My name is Michael Schmidt, Senior Biotech Analyst with Guggenheim, and it's my great pleasure to welcome Aaron Rosenberg, CFO of BeOne , as well as John Scott, Head of Strategy. Welcome. Thanks for joining us.
Thank you for having us.
There are a lot of exciting things happening at BeOne Medicines. BeOne is one of the fastest-growing large biotech companies, in my view, and this is the first year in its history, really, that the company has reached profitability. At the same time, BeOne has one of the deepest product pipelines in the industry. If we maybe step back for one second, Aaron, what are the key competitive advantages of the platform as you see it?
Great. Thank you again for having us. We could probably spend the entire time, I think, talking about the differentiating features of BeOne Medicines. We will focus on a few. I think what we often point to is our fully integrated CRO-free clinical development organization. Clearly, we have incredible discovery capabilities. You see that in action in our performance, putting 10 internally developed NMEs into the clinic in 2024 and 16 since that time to date. Clearly, we have that capability in basic science. What we recognized upon our founding was the critical importance of clinical development in terms of realizing the value of that innovation ultimately to the patient. Core to our mission is this focus on access, global access, and in fact, to many parts of the world that typically the industry does not serve.
We looked at how do you solve that problem. It was recognized how much expense and development and time goes into the clinical development process. I think we often talk about 70% of the cost to develop medicines is in the clinical development process. To solve that problem, the company invested in a vertically integrated clinical development organization that has now more than 3,600 clinical development professionals. Now that extends to our global manufacturing capability. The value of that is our ability to take our inventions and bring them to market with incredible speed and time advantages. Just to bring it to sort of what does it mean in practicality, I think we point to a few examples.
We can look at some of our really exciting solid tumor candidates, say, our CDK4, where I think when we look at this program, we started maybe three years behind competition, give or take. Now we've closed that gap as we've announced our intent to go with our first line pivotal trial in the mid-part of next year, maybe cut that down to about 15 months. We look at our Celestial trial in treatment-naive CLL for cyanoplasmia. We enrolled that study in about 14 months from start to finish. You think about what really matters in this industry, that's being able to develop your medicines with incredible time advantages. We're seeing that in action through that capability.
Right. Obviously, it's a super efficient development platform. You also have been very successful commercially, though. Brukinsa, your anchor product in a way, has now captured sort of the leading market share in the BTK inhibitor market. Yeah, maybe let's touch a bit upon that. What is driving Brukinsa growth right now in this stage of its life cycle?
Sure. I think when you talk about Brukinsa, it starts with the medicine. This medicine was designed from inception to be fundamentally different with 24/7 target inhibition. Ultimately, that design has played itself out in the incredible differentiated data profile. We're really excited to share a lot at the upcoming ASH, one of which is the 72-month data, a Sequoia data, which really shows how durable Brukinsa is in terms of sustained PFS with 74% landmark PFS, 77% on a COVID-adjusted basis. This is really unprecedented. When you think about particularly CLL, the importance of sustained long-term PFS for patients, because this is an indolent disease, and often you look at other medicines in the class, both existing and emerging, it's really two to three years, it's just not enough to see that sustained durability of the mechanism.
We're seeing that with Brukinsa in a fundamentally differentiated way. What does that mean? That's translated to its impact for patients and what's happening in the real world with prescriptions. What's driving Brukinsa? Clearly, we're doing incredibly well in the United States with 47% growth on a year-over-year basis. In our most recent report, more than 40% volume. We are the leader within our China business from a market share by far. We're really in the earlier days of launch globally. You think about in our European business, where we grew 71% on a year-over-year basis much earlier in the product launch cycle, where we're growing share across all the major markets. There are many markets around the world where we're much even earlier in launch, and we're seeing incredible growth.
We're really excited about Brukinsa, what it's doing for patients, and what it means for the long-term sustainability of our franchise. Obviously, this is the foundation of our CLL franchise. I'm sure we'll talk more about our pipeline assets, but this is really where it starts. We're really pleased with the performance and ultimately what this medicine is doing for patients every day.
Great. As we think about the CLL market longer term, and especially around market dynamics, how will the potential increased uptake of fixed duration regimen affect the market opportunity longer term? Maybe stepping back, how do you think about fixed duration treatments in general in the CLL space? Do you expect them to gain more uptake? If so, how will it affect the market overall?
Sure. Why don't I start, and I'll invite John to jump in as well. First and foremost, we're big believers in finite treatments. We do believe that they need to meet four specific criteria. We've talked about this a lot in our various discussions with investors. First is to have a deep response measured through UMRD. The second is to have deep and sustained PFS, and really looking at continuous use Brukinsa as that benchmark. We just talked about the 72-month SEQUOIA data. The third is having a safety profile that's no worse than what you can get today with continuous use Brukinsa. That's obviously a very high benchmark. Lastly, when you're talking about fixed-duration therapy, it's having the convenience effect. What we know is while VEN is a very effective medicine, it's actually very difficult to administer.
That has really limited its uptake. When we look at existing offerings for fixed-duration treatment with respect to VEN-based treatments, it really does not meet the mark across any of those four variables. We are really excited, of course, about our potential combination with SONRO plus Brukinsa, which we believe meet all four of those criteria. We could talk a bit more about the data. In terms of the market opportunity, as we come with our treatment around Zanu and Sono, this is really a market-expanding opportunity. This is even before we get into our BDK CDAC. Today, if you focus on the U.S. as an example, continuous use BDKs are basically getting about 50% of the market, of which we are getting approximately half. About 20%-25% is getting a VEN-based regimen. CD20s and chemo-based therapies are getting the balance.
There is a significant opportunity to grow the entire market, to bring an offering that solves patient needs for that fixed dose treatment, as well as the subset of patients that continuous use BDK will continue to be the right offering. Overall, we see this as a market expanding opportunity. What BeOne Medicines is doing is bringing offerings that can fill all portions of the patient journey. Whether you're treatment naive and you're seeking a fixed dose treatment, continuous use BDK, and certainly in the relapse refractory setting, between Brukinsa, SONRO, and our BDK CDAC, we can really fulfill all patient need. That is really what we're seeking to bring.
Maybe I can just add, if we talk about then sonrotoclax and adding on to what Aaron said, if you step back and you think about VEN, it's a great drug, actually. It's nearly a $3 billion drug. It's still growing. Its use, as Aaron mentioned, is effectively capped in the academic setting, primarily in CLL. There are reasons associated with that that have to do with the fundamental characteristics of the molecule and the convenience challenges associated with the TLS ramp-up, the lab monitoring, et cetera, as we all know. When you think about a drug like sonrotoclax, which is our BCL‑2 inhibitor, we essentially designed a molecule that is 14-fold more potent. It's six-fold more selective. There is a half-life of five hours, which is very different from the 26-hour half-life of venetoclax. That's important because there's no drug accumulation.
Number one, we have a molecule that is hitting the target harder. It's doing so with a wider therapeutic index. It's doing so in a way that we hope will enable much broader access outside of the academic setting. That's why we view this as a marketing expanding opportunity.
Right. I'll come back to SONRO in a second. You did mention that you completed enrollment of the Celestial 301 study earlier this year, which is obviously built on some very exciting phase II data that I think you'll update again at ASH. On the earnings call recently, you also announced another phase III study of the same combination, head-to-head versus venetoclax, acalabrutinib. What drove your decision to add the second study?
Maybe I can answer that one. I think when you think about the way this market has evolved, and if you start first with Brukinsa, we have, as Aaron mentioned, an overwhelming body of evidence from human PK to head-to-head trials to real-world evidence that this is the best-in-class BTK inhibitor. Yet, despite all that, there are still some physicians that ask us, well, where is your head-to-head data against acalabrutinib? I think when you think about SZ, which, as you know, we have an ongoing study against VEN, which is the Celestial 301 study that's fully enrolled as of February this year, that is the standard of care in the U.S. from a fixed-duration standpoint. This is a company that is unafraid of running head-to-head trials because we view them as critical to delivering the best drugs to patients.
Fast forward to AV, our view is that ultimately we want to dispel any doubt that could possibly exist in the market that SZ, when it eventually hopefully is approved and used in CLL, is the best regimen against any comparator that exists in the market. That is really the genesis for the trial. Ultimately, we feel very confident about the trial because if you look at the amplified data of AV, they had 34% MRD. What we are seeing in phase I with ZS is 92%. It looks very different. Again, this is due primarily most likely to the characteristics of sonrotoclax, et cetera.
To Aaron's point earlier, our goal is to deliver a fixed-duration regimen that patients and physicians can feel confident enough that they have achieved a deep enough response so when they stop therapy, they can sustain long-term outcomes that are comparable to what we're seeing with Brukinsa, which we really do feel like is the bar. Aaron referenced the seven-year or six-year 74% COVID unadjusted, 77% COVID adjusted PFS. That's our goal.
Right. Super helpful. Maybe just one more on the CLL space. You talked about the value of the long follow-up you have on the Brukinsa data, the multitude of trials that are ongoing, fixed duration, et cetera. As we think about non-covalent BTK inhibitors entering the space, how do you think that will shape the landscape?
Yeah, maybe I can take that one as well. We are all aware of the BRUIN 314 study, which is the pirtobrutinib head-to-head against ibrutinib that was in the ASH abstracts. Just keep in mind, this was a mixed population study. About two-thirds of it were relapsed refractory. One-third was frontline. When we look at the data, particularly on the relapsed refractory setting, we compare those to our data, which is zanubrutinib against ibrutinib in the Alpine trial, in which we demonstrated head-to-head superiority on PFS. If you look at their data at 18 months follow-up, they have about a 9% delta in response rate versus ibrutinib. If you look at our data, again, cross-trial comparisons and all the caveats that go along with that. If you look at our data, our delta versus ibrutinib is about 12% on response rate at roughly similar follow-up.
What's most interesting is if you look at the deletion 17p subset, which are the most aggressive clones, these are the clones which arguably require the deepest level of constitutive BTK target engagement. They had virtually no difference between pirtobrutinib and acalabrutinib. I think their response rate was pirtobrutinib response rate was 80.6%. Acalabrutinib was 80%. If you go and look at our data at roughly similar follow-up, we had a delta north of 20% in that population. We feel very good about how zanubrutinib is performing in that population. Mechanistically, if you ask, how does that make sense, we feel that zanubrutinib really does not leave that much BTK engagement on the table. This is a drug that at trough is fully engaging the target.
have presented data and published data to the effect of target engagement across all disease compartments and tissues at very, very high levels. Peer-to-brutinib, as you know, is a non-covalent inhibitor, which by default requires a thermodynamic equilibrium between on and off states, which is very different than covalent. If you think about the frontline setting, which of course was part of that trial, I think it is just too early to say much about that. Aaron alluded to this earlier. In that trial, in the BRUIN 314 trial, only a third of patients were frontline. The follow-up was, I think, 22.5 months. We are talking about 18-month landmark PFS, in which just over half the patients are really reaching that point. CLL is an indolent disease. It takes time for patients to progress.
Ultimately, those data are really just a handful of events at this point. We're going to have to wait for a much longer follow-up to see how those pan out again against the bar of 74% at six years that zanubrutinib has set.
Right. John, thanks. Yeah, this may be a good segue to talk about your BDK CDAC , actually, before we come back to sonrotoclax. But as we obviously are running a head-to-head study against pirtobrutinib. Yeah, maybe just stepping back high level, how do you think about your BTK franchise strategy beyond Brukinsa using or leveraging the BDK CDAC?
The BDK CDAC is a very exciting molecule. It's a degrader. It's a fundamentally different mechanism. There are a few key differences between the degraders and the inhibitors. Number one is it's catalytic. One degrader can degrade several thousand copies of BDK protein. It's very different, of course, from the standard one-to-one stoichiometry that is associated with small molecule inhibitors. It also, by virtue of degrading the entire protein as opposed to binding solely to the kinase domain, degrades the protein such that any scaffold function associated with that protein that is independent of the kinase domain is also obliterated effectively. There are mutations associated with zanubrutinib and also non-covalent inhibitors like pirtobrutinib that are in the kinase domain that aggregate kinase activity, yet still result in BDK signaling. These are so-called kinase dead mutations.
They have implications from a durability of response, if you think longer term. Also, those drugs are not active against those mutations. Our degrader retains activity against those mutations. As a result of that, it seems, at least where we're going initially with the program, is in the relapse refractory setting. Intuitively, this makes the most sense initially given the profile of the molecule. We have a potentially pivotal phase II cohort that is fully enrolled and will have data in the first half of next year. We hope to be able to use those data to register the product. We'll see. That is in the relapse refractory CLL post-BDKI and post-BCL‑2 setting. We also have multiple phase IIIs ongoing, one of which is versus investigators' choice, the second of which is head-to-head against pirtobrutinib.
Again, we're confident in the profile of the molecule. We had an 84% response rate thus far in very heavily pretreated fifth-line patients, of which 80% of them have seen a BTKi and a BCL‑2. In that data set, the 12-month landmark PFS was 79%. When you look at, for example, the late-line pirtobrutinib BRUIN 314 study, excuse me, they had a slightly less pretreated population and a median PFS of 14 months. We will see how those data hold up in phase III. There is a reason why we're confident here. I think KOLs have been very enthusiastic about this molecule because they're seeing responses in patients where they really do not have any other options.
Right. All right. So looking forward to that first registration data next year. What else will we learn at ASH about the BDK CDAC?
At ASH, we're going to have several abstracts for the BDK CDAC. We'll have updated data across several B-cell malignancies, CLL, Waldenstroms, et cetera. We're looking forward to sharing some of those data in a month's time.
Great. Yeah, maybe then a couple of questions on sonrotoclax. You already mentioned its profile and areas of differentiation versus venetoclax, which is always an established BCL‑2 inhibitor in hematology. I think this product is nearing disclosure of first registration data later this year, I believe, at ASH and MCL initially. Yeah, maybe talk about how much more we will learn about its profile in MCL and how that will translate into the overall product offering as you think about it.
Of course, at earnings, if you look at our earnings call, we had some data in the abstract on MCL. Maybe stepping back just a second, this is a product that received breakthrough designation in relapsed refractory MCL. We plan to file globally based on those data later this year. Those data at longer follow-up will be presented at ASH in a month. What's interesting about those data is when you look at them, again, this is a single-arm trial, so keep that in mind. When you look at them compared to historical benchmarks of venetoclax in the literature, you see trials of venetoclax in which venetoclax was used at three times the approved dose. Even despite the fact that it was triple the dose that is typically used of venetoclax, you see response rates comparable to what we're seeing.
Our PFS and duration of response outcomes are nearly double. Again, in our view, when we look at the data that is emerging from that program as a single agent, we see the 14-fold increased potency, the greater therapeutic window really translating. Those are the data that you're going to see in a month at longer follow-up at ASH.
Okay, great. We already talked about sonrotoclax's important role in your fixed-duration regimen in CLL. You also announced on the earnings call, actually, a phase III study in multiple myeloma. Stepping back, how do you think about the longer-term opportunity for sonrotoclax and specifically in multiple myeloma? What is the size of that opportunity?
Yeah, for multiple myeloma specifically, you're correct. We did announce that we will move forward to a phase III later next year. Specifically, this is going to be in the translocation 11;14 population, which is about, give or take, 20% of multiple myeloma. This is going to be sonrotoclax as part of a triplet regimen with daratumumab and dexamethasone. We acknowledge the competitiveness of this space. There are many, many options for patients with multiple myeloma, which is fantastic. A lot of the bispecifics, as you know, right now are IV. This would be a regimen that does not require infusions given subcutaneous daratumumab. That's point one. Point two, we saw early data from which we actually presented at R&D day for venetoclax, sorry, for sonrotoclax versus venetoclax in a combination with dexamethasone.
As you know, venetoclax in the Canova trial was close to reaching to being successful, but it did not quite make it. Again, cross-trial comparisons, but we are seeing greater evidence of activity for sonrotoclax versus venetoclax in multiple myeloma, specifically in that translocation 11;14 setting, which is underpinning our confidence to move forward with a pivotal trial.
Okay, great. Obviously, between the three molecules, the Brukinsa, sonrotoclax, and the CDAC, you have really the CLL and hematology market in a broader sense under control, in strong control. As we think about your solid tumor pipeline, the CDK4/6 inhibitor kind of stands out as one of the more advanced programs. You did commit to a phase III trial next year in first-line breast cancer. Maybe just stepping back, talk about differentiation, perhaps relative to Pfizer's palbociclib.
Yeah, maybe I will just, for the sake of the audience here, just remind everyone of what we disclosed on our earnings, and then I'll come back and answer your question. We decided to prioritize the first-line phase III. Subsequently, we also decided not to pursue a phase III in the second-line setting. Let me just walk through the logic behind that decision. First and foremost, we're seeing some very encouraging data in the first-line setting for our CDK4/6 inhibitor. When you think about the second-line setting, this was always intended to be a transitional opportunity. The PFS of CDK4/6 inhibitors in the post-CDK4/6 setting is unfortunately only on the order of months, six months or so. You compare that to a couple of years in the first-line setting.
On top of that, the second-line competitive landscape, as you all are aware, is extremely heterogeneous. It has gotten even more competitive just in the past few months with recent data sets from other additional regimens. When we stepped back and we looked at our data in the frontline setting and we thought in the second line in three, four years, if and when this would have made it to market to the second line, it was not likely to be an extremely impactful medicine in that setting. We decided to prioritize in the frontline setting. Now, with respect to Pfizer, Pfizer presented some what we felt to be very interesting data at ESMO for their CDK4 inhibitor. They showed a 68% response rate, which is above the response rates that you would expect for a CDK4/6 inhibitor in the frontline setting.
Importantly, given they have longer follow-up, that response rate did appear to translate to a greater degree of PFS benefit than you would expect, again, with the CDK4/6 inhibitors in the frontline setting. They had 67% PFS at 24 months. What I can say about our molecule is that we're seeing a similarly high response rate as Pfizer. Obviously, we do not have the duration of follow-up yet to comment on durability. We will definitely be presenting data for our CDK4 inhibitor in the frontline setting next year, primarily to give investigators confidence ahead of starting that phase III in the first half of 2026. I just want to make one more final comment. This is a molecule that entered the clinic 40 months behind Pfizer. They started their phase III earlier this year.
We have really, by virtue of the infrastructure that we have, it's incredibly valuable. We have been able to catch up materially in the clinic from quite behind to within roughly a year, give or take.
Great. Thanks, John and Aaron. Our time's up, unfortunately. We have to wrap up here. I did have more questions about your pipeline, which has a lot of moving parts, a lot of molecules advancing. We'll save that for next time. Thank you. Really appreciate the time.
Great. Thank you very much.