as monotherapy in a later-line setting. We received a question at the ASCO investor event, well, what about [indiscernible] with TKI? We're considering that, but then we would be giving up this favorable safety profile that we have. But we also have already initiated a combination with tisolizumab, or PD-1, along with bevacizumab, to give us line of sight to a frontline opportunity as well as ultimately also early stage for intermediate-stage patients as well. Those cohorts are just now starting to enroll, but we're off to a good start. And we're very optimistic about not only the late-line registration opportunity but the earlier lines as well.

Curious about the drug design of this bispecific. We've seen other 4-1BB-based bispecifics. I think a common tactic is to have differentiated binding affinity between the 4-1BB versus the other target, usually having a lower affinity for 4-1BB just to achieve conditional binding. So what is our strategy for this molecule?

Yes. The idea is similar overall, that we wanted to have conditional T cell activation really in the tumor microenvironment, not to have broad T cell activation. So indeed, the idea is that, first, what happens is through the high-affinity GPC3 anchor, that it gets anchored in the molecule and then you get local T cell activation. It's important to highlight there are other features. We have a unique 41BB binder. We have made modifications through the constant change to improve the half-life of the molecule. And we're very excited about the data. We're very excited about the platform. So you all can expect to see other tumor-associated antigen by 4-1BB targeting bispecifics coming forward for us because we think that this might be an important platform technology where we can again improve responses within favorable safety profile.

Sure. And you mentioned about the trispecific antibodies or -- and I think there's no doubt that Lai seems to be very excited about that. And we've noticed that BeOne Medicine, we are a kind of a pioneer in the PD-1 [indiscernible] has been an extremely commercially successful product. But if we came to the PD-1 VEGF field, this recent collaboration is really like the first milestone event for BeOne Medicine to enter PD-1 VEGF. And we have the option to license this trispecific. We know that the Phase I trial has recently been initiated. Can you share what are you looking at in this Phase I trial in order to treat the option? And what is your view on the overall survival benefit that we've seen from the ivonescimab and to share your perspective on what is our general plan for this trispecific?

Yes. I think to start at the end of your question, we recognize the data that was recently presented at ASCO for ivonescimab, the HARMONi-6 study is a positive study with overall survival benefit. Our review was twofold. So one is that it is now a highly competitive space, the PD-1 or PD-L1 by VEGF. We didn't want to enter late and end up with an undifferentiated molecule. We view CTLA-4 as a mechanism that has tended to have a positive effect on overall survival. So we saw the trispecific as an opportunity to provide additional benefit with, hopefully, greater weight towards overall survival. The preclinical data, again, was very strong. This was an IND-ready molecule. The clinical trial applications are now submitted and we anticipate to have the first patient dosed this month. And again, it's a Phase I molecule where we will have clear go/no-go criteria, and we'll be excited to see how this data unfold.

And I think just to add, I think this shows 3 elements of strategy in one deal. I think first, as Mark said, BeOne is not going to chase the seventh, eighth, ninth asset in a crowded space that doesn't support our mission, it doesn't support patients, just to have a me-too medicine. I think it highlights our business development efforts to identify interesting science and to deploy our capital in a smart and efficient way to test the hypotheses embedded in that science. And finally, I think it showcases our global development superhighway capability where we will be able to take that potential medicine, explore, test the scientific hypothesis. And to the extent it hits, we'll move super fast. To the extent it doesn't, that's why we have a prioritization criteria.

Great. One last question. I do want to touch on our lung cancer strategy. I believe that our last significant trial in lung cancer was dated back to the [ TS ] portfolio. And with discontinuation of EGFR CDAC program, what is the current strategy for lung cancer? We talk about the trispecifics and we have plenty of other great candidates. We have the bispecific ADCs or even trispecific ADCs that could be potentially targeting lung cancer. So just can you share a little bit more about the thoughts in lung cancer?

Yes. So we are strongly committed to lung cancer. You will see more innovative molecules from us entering the lung cancer space. When you look at our portfolio to date, what you see are a group of molecules that capture the biologic heterogeneity of lung cancer. So we're not focused on any one target, but rather bringing benefit to multiple patient segments. We have high conviction in our PRMT5 inhibitor. We'll have our first disclosure for that molecule in the second half of the year. We're excited about our EGFR [ met ] trispecific biologic, which is progressing well, and again, multiple other therapies, multiple ADCs and testing in lung cancer as well.

Cool. I think with that, we've reached the time. And again, thank you all for the time, especially, Mark, for the very insightful conversations. We're really looking forward to hear more updates about BeOne particularly from the solid tumor pipeline. Thank you so much.

Thank you.