Okay, good morning, everybody, and thank you for joining us at the 45th Annual TD Cowen Healthcare Conference. I'm Yaron Werber from the biotech team, along with my colleague Jaena H an, and it's a great pleasure to moderate our first fireside chat today with BeiGene, soon to be known as BeOne. To my immediate left is Mark Lanasa, Chief Medical Officer of Solid Tumors, and to his left is Aaron Rosenberg, the new Chief Financial Officer, incoming as of about three or four months ago. Was it five months ago?
Six or seven.
Six months ago, my God.
Time flies.
Time is flying. So we have a lot to talk about, Aaron. This is the first one with you for us, and you literally just gave guidance on Thursday for the first time with BeiGene, showed a very nice outlook for the year, both in terms of revenues and profitability. You obviously didn't guide for the bottom line, but we can obviously get there. Brukinsa is doing really well. Revenues are outpacing expenses, and you're growing globally at the same time and investing in the pipeline. Clearly, Brukinsa is crushing it. Can you talk a little bit about how did you come to your guidance? Kind of what were the pros and cons?
Sure. Thanks for the question, and it's great to be here with you all. We're exiting 2024 in a really strong position across all products and all geographies. As we think about 2025, just walking through our profile, in the United States, as you said, Brukinsa continues to perform really, really well. You know, as you think about the opportunity in front of us, we are now established as the market leader in terms of new patient share in both the first line and the relapse refractory setting. We've actually eclipsed Calquence in Q4 in terms of value share and very close to Imbruvica at this point. As we talked about in our prepared remarks during our earnings call, about a third of the patients in the U.S. were from new patient starts.
So the dynamic that that creates is with a therapeutic area with long-lived therapy, you get a stacking effect of patients. So you think about that third of patients rolling over into 2025, that creates growth opportunity on top of our market share increases that we're experiencing. And it's really not just a U.S. story. Our European business with Brukinsa nearly tripled in 2024. We are in the earlier stages of our launch trajectory in those markets, and we continue to launch in important rest of world markets. We've talked about Japan, which was approved in December. That'll be launching in the early part of this year. That's a $200+ million BTKi market. Similarly, we're very early in our launch trajectory in Brazil. That's another $200 million launch opportunity. Outside of Brukinsa, we also are seeing really nice growth across our brands and geographies.
Tevimbra is the market leader in the PD-1 class in China, grew 16% on a year-over-year basis in 2024. Importantly, 2024 had a double-digit price impact. So as you think about 2025, where we have the broadest NRDL coverage in the class, three new indications and no price headwind, that creates opportunity for growth. And we are continuing to do really well with our partnership with Amgen and with that business nearly doubling in 2024 as well. So we exit 2024 in a real position of strength, which sets us up for the guidance that we provided.
As you think about Brukinsa in Europe, as you said, it's tripled, but Brukinsa in Europe is still, as a class, actually a BTK class, is dramatically underpenetrated relative to the U.S. Can you give us a little bit of a sense trajectory there and how close is it to saturation right now?
No. So as I said, we are earlier in the launch trajectory. If you look at like the example with Imbruvica as sort of the market leader, you saw about a 50/50 kind of split at peak between U.S., ex-U.S. So we are in an earlier stage of launch. I always give the analogy. France is obviously a very large market. That just launched in January of 2024. So you know when you compound that with the stacking effect that we talked about, that I talked about earlier, there is still a significant opportunity for us where launch and reimburse really across the continent, and we continue to drive share in this important area of the world.
With Tevimbra, I'm just going to shift over. You have now U.S. and European approval for gastro, gastroesophageal. How big is that market for PD-1?
It's a large market for PD-1, obviously with entrenched players. We are launching both in the U.S. and in Europe in a very targeted fashion. We do feel really good about the profile for Tevimbra in both gastric and in ESCC, and we'll look forward to reporting our progress over 2025. Initial feedback from clinicians is very positive, and we look forward to sharing more updates over the course of the year.
And can you just remind us, how big is that market now for PD-1s? What are they selling in those two tumors, U.S. and Europe?
It's a $1 billion+ market. So this is a significant market opportunity and an area where we believe we have the opportunity to really make a difference. The other competitors are obviously focused on lung cancer and their adjuvant therapies. We're really in an area where we feel like we could be quite competitive and offer solutions for patients.
And so far, what's the differentiation for Tevimbra over the incumbents?
So we don't have the benefit of head-to-head trials in this class, but in ESCC, as an example, we do have the longest demonstrated PFS at 17 months in ESCC. So again, a really competitive profile. And obviously, Tevimbra has been used significantly globally, and we really have the experience from many, many patients in these treatment areas.
If I may, the 17 months at ESCC was actually the overall survival. We had an incremental benefit in overall survival in ESCC of 6.6 months. We had the longest point estimate of overall survival at the median and the longest or the greatest improvement in overall survival of any of the PD-1s or PD-L1s in the ESCC space and have a very competitive data set in gastric as well.
When you're looking, just to go back to Brukinsa, you're going to be stacking now Japan, you're going to be stacking Brazil, you're still obviously rolling in Europe, and you're still capturing some share in China, even though you're the number one brand in China now. What is it? If you look at the new share from Imbruvica, I think it's like between 5% and 10%, right? Imbruvica has really fallen off, and now you're taking the lion's share of new patients even from Calquence. As you think about your guidance for the year, how much of that guidance was in Brukinsa? I know you didn't break it out that way versus Tevimbra. Maybe just give us a little bit of how you thought about both.
Sure. I think you can look at our profile and get a perspective. As I mentioned, we do see growth in both brands, but of course, Brukinsa is a meaningful part of our business, and we expect to continue to gain share and obviously benefit from the lapping effect that we described.
Maybe I'll turn it over to Jaena on the pipeline.
Oh, yeah. Okay. So yeah, you have a pretty exciting solid tumor pipeline, heme franchise obviously with some R&D solid tumor pipeline with a lot of proof of concept data potentially internally and a couple of data sets maybe at ASCO this year externally. What is the strategy behind your solid tumor pipeline?
So overall, within the solid tumor area, we have three disease areas of focus. These disease area franchises are lung cancer, GI malignancies, and breast cancer. Jaena, as you alluded to, this year's ASCO, we intend to provide an update for our breast cancer franchise, sharing data for our CDK4 selective inhibitor, our CDK2 selective inhibitor, and our B7-H4 targeting ADC. We're very excited to bring molecules forward across these disease areas that have substantial global unmet need. And the long-term strategy aligns to what we're doing in hematology of having a complementary group of products that can enable us to have a successful commercial franchise in each of those disease areas.
Very nice. I actually want to dig a little deeper into your CDK4 asset. I think that's the one that's kind of furthest ahead, the one that has garnered the most interest. Obviously, you're continuing dose escalation. You've treated over 130 patients to date with pretty promising initial safety and PK data. I kind of want to get into, how do you think that this target inhibition and this monotherapy safety that you've seen so far compares with kind of Pfizer's competing asset?
Great. Thank you. So we're very proud of what we've accomplished operationally with our CDK4 inhibitor. So that molecule first entered the clinic in December of 2023. And as of last week, we actually now have enrolled something like 180 patients. Between JPM organ and today's conference, we've enrolled 50 patients. So we're moving very quickly with that program while delivering a very high-quality data set. Part of this relates to the internal operational capabilities that we've built. Part of it transparently is just investigator excitement and belief that a CDK4 selective inhibitor can improve upon the substantial benefit that's been conveyed by CDK4/6 inhibitors. The data that we presented at last year's San Antonio was an initial look at safety. We also shared some PK and PD data.
As that data continues to emerge, what we're seeing are clinical data that are consistent with our preclinical predictions of what one would expect of a more CDK4 selective molecule. So greater potency in terms of target inhibition while having a more favorable hematologic safety profile. So we will have data that we're presenting at this year's ASCO or intend to share at this year's ASCO that will be our first disclosure of efficacy in terms of the objective response rate. And we think that those data will enable more of a conversation to the question that you're asking in so far as how our molecule might compare to competitor molecules.
Great. So at this ASCO readout, can you give us any more granularity on what we can expect in terms of patient numbers, follow-up, et cetera?
The data are actually still emerging. We haven't had the data cut off yet. It's a bit difficult to answer the question. But again, as of today, we've enrolled 180 patients across dose escalation of monotherapy, fulvestrant combo, and letrozole combo. We also have opened our dose optimization cohorts specifically for the fulvestrant combo. We should have a relatively large body of evidence by June of this year to speak to the response rate across dose levels in our combination cohorts that have essentially deep pharmacodynamic activity. We have strong target engagement. We're seeing emerging clinical responses, and we're optimistic that that's going to convey to a good response rate. We probably still won't have a lot of data for time to event endpoints even at ASCO.
So our intent is to have another data follow-up at this year's San Antonio to be able to speak to duration of response and progression-free survival from those cohorts.
Great. So some exciting things coming up. Yeah, you've noted that planning is already underway for phase III studies in the first and second-line HR positive breast cancer setting with a second-line start potentially by the end of this year in Q4. So what gives you confidence to commit aggressively to phase III at this stage?
Again, we are seeing evidence of clinical activity in patients who have had prior CDK4/6 exposure, and we're seeing that with what we believe is favorable differentiation in terms of the hematologic toxicity compared to available therapies, so again, we think that this molecule does have the promise to improve both efficacy and safety, and therefore, in consultation with our investigators, we feel comfortable moving into a later line opportunity where the magnitude of unmet need is larger, and then we also are willing to make that logical step that giving greater potency against the target, giving a more favorable safety profile that we think we can show head-to-head superiority in a front-line setting as well.
Got it. And then if we could move on to kind of some of the other assets in your breast cancer franchise, you mentioned briefly that you have a CDK2 inhibitor, also a B7-H4 ADC that are also being developed for breast cancer. I think right now they're in monotherapy dose escalation. Right now we know so far they have expected PK, no DLTs. When can we actually expect to see some more substantial data updates from these programs?
So we'll share data. It is our intent to share data from both of these programs at this year's ASCO. I'm hedging around the language because, of course, we're waiting for the abstract disposition, but we're quite hopeful given the strength of the data that we've submitted. For the CDK2 inhibitor, that is a partner molecule from Ensem Therapeutics that we licensed because we really like the preclinical characteristics in terms of selectivity and potency. That molecule has progressed very nicely through monotherapy dose escalation. We are seeing a favorable safety profile in terms of hematologic toxicity, which is predicted for a more selective inhibitor. So we're excited to share those data at ASCO. We actually have begun combinations with fulvestrant with CDK2 as well, with intent to also have the triplet combination of CDK2, fulvestrant, and CDK4 initiated by this summer.
We wouldn't have any data from that triplet at this year's ASCO. For B7-H4, that has also progressed nicely through dose escalation. We have observed a few DLTs, so we probably are getting close to our ceiling in terms of the maximum tolerated dose. Nevertheless, we're seeing objective responses across virtually every dose level tested to date. We're very excited about what we're seeing in terms of efficacy across target indications of breast and gynecologic malignancies and are excited to share those data at this year's ASCO so we can talk about it in more detail.
Of course. Do you have an overall strategy for how you're going to kind of position these breast cancer assets as part of your franchise?
Sure. So for the majority of the work right now is focused on hormone receptor-positive breast cancer with CDK4, CDK2. We recently had our global first human dose in a combination study with BCL2. We've also disclosed that we have a KAT6A/B inhibitor coming, so the fundamental strategy for hormone receptor-positive breast cancer is that we think our CDK4 molecule is the cornerstone molecule that can replace CDK4/6 in all patient populations that are currently addressed, so including front-line, including adjuvant, using our CDK4 as a backbone for combinations in later line with CDK2, BCL2, KAT6A/B, perhaps others, and then for patients who are endocrine insensitive, who have progressed to that point, this is where the ADCs will come in, so initially B7-H4, but we have other ADC targets, including bispecific ADCs that we hope to bring into the clinic in 2026 that could also be developed in breast cancer.
Got it. And then even beyond breast cancer, obviously you have so many assets going into the clinic. I kind of wanted to dig a little deeper into a few of them. I know that you have a Pan-KRAS inhibitor, an MTA cooperative PRMT5 inhibitor, EGFR-CDAC, et cetera, et cetera. So starting with the Pan-KRAS, kind of what do you think the advantages are for having this Pan-KRAS approach over a KRAS mutant selective approach, or maybe even a pan-RAS approach?
So our Pan-KRAS inhibitor is an on-off inhibitor, non-covalent on-off inhibitor. So it inhibits both the GTP bound as well as the GDP bound states. The advantage that we think that this brings is that the initial covalent inhibitors that were mutant selective, while they certainly have efficacy, the challenge is ultimately in durability. We think that this type of approach by inhibiting both on and off can improve durability. It also can inhibit patients who have RAS amplifications, KRAS amplifications, which are prevalent in certain diseases as a driver like gastric cancer, but also there's data to suggest that they are a potential mechanism of resistance to covalent inhibitors. Now, from there, we think that having selectivity for KRAS and not having inhibition of HRAS and NRAS is likely to convey a better safety profile, better tolerability that will enable us to have greater potency against KRAS.
That molecule is now in the third dose level dose escalation, progressing really, really well. High investigator demand to participate in a study given unfortunately the large magnitude of unmet medical need for patients with KRAS mutations.
What indications will you be focusing on initially?
The initial indications, perhaps unsurprisingly, will be colorectal cancer, pancreatic cancer, and lung cancer, but certainly would be interested in moving into other less common tumor types with oncogenic KRAS mutations from there.
I see. And then moving on to your MTA cooperative PRMT5 inhibitor, I'm a little curious, how do you think that you're differentiated given that there are already a couple of competing assets in the clinic?
So we're very excited about the preclinical characteristics of our PRMT5 molecule. We believe that our molecule has the best combination of potency, selectivity, with CNS penetration. And we think that that combination of attributes is really critical for success. Again, early days, but we are progressing through early dose escalation. We are happy with what we're seeing in terms of both safety and PK. Won't be able to disclose at this year's ASCO, but we do think that we have a very potent and selective molecule that is also CNS penetrant, which is really important for indications like non-small cell lung cancer. And as further proof of CNS penetration, we also have intent to develop in GBM.
Now, as we were preparing for our dose escalation, our research team was continuing to do more preclinical research, looked at combinations with PRMT5 with MAT2A, and preclinically we saw extremely high synergy scores because that's hitting two targets in the same pathway. And therefore, we in-licensed the MAT2A inhibitor from CSPC. Again, we like that molecule because of potency and selectivity and the potential for CNS penetration. With the recent termination of the Amgen IDEAYA collaboration for the combination of PRMT5 and MAT2A, we really think that this places us in a leading position to explore that combination clinically. Both the MAT2A inhibitor and the PRMT5 are in early dose escalation, and it's our belief we can start testing that combination clinically this summer, probably in the third quarter.
So when we see initial efficacy data, is it going to be from the combination? Is this kind of your strategy going forward?
So it is our expectation that both components will have activity as monotherapy. So we will look to share data for both components as monotherapy, but also with the belief that combination could be better than monotherapy in essentially all key indications.
Got it.
A quick follow-up. So Amgen and IDEAYA, as you mentioned, did not make it. What do you think the issue is and where is your differentiation? Is it a question of potency?
Yeah, so my understanding of what's been publicly disclosed is it related more to the dynamic of IDEAYA having disclosed an in-house PRMT5 and the capacity to develop that combination fully internally. Again, I would highlight that we believe that we're in a position that we'll be the leaders and again, with our operational advantages, we fully expect to maintain our lead mover advantage. When you look at our preclinical data, and we've shared some of this publicly, we have a molecule that we believe is meaningfully more potent than the Amgen PRMT5 that's in the clinic. Again, the clinical data will tell the tale, but we look forward to sharing that clinical data in due course.
Maybe any questions from the audience? Go for it.
So you mentioned for your CDK4, we are going to get "a good response rate." Can you tell us what, in your opinion, is a good response rate?
Maybe we'll just repeat the question.
Sure. So the question is, what are we targeting in terms of efficacy with our CDK4 at the upcoming disclosure? So I think that there are benchmarking data sets that are available. So abemaciclib has published data in the CDK4/6 pretreated patient population. Actually, there's data for abemaciclib in the postMONARCH study in the CDK4/6 pretreated patient population. So both of those data sets yielded an objective response rate of about 30%. So we're using that to benchmark where we will land. And again, the data are emerging right now. So I'm sitting here today, don't know what the number will be, but sharing our target with you.
I'm going to maybe ask a quick follow-up on B7-H4. Can you talk about your payload and are you looking at patients who are previously failed in other ADC that is topo based? And then you mentioned you are seeing responses. Can you maybe talk about that a little bit? So it's essentially doing topo-topo.
The platform for the B7-H4 molecule, this is the ADC that we in-licensed from Duality Therapeutics. It's the Duality Linker Topo I payload. It has a DAR of six. We have been focusing, it's not a requirement in the protocol, but we have been focusing on patients who are Topo I ADC naive, independent of the target. We are hearing investigator feedback that Topo I after Topo I might be of limited clinical efficacy, again, independent of the target administered. We are focused on patients who are naive to Topo I for the development programs of this B7-H4 targeting ADC. To date, we have not been selecting patients based upon B7-H4 expression. What you'll see from us at ASCO will be the phase I dose escalation, which is an otherwise unselected patient population of B7-H4 expressing malignancies, including breast, gynecologic indications, and cholangiocarcinoma.
And in that population, you are accepting prior ADC therapies. So you might have some patients that have seen a Topo I ADC previously?
We may have some. Again, my expectation is most of the patients will be naive to Topo I. Both also because of investigator selection, right? They want to choose investigational therapies for their patients that they think are going to give the patient the best opportunity for benefit.
To go back to CDK4, as you think about a phase III trial design, is that going to be in second line initially, or would you move into first line? And when you're thinking about going head to head against a CDK4/6, is it a plain vanilla CDK4 versus CDK4/6, or is it going to be in combination with another novel agent?
We will have data to inform a phase III start initially in the second line setting. Those are the data that are maturing right now. They will mature faster given the greater unmet need in that patient population. So yes, our expectation is our initial phase III start will be in a CDK4/6 pretreated patient population. Now, for our ongoing phase I study, that study is operationalized in parts of the world that do not have effective market access to CDK4/6 inhibitors. Therefore, we do have cohorts of patients who are enrolling who are CDK4/6 naive. That data set will give us confidence to move into the first line setting, which really we believe is the key opportunity for these molecules. As you said, it will be a straightforward substitution design of CDK4 plus non-steroidal AI versus CDK4/6, likely investigator choice of CDK4/6 versus non-steroidal AI.
We're open to next generation ovarian suppression molecules like SERDs, what have you, but the data simply aren't available in the front line setting yet, so that will be ultimately a data-driven decision once the data sets become available.
As you think about the second line strategy, I think Pfizer is running head to head against everolimus. Maybe talk about their trial design and your thoughts on that strategy.
Their study is an investigator choice of either fulvestrant or exemestane plus everolimus. We've received some feedback on that study insofar as does it fit with global standards of care. We are thinking about some alternate designs for a later line study, additional combinations, or other standards of care that could be in the control arm that might make it a bit more, shall we say, compelling and reflective of global standards of care, particularly here in the United States.
Another question from the audience. This is your chance. Go for it.
So once we get this data at ASCO, and this is best guess, how long before we could see this drug approved and on the market? I know it's probably going to be approved first on the later lines. Is that the easier path?
You know, we have certainly modeled that. I think it's a little bit early for us to say because there are a number of milestones that we need to complete. So again, we're working on our Project Optimist requirements, but we need to make sure that our dose selection meets the needs of global health authorities. We haven't fully landed what our control arm for the study would be in a second line in the patient population. So this is something we could come back and give a more clear answer perhaps in a year's time.
Yeah. Going back to the rest of your pipeline, can you describe your EGFR- CDAC program, how it's differentiated, why you're excited about it?
Thank you. So we're very excited about our degrader platform in general. We have very compelling data with our BTK degrader. We're starting two phase III studies this year. The emerging data with our IRAK4 degrader also looks really good. So our third degrader to enter the clinic is an EGFR targeting degrader. And as an aside, there are many more degraders to come. We have 14 preclinical programs right now working on different degraders. So we're very excited about both the potential of degraders as a technology and also specifically our internal platform. Now, with BTK, we know that it's safe to degrade all of the patients' BTK. EGFR, you would not want to degrade all of the patients' EGFR because that would cause unacceptable GI and skin toxicity.
Our molecule was designed to have selectivity for EGFR mutations occurring in exons 19 and 21, so lung cancer driver mutations, while not degrading wild-type EGFR. This was a tricky molecule to design to have both that selectivity for mutant over wild-type, but to also have broad coverage over a number of different mutations across those key exons for non-small cell lung cancer. We believe that this is a first-in-class investigational therapy. Again, we intend to make sure we maintain a leading position with this target. It's very early days in terms of clinical investigation, but we're really excited about what we're seeing in terms of safety and PK so far. We look forward to sharing those data in due course so people can share in our excitement.
Mark, do you think we're going to see data, it sounds like, this year from both the IRAK4 and the EGFR?
I don't know about the IRAK4. The tissue testing insofar as IRAK4 degradation in the target tissue of skin, that's ongoing. I don't know what the publication plan is for that molecule. EGFR, it's really early days, but we'll look for the earliest opportunity to share data.
Maybe on the IRAK4, what is the strategy? That's obviously one of your leading INI programs.
I'm sorry, you're on. I'm not the best person to speak to IRAK4.
Maybe I should ask Aaron then to comment your thoughts on timing, maybe.
I mean, I think this is, as Mark said, timing is data dependent. We're in the clinic. We're testing on patients. Obviously, immunology is an extension of our strategy. We are an oncology company, but there's obviously tremendous synergies between oncology and broader immunology. And we look forward to prosecuting these programs. Obviously, particularly this one, leveraging the degrader capabilities that we've established. It's a program we're certainly excited about.
Okay. I know we're out of time, but maybe I'm going to ask one important final question. The pipeline is impressive. And this is arguably one of the best, if not the best oncology pipeline in the industry at the moment. You have plenty of bandwidth to invest, but not unlimited. And we're talking about multiple phase IIIs, which they do tend to run and be costly. Is this something you can all do in-house, or is this something you ultimately partner?
No, thanks for the question, and I always speak about running our business with a dual mandate. It's about investing for growth. We are a growth company, but doing so in a sustainable way. Having such a great and prolific pipeline, that's a strength that any business in our space would want that. I think as we run the business, we're doing so with leverage, as we've talked about. Our top line is growing at factors ahead of our bottom line, which leads to strong operating leverage. As you think about the clinical investment, that obviously provides headspace to be able to do that. We are running a portfolio, so we have late-stage assets that are rolling over, which will provide headspace for our emerging early-stage pipeline, and we've talked about being in a very fortunate position where our pipeline is effectively fully owned. That creates optionality for partnerships.
We've talked about inbound with great assets like our MAT2A inhibitor, which we brought in in combination with external science that really can work in combination with assets that we're excited about internally. But we've also talked about, and really it's embedded in our DNA, about being open to collaborations that maximize the value of both the assets and obviously maximize shareholder value.
Terrific. Aaron and Mark, great seeing you as always with Liza and Dan. Thanks so much for coming. We appreciate it.
Thank you.
Excellent. Thank you.