Great. Well, good morning, everyone. Day one of our global healthcare conference, year one, destination conference. Before we get started, I just want to thank everyone. This time last year, we were part of a company that was upside down, and we didn't really know what our future would look like. But thanks to you guys sticking with us and some perseverance at the senior level of Leerinc, we come out of this okay, and we owe it to you guys. So, thank you very much. This morning I want to start the conference with BeiGene. Thank you for joining us, gentlemen.
Thanks, Brad.
We have with us, Mark Lanasa, CMO Solid Tumors. We have Mehrdad Mobasher, CMO Hematology. And then Michael Schoen, the strategic advisor and special assistant to the CEO. Really appreciate you guys joining us.
Thanks for having me. Thanks for the invitation.
Why don't we start with a broad question? I mean, you guys now are a commercial company, global commercial company, with a blockbuster asset. Congratulations on that transformation. You know, what, how should we look at the strategic directions for the company going forward? I guess what I'm interested in is obviously you have a lot of R&D that's ongoing, but, should we think of, external opportunities? How, how is that going to play a role in the BeiGene of the future?
You want to take that one?
You can start and we can make it.
Yeah, look, I think BeiGene's mindset has always been, and John says it well, following the science. And I think if you think about BD for us, it's going to fit into that. You know, we have an incredible internally developed platform where we feel we need something in the portfolio to help patients. We'll go look for it outside. And as we've shown time and again, if there's opportunities to use things that we've developed in-house, in conjunction with somebody else, we'll look at those things as well. So I think it'll be part of our DNA forever, but clearly we're super excited about what our internal platform is developing. And these gentlemen can, I'm sure, talk more about that and also where they're working with things we've brought in or we're outlicensing.
So within the solid tumor space, our three key priorities for this year, one is the regulatory submissions and hopefully approvals for tislelizumab. The second is to establish proof of concept for, you know, oncology portfolio. And the third is the delivery of the 10 NMEs. As it relates to external opportunities, we in-licensed two molecules last year, the CDK2 from Ensem and a B7H4 ADC from Duality. And I highlight those because we brought those in because we thought they had high complementarity to our internal portfolio. So we are looking for things that complement our portfolio, though, of course, we have a very diverse portfolio. We're happy with our internal pipeline.
Yeah, and maybe in hemo add around the same line, in hematology, we are truly part of the big leaders in hematology, with BRUKINSA as big success. And we are really leaders in, in B-cell malignancies. And as we go through our other assets, we strengthen our leadership position in B-cell malignancies and also branch out to other unmet need areas like AML, MDS, and multiple myeloma. And the way that we see about our internal pipeline, early pipeline, and also other opportunities, whether it's clinical collaborations or external, we will follow the science, as Michael said, and also the unmet needs in hemo malignancies.
Okay. Maybe we could chat a little bit about what each of you see as the most promising pipeline assets that are up and coming. I mean, we know BRUKINSA has been a big success, and we'll talk about that shortly. But I think a lot of people in this room and a lot of your investor base, you know, is curious to see what what's next, what's the next BRUKINSA in the BeiGene portfolio. So maybe we start.
Maybe we'll start with him since we were talking about BRUKINSA. So, the next one in terms of where it is in development is certainly sonrotoclax, our BCL2 inhibitor. It's now in pivotal stage. We have started our first phase 3 study. It started enrollment end of last year. And we have three phase 2 studies that have the potential to have, you know, accelerated approvals and fast-to-market opportunities. And the story of sonrotoclax is very similar to BRUKINSA. It was basically how it was designed and the characteristics that it has that will lead to better potency, better efficacy, you know, safety profile, and in general have a best-in-class opportunity.
Then within the solid tumor space, I think the reason why we're so excited about having the 10+ NMEs this year is the diversification that it brings. In that way, it's a little bit hard to pull out one or two. In an effort to answer the question, I would say that, within the breast cancer space, we're very excited about our CDK4 selective inhibitor. That's now a clinical asset and is progressing quickly through dose escalation. We have our internal ADCs coming forward. We're also very excited about our pan-KRAS inhibitor, which we think can cover a large number of oncogenic KRAS mutations. And then our first solid tumor degrader targeting EGFR.
Okay. Maybe we dive a little into each of those, the BCL2. So what are the characteristics of venetoclax that you think could be improved upon and how does your effort address that?
Cool. Yeah. So sonrotoclax was specifically designed to address some of the characteristics that were problematic with venetoclax. Number one, sonrotoclax is more potent and, you know, potency matters in BCL2 inhibition and how you can reach a higher target occupancy. The second aspect of it is more specific against BCL2 only versus the other members of the BCL2 family. And also there it has a very important PK property in terms of the short half-life. So sonrotoclax has a pretty short half-life of 4 or 5 hours as opposed to venetoclax that has a half-life of 26-27 hours and also accumulates. So with venetoclax, that means that patients have constantly the BCL2 inhibitor in the peripheral blood that actually increases the level. That comes with, of course, the toxicity and cumulative toxicity in general.
Particularly a very important toxicity of BCL2 inhibitors and particularly venetoclax is TLS. So that's how we try to address the immediate risk of TLS, with shortening the half-life. So patients are out of that big risk of TLS for an extended period of time. So we can actually monitor those patients for shorter hours and potentially even get rid of some of the monitorings. And also the toxicity that builds up over time that leads to more discontinuation, infection and all that with venetoclax. We haven't seen those with sonrotoclax. So the preclinical thinking, or we call the preclinical promise now with more than 600 patients that we have treated with sonrotoclax in different diseases and different combinations has really panned out.
Okay. Can you just remind us what data sets we're going to see? I know you have the combination with BRUKINSA coming, but what, what are some of the near-term data sets where we'll get a better idea of the, the profile?
Sure. We have a pretty comprehensive and complex phase 1 study in B-cell malignancies, so across diseases. We started with monotherapy, which we always have to do, and then combined with BRUKINSA. We have released some of those data before and we will have more of the combination with BRUKINSA. Most importantly is our combination with BRUKINSA and frontline CLL. And at ASH last year, we showed some data really showing very deep and durable responses, and very tolerable safety profile. And that was a data set that convinced us to start the phase 3 study. We'll release those data, the longer follow-up. Similarly, this combination in other B-cell malignancies, even in relapsed CLL, we have the data accumulating and all on the same line. In terms of the myeloid malignancies, both in AML and MDS, we have combinations with azacitidine.
In multiple myeloma, we have a pretty active program in the subset of multiple myeloma that's dependent on BCL2 with the translocation 1114, that we show some data at ASH and we'll continue to release those data.
Okay. Before we move to the solid tumors, maybe, you also have a BTK degrader. I know that you've been excited about. What's the status of that? And can you give us some idea of where you see a degrader fitting into the treatment paradigm? Obviously, the BTK agents are very well entrenched in CLL and a number of other pathologic diseases.
Sure. Absolutely. Mark mentioned about the degraders. The degrader platform is something that we developed internally. The BTK degrader was the first one that entered clinic. I think what BeiGene did, similar to the other assets that we just talked about, is really try to optimize the platform in terms of the myelotoxicity, lack of IMiD properties that our BTK degrader has, because we knew that would lead to toxicity. Now, our BTK degrader is the most advanced in the clinic. So we have announced even at the JPMorgan that we had more than 160 patients enrolled in our trials with the BTK degrader. We showed some data at ASH, and we had some preclinical data even in during the summer. So the program is coming together really nicely.
The safety profile and efficacy, we have shown efficacy across B-cell malignancies, including CLL and mantle cell lymphoma, in patients who have received covalent BTK inhibitors, non-covalent BTK inhibitors on top of previous BTK covalent BTK inhibitors, and in fact, patients who even had BCL2 inhibitors. So clinically, we show evidence of activity in all these patients. Preclinically, we saw degradation of protein regardless of the mutation. And right now we are in phase two in two cohorts of relapsed refractory CLL and mantle cell. That would be automatically before, after BTK, so pretty much later line patients. But we are working on combinations and how we can bring this molecule to earlier lines. The nice thing about the degraders is not just it is, you know, mutation agnostic, which becomes a problem. It's also that it's more potent because it destroys the scaffolding of the protein.
We think that it can have the capacity to even move to earlier lines of therapy. We are working on rational combinations, but some of them are with our own assets. For example, sonrotoclax is a natural combination that we are pursuing soon.
The idea would be to get it ahead of the covalent inhibitors?
So ultimately, if the data speaks that way, yes. You know, as I mentioned, we showed some data at ASH on a small number of patients. We like the response that we see. We definitely need durability. Our studies are certainly enrolling all categories of those CLL and mantle cell patients. And if the durability and depth of response pans out, goes to that direction, that would be the aspiration.
Okay. A number of companies included, well, you guys are still pursuing the fixed duration therapies. A number of other companies, I think, have started those programs, but they haven't gotten as much traction, at least as far as I'm aware. I guess would the idea be with the BTK degrader, that it'll be a fixed duration therapy, and you could stop it at some point and?
Yeah. So that is something that for the past few years, the field has been interested in. And when I say the field is physicians, patients, even patient advocates, they all want time-limited therapy, particularly after the era of COVID when a lot of patients who were on these long treatments had more toxicity and more COVID issues. So really we are focusing on what the unmet need is now, and one of the main areas is fixed duration. The monotherapy, BTK monotherapy has its own place and will continue to have it. But that small amount of fixed duration that was available, again, venetoclax had its own issues. That was the only treatment that in B-cell malignancies we could provide time-limited. But if we can address that, we can really expand the pool of patients that can take time-limited therapy.
That's an area that we are approaching. Initially it would be sonrotoclax plus BRUKINSA, but also with other combinations, as you mentioned, BTK degrader is probably the path that we are going to take to make sure that we shorten the treatment for patients.
Would the goal be like minimal residual disease, get to that, and then you monitor the patient continuously for any relapse? Is that?
Yes. So the nice thing again, with adding a BCL2 inhibitor to other mode of action is that you can really bring the level of the disease down to the eradication of minimal residual disease that now we have in our doublet with BRUKINSA you have shown that we can do. That's what gives us the confidence to stop treatment, so the cessation of therapy after one year. And there are data that others have generated that when patients are on shorter treatment duration, they don't have the mutations that gets them in trouble, right? So neither BTK mutation or BCL2 mutation happens in these time-limited therapies. So then patients can be rechallenged with, you know, same class of sonrotoclax or something.
That's the idea that we will give the time-limited therapy to patients, stop the treatment, and down the line, if they need treatment again, they can be treated with one or both or different combinations of the same drugs.
Okay. Well, we'll come back to the BRUKINSA commercial launch in just a minute, but I want to, kind of discuss some of the ones you mentioned, like the KRAS, the pan-RAS inhibitor, and then the ADC program. You know, I guess give us an idea where you see the RAS. You know, there are a couple other companies that are trying to develop pan-RAS inhibitors. How is yours different and, and how do you see the field evolving?
Right. So our molecule is a pan-KRAS inhibitor. So it broadly covers oncogenic KRAS mutations, but it spares HRAS and NRAS. So the mutant selective inhibitors, the G12C inhibitors, have been an important step forward. However, they only cover a small minority of the total number of oncogenic KRAS mutations. And duration of therapy or duration of response has been a bit disappointing. So we think that having broader KRAS coverage would be advantageous. Now Revolution Medicines and others have pan-RAS inhibitors. So we think that, by having selectivity for KRAS over HRAS or NRAS, that's likely to lead to an improved safety profile given the pleiotropic effects of RAS biology across lots of different normal tissue types. And then there's also preclinical data that we've generated that shows that by sparing HRAS and NRAS, that actually better preserves immune function.
That blocking KRAS and NRAS can inhibit T-cell proliferation and activation.
Okay. And would the goal be to replace the existing inhibitors, the G12Cs, or?
Potentially. I think that from a prescriber's perspective, it certainly would be nice to have one medicine that you could use across the range of KRAS mutations. So for example, in lung cancer, G12C is the most common mutation, but it's only about half of all the KRAS mutations. We're certainly cognizant of the fact that the G12C covalent inhibitors are already on the market. So, certainly we want to be as good as or better than those molecules.
Okay. What's going to be the data flow from that program?
That's going to start in the second half of the year. Likely we will not have any public disclosures around that program until, say, until 2025, hopefully in the first half of the year.
Okay. And then you mentioned the ADC platform. Obviously a lot of ADCs coming out of China, a lot of deals, a lot of drugs being developed here in the U.S. too.
Right.
What, what is the focus for BeiGene?
Two points I'd like to make. One, going back to what Mehrdad was saying about our degrader platform, is that we wanted to improve upon the platform itself. We have proprietary technology related to the TOPO-1 warhead. We have proprietary technology related to the linker. We have a peptide hydrophilic linker that should improve tumor penetration and also improve stability. And then we have intellectual property around the site-specific conjugation, which gives us a very narrow, precise, drug-to-antibody ratio, DAR, of 8 for all of our internal molecules. We think that we've engineered advantages to the pipeline. The other thing, the other broad point, is that we're interested in targets that are, shall we say, not heavily explored.
So we're looking at CEA, FGFR2B, which we think have both first-in-class opportunities in the ADC space, and then B7H3, while DS has been exploring that in small cell lung cancer for a couple of years. We think there's a lot of other tumor types that remain white space opportunities for that mechanism. And again, our platform, we think, provides certain advantages over the DS platform.
What, I mean, what are the criteria you use to try to pick the different targets that are compelling besides the fact that there's not a lot of people developing it?
So, we do have a number of targets that we're bringing forward. We have other undisclosed targets. And another point that I think is important is we're about to open an in-house manufacturing facility for ADCs. So, to get to your question, when thinking about how do you in parallel develop a number of ADCs against different targets, keeping in mind that they all have a TOPO-1 payload, I think the way we're thinking about this is to pick tumor-associated antigens that give us broad coverage of different tumor types that are non-overlapping in terms of the high levels of expression in our priority tumor types of lung, GI, and breast cancer.
Okay. And then in terms of, I mean, as we see drugs like Enhertu get more usage, there's obviously going to be a need for downstream treatments for patients that get resistance. Do you think that using a TOPO-1 payload or is the best approach, or, you know, possibly changing the payload to a different model?
So, we don't know yet. It's a great question. We have two answers to the question, and it's really ultimately driven by what is the mediator of resistance? Is it target-mediated or is it warhead-mediated? So if it's target-mediated, meaning HER2 gets downregulated and HER2 doesn't work for that reason, then one could logically retreat with a TOPO-1 warhead against a different target. So we're open to that possibility. It's also possible that there would be warhead-mediated resistance. And in that way, that's why we're also focusing on novel targets where there might be higher-level expression, where we might be able to improve upon the data that's already present in certain patient segments.
You mentioned manufacturing. Is that in China or is that going to be part of the Princeton, New Jersey plant?
That is in China. That's at our Suzhou site.
Guangzhou site?
Guangzhou site, yeah.
Okay. Great. Why don't we talk a little bit about BRUKINSA, you know, how the commercial launch is going? It sounds like you guys are making a lot of inroads, enough so that your competitors, I think, have taken notice. And, you know, what, I guess, can you give us some color? I mean, I think we watched Calquence make inroads for AZ over Imbruvica. And one of the metrics I think they kept citing was first to BTK, you know? So, and I think that's an important metric because as physicians get anecdotal experience using a drug, you know, maybe in later line patients or patients that have had some problems, they may ultimately say, "Hey, I like this and I'm going to use it in all my patients." So what kind of adoption are you seeing in that regard?
Like patients, the first BTK that a doctor reaches for is it starting to gain traction there?
Yeah. So the short answer for that would be yes. But the reason for that is that, you know, that BRUKINSA has the broadest label now. We have five indications. And most recently, just last week, we got our follicular lymphoma approval from the U.S. FDA as an accelerated approval. And we are internally very pleased about that for several reasons. The most important thing is that now we are providing another option for patients that was not available, and it's the first and only BTK inhibitor that has been able to do that, which really actually shows that BRUKINSA is differentiated. Now we have five indications and none of the other BTK inhibitors in the market now have that. And that also gives physicians the ability to have one BTK that they can give for everything else as well.
So it's easy instead of picking and choosing to have one drug that they can give to all these subjects. The majority of physicians see all of these B-cell malignancies. But then in terms of the bigger market for BTK inhibitors is, of course, CLL. BRUKINSA is the only BTK inhibitor that has shown superiority versus another BTK inhibitor. Of course, the ALPINE study that we showed the initial data and we showed the long-term follow-up of the data with 30-month median follow-up, the superiority versus ibrutinib sustains in all tumor population and the high-risk population that Calquence has only shown non-inferiority with a hazard ratio of one. So across the board, we have seen deeper and more durable responses. And I think the physicians are seeing that in terms of their usage.
Right. Okay. And I think you guys did an analysis and AstraZeneca also did an analysis. We had talked about that at one point. What did you guys show, relative to Imbruvica and then how that could be extrapolated to Calquence? And I think they did their own analysis that kind of was slightly different.
Yeah. I assume you're talking about our MAIC that we recently released. So we also believe that the head-to-head trials are the gold standard for evidence generation. I mentioned the ALPINE trial. We showed superiority in all tumor and, you know, high-risk patients. Calquence did a study against ibrutinib and they showed non-inferiority with a hazard ratio of 1 in a subset of patients. Last year there was a publication with an MAIC. So these matching-adjusted indirect comparisons are when we don't have a head-to-head study. So it's one of the tools that we can use and adjust for some important factors, and compare two different arms of two studies. So that publication was published in American Journal of Hematology.
Actually, the authors mentioned some of the problems that their analysis had, including the smaller sample size and also the timing of the study, which happened during the COVID period. Of course, CLL patients were really affected by COVID-19 and they didn't have those data to address. Well, we had the data set in our hands, so we had more patient numbers to use in the same analysis. Also, we used the longer follow-ups. So one of the problems with the earlier MAIC that was published by AZ and some of the investigators was that they used the shorter follow-up of ALPINE. We used more number of patients, more follow-up. We matched for more factors that are relevant to disease, both from demographic and also disease characteristics and, of course, COVID-19.
So our analysis actually showed both in terms of PFS and CR, BRUKINSA is superior to acalabrutinib. And there was even a nice trend for overall survival while their earlier MAIC had shown that the two drugs are the same. So we think this is nice evidence for physicians when they're trying to choose a treatment for patients and is in line with what we had thought about BRUKINSA being best-in-class based on the head-to-head trials that we had done.
Now that won't be in the label, obviously, but are you allowed to speak to physicians about it, commercially?
Once it's published, you're allowed to speak to physicians as part of educating them about the totality of the data. And I think since that presentation was published, it's available for our team to speak with physicians. In fact, we have had several discussions with the CLL society physicians who treat CLL and the opportunity to have that debate.
Okay. And then you recently got PFS in the label. How important do you think that is?
So that PFS, it was important to have it in the label, but that's the earlier PFS data. So that was the primary analysis of PFS that we showed at ASH 2022. So I think it makes our label very strong and comprehensive. Again, when a physician wants to know everything about BRUKINSA, they can go to one document and see all the way from CLL to follicular lymphoma. All the data is there. So we thought it was very important for us to submit another sNDA, but that data was available because that's from the ASH 2022. We also published the follow-up, as I mentioned, at last ASH.
So our team is able to speak about the longer follow-up with physicians because that was one of the questions and concerns that was out there that maybe with the longer follow-up, the curves will come together, same as the ELEVATE-RR of acalabrutinib did, but we showed that no, our PFS superiority sustained.
Okay. And OS is, I mean, I know it takes a long time.
OS is very immature, and that the study was not powered and smaller to show that. But I think there is a little difference between the OS of the two RNs. But one of the great things about the advances in the field of CLL is that these patients have lines of therapy available too.
Right. Okay. Why don't we open it up to the floor to see if anybody has any questions? No questions? Okay. I guess with the last few minutes we have left, obviously you're a global company, headquartered in China. We know that, there's obviously been a lot.
Not headquartered in China.
Not headquartered. Correct. I'm sorry.
Okay.
Headquartered out of China. Correct. I guess in terms of, you know, how you think geopolitical tensions have affected the company.
Sure.
You know, what, what can we look forward to in the future?
Yeah. Look, I think it would be naive to think that the BIOSECURE Act, Biden's executive order doesn't have people thinking about stuff. I think it's important, though, to look at what those are specifically addressing and what we do. We're focused on helping cancer patients. We develop innovative medicines. We manufacture, distribute them globally. Everything that's come out of D.C. over the last X months is around genetic data collected in the United States and getting it, you know, to countries of, you know, of concern, and companies of concern. So from a direct effect upon BeiGene's business and our focus, nothing in there. You know, I think it's, you know, geopolitical tensions will continue to be the case. But, you know, you mentioned we're a global company.
China is an incredibly important part of what we do, both on the R&D side, but also on the commercial side. But, you know, majority of our revenue is now outside of China. That percentage will probably continue to grow outside of China as we continue to have great success with BRUKINSA and we come online with TEVIMBRA and other assets. So I think that, you know, we're not able to gonna stay totally out of the news, so to speak, because it's obviously geopolitical tensions affecting a lot of things. I think actually if you step back a second and some of the reactions from BIO and other organizations, pharma, et cetera, you know, there are concerns about unintended consequences around some of this legislative activity, but those are pharma-related broadly, not in any way BeiGene-specific. So we're just going to continue focusing on our business.
We're going to, you know, have a grand opening of our U.S. manufacturing facility this summer. So we'll be totally global in manufacturing as we already are in commercial and R&D, and just really a totally global company.
Is the goal eventually to diversify? I know that some of the concerns were manufacturing and you know, a lot of the wishy-washy, you know, people worried that.
Yeah. So, I mean, specific to that, and again, I mean, there's nothing in the current legislation that's about the wishy-washy world of API, which is where people want to have, rightly understand that their focus. So importantly for us, we are already in line with second source manufacturing for API, very far along on that and a non-Chinese supplier. We stockpile and our actual manufacturing for the United States is with Catalent out of Kansas City. So for that specific API risk that some people have talked about, we, you know, it's kind of smart business, forget any of the legislation. We've got other suppliers and stockpile capabilities to make sure we're comfortable that we can continue to supply patients with this, great medicine.
Okay. And with the last minute, any comments on the AbbVie litigation? I know you feel like your, your patents are strong. The drug's obviously unique, but it's, it's a concern to some investors.
I mean, I was.
I can briefly add to that. So in terms of the patent, it's the molecule itself. It was homegrown from the chemical structure. There is no concern and it is not actually part of this patent litigation. So AbbVie Pharmaceuticals filed this patent that we believe is very broad. And that's the approach that we have taken, that we have filed with the patent office that we would believe this patent is too broad to be relevant to our drug or any other. So we are waiting for the outcome of that. That will, what we'll know in May of this year. We are very confident in our approach that our own patent is strong and this particular patent is too broad and we want it to be invalidated. So that's the approach that we are taking.
Okay. Thank you, gentlemen, for joining us. Appreciate it and look forward to the future.
Thank you. Thank you. Thanks for having us. Appreciate.