All right, good afternoon, everyone. It's the post-lunch panel, BeOne Lyric Healthcare Conference. I'm Andy Beren, Senior Biotech Analyst, and we're very excited to have BeOne with us. Thank you for joining us, gentlemen. We have Marc Lanasa, CMO, Matt Shaulis, General Manager of North America, and then Aaron Rosenberg, CFO.
Great, thank you.
Feel free in the audience to ask questions. I have a prepared set, but definitely will welcome any questions from the audience. Why don't we just start with a general overview of the company? I mean, you've obviously changed a number of things over the last 12 months. Momentum seems to be growing amongst investors, clearly, as Brukinza continues its successful launch and the company's footprint is expanding more internationally. Maybe we can just start with a general overview of the company. I don't know if you want to take that one.
Yeah, I'll start there. First, thanks for having us today. As you said, there's been a lot of great things that have been happening with the company. Our company was founded in 2010. It was founded under the premise and mission to bring innovative medicines and oncology to more patients around the world. As you said, we built a business model that's really designed at its core to be able to do that effectively in ways that the pharmaceutical industry has failed to meet in the past. I think 2024 demonstrates that vision coming to reality. You mentioned so many of the factors in which we delivered in 2024.
It starts, of course, with Brukinza, which is now the leading BTK inhibitor in both the first-line and relapse refractory setting in the US and is growing incredibly well outside of the US and really bringing this differentiated medicine to patients all over the world. That serves as our foundation for our hematology franchise. I'm sure we'll talk at length about those opportunities with sonrotoclax, our next-generation BCL-2, as well as our BTK degrader.
As you mentioned, continued incredible advances in our solid tumor portfolio, which Marc, I'm sure, will spend time talking about today, 13 NMEs into the clinic in 2024, and a number of really exciting programs with potential proof of concept readouts in 2025 and 2026, which really highlights we talked about what makes us different, really building a fully in-house clinical organization that could bring new medicines through to proof of concept in a fundamentally time and cost-advantaged way. All of this is showing in our financials. 2024 showed 73% product growth.
We're really focused on driving growth with sustainability, a focus on driving operating leverage, three consecutive quarters of non-GAAP operating income, full year 2024 adjusted operating income, and two consecutive quarters of cash flow from operations generation as we close the year, which then really informed our guide for 2025, where we see revenue of $4.9 billion-$5.3 billion. The business is really delivering across the board, and we continue to globalize. You mentioned some of those examples. As you think about our revenue base, we're now more than 60% in the US and Europe in total, 55% in Q4 for the US and 10% in Europe. We had made a number of other key milestones in 2024. We announced our plans to re-domicile to Switzerland.
We announced our planned name change to BeOne Medicines, which really strikes at our core mission of being one with the oncology community and bringing our medicines to more patients around the world. We continue to globalize our infrastructure. One of our flagship moments was the opening of our biologics facility in Hopewell, New Jersey, in July 2024. It is really exciting across the board and really sets ourselves in a position of strength as we enter 2025 and beyond.
Great. No, very impressive. I have followed you guys for quite a while, obviously, and definitely have always been a fan of what you guys are doing. You invested very heavily in China, obviously, and the infrastructure. Now you are at the cusp of being a profitable company. Congratulations on that. How important do you think that is outside of the US? Like in China, I know for a while you could not even list, have a public listing unless you are a profitable company. Do you think that that is a really big—I mean, it is a big milestone for any company, but is it really a big milestone if you are listed in the Shanghai and the Hong Kong indices?
We're already triple listed, as you know, with our A-shares, our Hong Kong listing, and the US market. I really would focus this strategically on what we call a dual mandate. This is how I refer to it. We are a growth company. We're investing for growth. We're doing so in a disciplined way to ensure that we're getting a high ROI on every incremental dollar we're spending. That's translating to this operating leverage that we talked about, including our 2025 guidance of GAAP operating break-even income and GAAP cash flow from operations. At the same time, we fulfill that growth mandate. It is very important to us that we do so in a sustainable way. We're balancing that quite effectively as we think about running the business.
Right. Okay. Definitely the engine right now, and we'll talk about some of the other engines, is Brukinza. What has led the commercial success of Brukinza? I think it now is the market leader, the BTK agent, surpassing Calquence for the first time this past quarter. What have you guys done that has allowed that success?
Sure. I'm happy to address that one. Maybe the point to pick up on is what Aaron mentioned a little bit earlier about operating from a position of strength. We're really pleased with the performance that Brukinza has had. We have over 50% new patient start share in CLL. This means that with patient stacking over an extended duration of therapy that sort of approaches three years, we'll continue to make strong progress in value share because of that effect. In fact, we were able to overtake Calquence in the fourth quarter in total dollar sales in the US We have approvals and launches coming in the EU and in the rest of the world.
All of this is based on that position of strength that comes from the molecule, its selectivity, its potency, the 24/7 inhibition that we think is really driving a clinician preference for the molecule. That extends into all five of the indications that Brukinza has in the US I think the foundation of the clinical support for the molecule comes from the head-to-head study, a superiority design versus ibrutinib. We think that is going to continue to be a source of driving new starts.
Right. There's been some concern about some of the data presented by AstraZeneca with the fixed duration combination therapy potentially eroding into the Brukinza success. You guys do have your own fixed duration program running, but it's a couple of years behind. I guess I know you've actually provided a lot of data analysis of what they—I think it was the Amplify trial. What can you say to investors that might be worried that Brukinza is going to face some erosion from this fixed duration?
Sure. I think we can sort of start out by saying that in the long term, we believe in fixed duration. We believe that that's a good treatment alternative for patients, for them to get a break from their therapy. Ultimately, we believe that the current treatment options today don't realize that promise of truly giving the break in therapy with what really is necessary to be successful in that setting, a really strong MRD, strong efficacy in PFS, and then strong safety as well. The first thing to do is really look at the patient populations where this should be evaluated and could be appropriate.
We see that in ven-based treatments in general in that treatment naive setting, patients that have high-risk molecular factors like unmutated IGHV that are 40% of treatment naive, that have TP53 about 10% of the treatment naive setting, and then also del(17p), another 10%, they tend to have poorer outcomes. That is not an ideal setting to use or an ideal molecule to use fixed duration. When we look at Amplify, again, we need three things: MRD, efficacy, and safety. The Amplify results were underwhelming. MRD was right around 34%. Their PFS at 36 months was 76%. They had increased grade three, four infections and hospitalizations.
This is all in a patient population that was younger on average, a mean of 61 years old versus about 71 for treatment-naive CLL in general, excluded those high-risk molecular factors, and then also had a relatively low comorbidity burden. You would have expected stronger results but did not get them. You mentioned some of our own molecules. On the other hand, part of the reason we believe so strongly in fixed duration is that we have seen very promising results with Sonro plus Xanu, also in that treatment-naive setting. In the case of the studies that we are working on, Celestial in particular, our global phase three, that is in an all-comers population. We did not pre-select heavily for some of those more favorable patient factors. In our phase one, we had a 91% MRD.
We are really excited that we believe that that regimen and the work that we are doing can realize the promise for patients of getting that break from therapy but having MRD efficacy and safety along with it.
Right. How far behind do you think you are from AZ on potentially having registrational data?
Yeah, I don't know, Marc, if you want to comment on timelines there, but we still feel pretty good about it.
Sure. We have completed enrollment in the phase three treatment-naive CLL study, the Celestial study. We enrolled almost 700 patients in 14 months. The control arm in that study is different from Amplify. The control arm is venetoclax plus obinutuzumab, which we think is a stronger, more relevant contemporaneous control. It will take time for the PFS events to accumulate. We actually haven't provided guidance insofar as when we expect the primary readout. We need to get a sense of how the events are reading out, and then we'll provide future guidance. Suffice to say, it will take a sublimited number of years for us to get to the PFS endpoint. We will have the MRD data in approximately one year's time from now as we complete the first year of follow-up on the full enrolled patient population.
I think that the study also provides a really great example of how quickly we can move with quality in terms of the clinical operation space. Fundamentally, we have controlled what we can control in terms of the timelines. We have enrolled the study very quickly, and now we will just wait for the data to mature.
Right. When I think about it, I mean, if a physician feels more comfortable with Brukinza than Calquence, that's become their BTK of choice. Why? I don't think the payers are going to push back stopping the drug. It's less expense for them. Why would a physician not just substitute Brukinza in that protocol, maybe with Venetoclax until sonrotoclax is approved? Do you think that it's really that much of a leap to combine those two and do the same protocol with the BTK that you're more?
There has been a clinical study called the Bowen study combining Zanubrutinib with Venetoclax. Those data are published, and the MRD rate was in the mid-50%. I want to be clear, we're not promoting off-label use. We have run a definitive experiment, a phase three study that will provide the necessary evidence in terms of both benefit and risk for that regimen.
Right. The only thing I'd add on an unrelated matter is we have two phase two trials that should be reading out, one in relapsed refractory MCL, one in relapsed refractory CLL in China. Both could potentially support accelerated submissions in those respective jurisdictions.
Okay. Okay. When I think about the fixed duration therapy, I mean, I could see why it would appeal to somebody in their 60s. If it's somebody 75, 80, it sounds like the first 18 months are a lot tougher, right? I mean, the quality of life, even with your regimen, is probably going to be a little tougher than taking an oral BTK. I guess it's not going to appeal to everyone. For those that want it, it's nice to have it. For the younger patients that don't want to be on the drug for the rest of their life, it's obviously nice to have it.
I think one of the points about made insofar as what would we look for in terms of a fixed duration regimen, part of the idea conceptually is that by having that period off treatment, that you should be free from the risks of therapy associated during that period. However, that should convey that that upfront period is not very difficult in terms of safety. And when we look at the Amplify data, what we see is there is actually a fairly high rate of grade three adverse events, primarily driven by neutropenia, relatively high rate of down-dosing, dose interruption, certainly more than what one would expect for BTK monotherapy. So we do, exactly as you're saying, think that remains to be a really attractive option for many patients.
Right. Okay. The other, I mean, it potentially has broad implications for subsequent therapies. I mean, you guys have your own BTK degrader, which we can probably talk about in a minute. I mean, there's some non-covalent BTK agents. I guess if patients are not on the drug, would you expect the resistance when they relapse to be different than what you would see on a patient that's continuously on BTK? I mean, is there any data to suggest what a fixed duration therapy might look like at relapse?
I personally am not aware of any data insofar as the comparative mutational profile of patients who receive fixed duration and then later relapse versus somebody who progresses on a BTK inhibitor. For the patient who was on a fixed duration therapy, certainly you could retreat with that same combination. That's something that we think about in a future state for the combination of Zanubrutinib and sonrotoclax is the ability to retreat. You could go on continuous exposure BTK, or you could go on to a degrader. I think what we're trying to accomplish with our B-cell malignancy franchise is optionality. By having the potential for in-portfolio combinations, we will, within our portfolio, have an attractive second-line option regardless of whether you had continuous therapy monotherapy or fixed duration combination therapy as your first-line treatment.
Right. Okay. Where do you see, I guess, the BTK degrader program fitting in? I know we've talked to you guys before, and you actually think it could fit into as a front-line therapy. In that setting, what's going to be important, I guess, it either has to have better efficacy, but maybe even more important could be quality of life. It's the safety, tolerability, ability to combine with the BCL2 for if you're going to go fixed duration. How do you think that drug will be positioned in the treatment paradigm?
Of course, we're going to start in a later line patient population because that's where the unmet need is today. There is a defined regulatory path to move forward. We're very excited about the data that we shared at ASH in terms of both response rate and durability. That gives us confidence to start two randomized phase three studies with our degrader this year, one against current standard of care that will start in the first half, the other against pirtobrutinib that will start in the second half of the year. Importantly, we're also starting a multi-cohort or an umbrella study to combine our degrader with zanubrutinib, to combine our degrader with sonrotoclax, to combine with a CD20 by CD3 bispecific antibody.
The idea here is that after these Phase IIIs, that will give us an evidence base that will allow us to move the degrader forward into earlier lines of therapy given the potential of that mechanism. We do think that that mechanism can be complementary with a BTK inhibitor. The front-line standard of care, Xanu, is very strong. In Sequoia, our five-year PFS rate is 78%. Such a study would take a very, very long time to conduct and read out. We are going to generate evidence in that treatment naive patient population and at least start to learn what a combination could deliver there.
Okay. How does that agent, 16673, compare versus the Nurix one, I guess? What, 2127? What do we know is different in the two molecules?
We have a lot more data than the Nurix molecule. We've enrolled over 500 patients and provided data for CLL, mantle cell lymphoma, I'm sorry, indolent lymphoma, including Waldenstrom's macroglobulinemia at ASH. We think the clinical data compares favorably in CLL in terms of response rate and Waldenstrom's macroglobulinemia in terms of response rate and time to response. We think it's a combination of both having a lead-mover advantage with the strong operational capabilities that we have that we can continue to move and leverage that first position that we have. We're also very confident in the characteristics of the molecule that it is a best-in-class molecule as well.
Right. Okay. Yeah, no, you're obviously very heavily invested in the heme franchise leveraging Brukinza's success, so not resting on your laurels, which is important in this market. I guess why don't we switch gears to some of the early compounds? We only have 10 minutes left. I know a lot of people have excitement, enthusiasm around the CDK4 program. What can you tell us about that molecule and how it compares to the ATERMO molecule that Pfizer has?
The preclinical hypothesis is that when we look at the substantial impact that CDK4/6 inhibitors have had for patients, for women with hormone receptor-positive breast cancer, it turns out that most of the cell cycle inhibition is derived from the CDK4 inhibition, whereas much of the heme toxicity is driven by CDK6. Therefore, by developing a more selective 4 versus 6, you can have greater potency against 4 while dialing back the 6. I.e., the potential is you could improve both efficacy and safety. We have generated a lot of evidence in a short period of time.
We have enrolled something like 180 patients in the first 14 months since our first human dose, not only in monotherapy, but in combination with fulvestrant to give us line of sight to a CDK4/6 pretreated patient population, but also with letrozole to give us line of sight to a front-line phase three population. Atirbiciclib did enter the clinic over three years ahead of us. Given the pace of our front-line study, we think we've substantially shortened the time gap between us. They recently announced their first patient dose in their front-line phase three study. Ultimately, that is our aspiration for the molecule to get to a front-line study. We are also exploring second-line registrational opportunities that could begin as late as later this year. Pfizer has taken 300 milligrams of atirbicycline forward into registrational studies.
We have talked about that we have been able to dose escalate beyond that dose level. We think that ultimately we are going to be able to achieve greater potency against CDK4, which we believe is related to the greater selectivity for 4 over 6 that our molecule has compared to atirbicycline. We are going to have a data disclosure at the upcoming ASCO where we will share our first efficacy data for our molecule so we can talk in a bit more specifics about how our data is emerging.
Right. Those are impressive enrollment rates. I mean, how can you enroll the trials that quickly? Is a lot of it in Asia or it's global?
Actually, it is a global phase one study. I think that this also, again, like Celestial, reflects the operational capabilities that we have built in-house, the deep relationships that we have with key centers and investigators around the world. The study was enrolled 80% ex-China. The leading country of enrollment is the United States. The leading center was MD Anderson. Those statements were true at least of a month ago. I believe that they're still true today. The majority of enrollment has come in the United States, France, and Australia. We have also operationalized the study globally in countries that do not have effective market access to CDK4/6 inhibitors, countries like Brazil and Indonesia, where we can generate a body of evidence in a CDK4/6 naive patient population to give us confidence to go into that front-line Phase III study.
Okay. Have you announced an oral cert or any sort of estrogen therapy molecule at this point?
We have not. We are combining, again, with non-steroidal AI, letrozole for front line and fulvestrant for second line. Certainly, we're following that space with great interest. We expect that the certs are going to start reporting data in the front line space. Clearly, the cert molecules, the oral certs, have substantial activity in the ESR mutant population, which is a really important subset of the CDK4/6 pretreated patient population.
Right. Okay. That's exciting. I know we only have a little over five minutes left. There's been a lot of enthusiasm in the ADC field. You guys have a lot of molecules in development. It seems like you've kept those programs pretty close to the vest. What can you tell us in terms of the targets that you're pursuing, the construct, the payload, the linker? Anything you'd want to share with us?
Sure. We have an internal portfolio of ADCs. The first group of ADCs are monovalent ADCs. They all have the same topoisomerase payload, which is an internal proprietary. We have internal technology around our linker and site-specific conjugation as well. The initial targets for our internal portfolio are B7-H3, CEA, and FGFR2b. Those molecules are progressing well through phase one development. We look forward to sharing some clinical data. We in-licensed an ADC from Duality Therapeutics targeting B7-H4. We've disclosed that we intend to share first data from that molecule at this year's ASCO that entered the clinic before our internal molecules. In due course, what you'll see from us is that we're very interested in moving from monospecific ADCs to bispecific ADCs. Two different targets for the ADC should facilitate internalization and delivery of the payload.
Our third wave will be novel conjugates. We are actively investigating different things that can be conjugated to an antibody framework, for example, degraders or transcription factors, other non-cytotoxic payloads.
Okay. That's exciting. We will see some data this year from those programs, the ADC?
Can't commit today, but likely, yes.
Okay. Great.
We will see data on the B7-H4.
B7-H4, yes, we intend to share at ASCO.
Right. Okay. Great. You have also got an MTA-cooperative PRMT5 inhibitor, which has become an area that there was a lot of enthusiasm, I guess, a year ago. There has been a little, I guess, some of the data sets have deteriorated that we have seen from some of the other molecules. Looks to us like the Bristol-Myers Squibb drug and maybe Tango have the more potent ones versus the Amgen one. What can you share with us about the PRMT5 program?
Yeah, I acknowledge the point that you're making. Our view is that our molecule was designed to address certain limitations of the other molecules that have already entered the clinic. We think that those limitations might be becoming evident in the clinical data sets related to either challenges in potency, challenges in PK, or limitations in CNS penetration. Our PRMT5 was designed to be highly potent, highly selective, and CNS penetrant. It meets all of those characteristics. It's entered the clinic. It's off to a good start. We're currently in the second dose level of dose escalation. It entered in the fourth quarter of last year. We're very excited about that target. Now, concurrently and preclinically, we were doing experiments and found that there is very high synergy preclinically between PRMT5 and MAT2A. Because of that, we in-licensed a MAT2A inhibitor from CSPC.
The reason why we like that molecule was, again, potency, but also CNS penetration, which we think is important. We are intending to actually initiate combinations of PRMT5 and MAT2A in the third quarter of this year. That molecule also has an ongoing phase one study. We think we'll be able to bring those two molecules together, continue to explore monotherapy, and then start to explore the combo, which potentially, based on preclinical evidence, could be better than monotherapy.
Right. Yeah, I mean, we've seen, I mean, Bristol, I thought, had some pretty good durability, at least in one cancer. It was over 10 months, which was pretty good.
Yeah.
As a monotherapy. Do you believe that by blocking MAT2A, you're going to decrease the resistance to the PRMT5? It prevents the shift away from MTA towards SAM. Is that the hypothesis?
Exactly. The two are ultimately there's a mechanistic rationale that predicts the clinical synergy. We do think that the ratio of the two components may ultimately be important. We look forward to testing that. We also think that it's important to have these potent molecules so that that could enable higher order combinations, potentially with immunotherapy, potentially with current standards of care such as chemotherapy, particularly in lung cancer and other indications where MTAP deletion is common.
Right. Okay. We look forward to seeing that. The whole space, I think there was quite a bit of enthusiasm, especially with the acquisition, Mirati, and the CVR. It seems to have died down a bit amongst investors. Hopefully, the new data sets will reinvigorate that. I guess lastly, just any comments about your EGFR program, the degrader, what's the strategy there?
Yeah. Continuous unbridled optimism today. Yes, we're very excited about the potential of an EGFR degrader. This is a first-in-class novel mechanism that provides opportunity to much more broadly degrade resistance mutations, but also provides good coverage of the initiating mutations in EGFR. This is, again, an exciting and novel mechanism that we think makes a lot of rational sense because it also, through the deletion of the scaffolding function, has the potential to also provide some coverage to bypass mutations as well. That molecule also, again, is in the second dose level of dose escalation, is progressing well in early phase investigation. We'd love to share data as early as possible. We just want to be able to tell a good story around the science of the molecule.
Right. That is great. We just covered just the tip of the iceberg on a lot of the programs. There is going to be a lot of data coming in the next 6 to 12 months, it seems like, from some of these programs.
Absolutely. Exciting times.
Let me see if there are any questions from the audience. Any questions for BeOne, formerly BeiGene? I still do not think everyone is aware of the name change.
The name change on our redomiciliation will be complete, effective in the first half of this year, subject to shareholder vote.
Right. Okay. All right. Thank you, everyone, for joining us. Thank you, BeGene.