Great. So good morning, everyone. My name is Dave Risinger. I cover diversified biopharmaceuticals for Leerink Partners, and it's very much my pleasure to welcome, Bristol Myers', Chief Medical Officer, Samit Hirawat. And, with him in the audience are, Tim Power and Janet Barth in Investor Relations. We appreciate, Samit joining us, taking the time out of, his busy schedule to be with us here today. So, I guess it'd be great to have you kick off just by, you know, framing, your vision for Bristol R&D, including, you know, some of the company's most substantial R&D, projects that we should be focused on. And I know there are a lot of them, but, but it'd be great to have you just provide an initial framework.
Sure. Thank you, Dave, and thank you, first of all, for having us. We're here. It's a great pleasure because I can tell you, I've been in the industry for more than 20 years now, and we've learned a lot about the biology of the disease. We understood the pathways, and we continue to innovate. When I think about the pipeline that Bristol has today, I truly believe that it is one of the most differentiated pipeline across the therapeutic areas that we are in. Maybe I can give you a flavor by walking through some of those across the therapeutic areas, and within that, let me start first by the non-hemo side, because we don't necessarily get to talk a lot more about that. But let me start with neurology first.
Significant progress being made over there, and we are accelerating our presence and entry into the neuroscience field through potential approval of KarXT later this year, once, of course, we're looking forward to closing the deal for Karuna. But KarXT is an important product, with schizophrenia being the first indication and then other indications that follow after that within the adjunctive schizophrenia, as well as Alzheimer's disease, psychosis, and potential future indications of agitation and others. And then there are other molecules in the pipeline that are very important. And in neurology, then neurodegeneration is the other part that we are following, with anti-tau molecule getting into a randomized phase 2 this year for Alzheimer's disease. And then other targets that we are pursuing, as in elF2B activator, as well as the fine MAG lipase inhibitor, et cetera.
On the immunology side, of course, there is Sotyktu, with multiple indications being pursued, and some of them will start reading out this year, such as psoriatic arthritis. But then Candakimab also reads out this year. LPA1 is in two phase 3 studies for IPF and PPF, and then there are other molecules that are in early phases of development in immunology. If you think about cardiovascular disease, milvexian is very important across three indications that we are pursuing in AF, secondary stroke prevention, as well as acute coronary syndrome. And then Camzyos, I think we've talked a lot about that, a transformational drug for patients with hypertrophic cardiomyopathy, and we are following the phase 3 study now with non-obstructive hypertrophic cardiomyopathy on that one as well.
If I switch gears and talk about hematology, oncology, and cell therapy, with cell therapy, probably, we are the ones with the largest targets in terms of the pipeline itself, with Breyanzi already approved and, and Abecma already approved, GPRC5D for multiple myeloma, getting into pivotal phase studies this year. Dual CARs following right after that with GPRC5D BCMA targeting. And we've talked a lot about, CD19 targeted, cell therapy entering into the autoimmune space with SLE, systemic sclerosis, myositis, and MS studies that started last year.
On the hematology side, of course, beyond multiple myeloma, through the protein degradation platform, and other molecules in development, we are venturing also into the lymphoma side with golcadomide as a protein degrader, entering into phase 3 trial later this year for diffuse large B-cell lymphoma, and we are looking at data in another couple of diseases as well. And then to round it off with oncology, we are certainly an immuno-oncology company with Opdivo and Yervoy, and certainly this year we presented the data for Opdivo subQ, and we are looking forward to bring that forward next year for patients as well, in the commercial setting. Then I'm sure you will have questions on Opdualag that I'm happy to talk about today.
And then beyond immuno-oncology, we have entered the precision medicine field now, and that's where Opdualag becomes very important for us for non-small cell lung cancer. Carvykti, sorry, Krazati, I'm sure Carvykti is on everybody's mind because of the briefing book that came out this morning. But Krazati is there, PRMT5, as well as several other molecules that are in early phases of development. So overall, if we look at the things that I've talked about, many first-in-class molecules, many first-in-class drugs, as well as best-in-class, and then diversification in terms of therapeutic areas. So truly, positively excited to be at Bristol at this time.
Excellent. That's a great overview. So, I guess before we go into some of the therapeutic categories and the product discussions, clearly, Bristol's engaged in M&A activity and is considering reprioritizing some of its portfolio. Could you speak to that and how to think about, you know, potentially rationalizing the portfolio a little bit, exiting certain products, and how are you thinking through that, and how do you plan to execute on that?
Sure. I think it is important that for any company, and especially the size that Bristol is today, that we think about the portfolio in a way that it's not just incremental progress, but rather transformational outcomes from a patient's perspective. And so we are taking a look at our portfolio and looking at what we are adding through the four M&As that we did last year, if you think about what Mirati brought in, what RayzeBio is bringing in, what Karuna is bringing in, and what SystImmune collaboration brings in, in terms of the large indications. And many of these are relatively de-risked because of the readouts or approvals of these drugs, with Krazati already approved, PRMT5 showing improving overall response rate in multiple diseases at this time. And then, of course, KarXT data that you've already seen.
RayzeBio, you've seen some of the data that are already published for RYZ101, and they are in phase 3 as well. So looking at the de-risked portfolio that we are bringing in, versus looking at things, that will be important but may not have sound, data generation from a scientific perspective or from a commercial perspective, if the promise of the growth and the forecast doesn't fit well for a large company like BMS, or both, in terms of, you know, me-too drugs that are not going to be best in class or first in class, or we are fifth, sixth, seventh in line, may not be the right things to pursue. So while I'm not prepared to talk about the specific molecules today, you've already seen some of the news coming out.
We have certainly returned the rights back to CytomX when we talk about CTLA-4 and antibody, etc. You saw that already in the news. But certainly, we are taking a very deep look to ensure that when we talk about the pipeline, we talk about a transformational pipeline, not just small incremental benefits.
Excellent. So then, could you comment on the briefing documents at a high level?
Well, I've not had a chance to really dig deep into it, but what I can talk about is Abecma from our perspective. When we look at the data, and the way we look at it is the major question is impact on overall survival. And we've always talked about there are two parts, that one has to really look at from a capital market perspective. One is the impact of crossover, and you will see when we present at the ODAC day after tomorrow, very clearly demonstrating what happens when patients who were on the standard of care treatment arm, when they crossover to receive Abecma, what the outcome for those patients are, versus those patients who unfortunately did not get Abecma, did not crossover, what the outcome for those patients is. So that addresses one part of the curve.
The other part of the curve is the early part of the curve, where there are early deaths, and that's where, again, we are going to be able to showcase and at least have a discussion around what is the impact of bridging therapy. Because remember, for Abecma and KarMMa-3, there was a limitation of less than or equal to one cycle of bridging therapy with a minimum of 14 days of washout period before patients could get the infusions, etc. So what is the impact of that in terms of patient outcome? So those are the two points that we will be bringing forth and looking forward to that dialogue.
I have not had a chance to dig deep into the other medicine that is for development, for discussion, that is Carvykti yet, because it just came out this morning and I was more focused on this discussion than looking at that for now.
Okay, that's very helpful. Thank you very much. And I guess maybe we could turn to specific pipeline cards that we'll be turning over. So what are some of the exciting pipeline cards we should be watching in the next year or two?
Well, let me focus maybe for the time being to this year.
Okay, excellent.
At J.P. Morgan, we talked about, I think, overall 20-odd impactful things that will be coming out. One of them that we talked about was Opdualag. We had said that for Opdualag, we will have the readout for the randomized phase 2 study that we were conducting in non-small cell lung cancer. I'm happy to say that we've seen the data just recently, last couple of weeks, and we are still analyzing the data. But what is certainly good for us, and more importantly for the patients, is we've been able to identify a very important segment, and I'm not going to get into the details of that for a multitude of reasons.
But we've identified an important segment in non-small cell lung cancer that we are looking forward to engaging with the FDA to discuss the phase 3 trial and initiating the phase 3 trial later this year versus pembro plus chemo. It clearly demonstrates the importance of adding LAG-3 on top of a PD-1 inhibitor and chemotherapy, and that's what we will pursue going forward. It also gives us a chance to now think about other indications where we need to look at specific populations, and so we're going to go back and take a look at where we need to focus as we look to the future. Beyond that, obviously, several other cards that are going to be turning over this year. As we think about Krazati, the confirmatory trial will be reading out soon.
We look at KarXT as an approval later this year. We look at, of course, Karuna has to close from a M&A perspective. When we talk about Cendakimab, that card will turn over this year towards the back end of the year. When we talk about psoriatic arthritis, that card will turn over this year as well. Of course, day after tomorrow, there is Abecma ODAC, which is going to be important. And then, one very important event that we're looking forward to is continuous enrollment in our SLE trial for cell therapy, that we hope to be able to share the data again towards the back end of this year as we enroll more patients in that study.
Excellent. Thank you for that, and thank you for sharing that update on Opdualag. So regarding... you know, you mentioned identifying a segment. Could you give us a sense for the potential size of that segment? You know, what slice of the pie?
I will not get into the details of that for two major reasons. One, competitively, it's important that we focus on how we're going to develop Opdualag. There are others that are developing LAG-3 inhibitors, so it is important to keep that in mind. But more importantly, there's a lot more analysis and engagement with the FDA that we have planned, that we will do. But what I can tell you, it is a very important segment with a high unmet medical need, where we need to be able to demonstrate that addition that we're bringing on top of a PD-1 inhibitor plus chemotherapy, so that's what we are focusing on.
I think we are late for ASCO already because we've just looked at the data, and we have to do more analysis, but we do intend to bring it forward from a data presentation perspective sometime in the fall.
Okay. And then, in terms of phase III, is it appropriate to assume that since the, you know, the dominant standard of care is Keytruda plus chemo, that that would have to be the control in phase III?
Yes.
Okay.
So remember, the way we designed the study, it is, I think, very critical. We know many drugs have been developed, and then when we go deeper into the data, it's questionable that the control arm didn't perform well, et cetera, et cetera. So the way the study was designed is two-part. Number one, identify the right dose. So we tested two doses in part one. Patients were randomized to receive one of the two doses. Then we took one dose into part two, where patients were randomized to receive the fixed-dose combination of nivo plus relatlimab or LAG-3 inhibitor plus chemotherapy, compared to nivo plus chemo. And the reason we did that was because we wanted to make sure for two parts. One is to show the contribution of components so that we don't have to answer that question in phase 3.
And number two, to evaluate the endpoints from a safety and efficacy point of view. So we've done the analysis comparing within the trial, the endpoints that we evaluated, and then we looked at the data that is available for pembro chemo for that particular segment, and we are happy to report that we see a benefit there that we can now take forward into a phase III trial.
Great. And regarding that segment, the super-secret segment, so how would you frame when, when we learn what that is later this year, that segment? How would you frame the competitive landscape in that segment from other mechanisms beyond LAG-3?
So I think non-small cell lung cancer is no longer just a disease of either squamous, non-squamous, or even PD-1 inhibitors as well. It's become segmented into nine different diseases or maybe even more, based on mutations, based on expression of receptors, based on expression of biomarkers. So we'll have to keep that in mind, that it's a competitive landscape. Certainly, because multiple IO therapies have been approved for non-small cell lung cancer, it is a competitive landscape from that perspective. So when we look at the data across the trial and segments within that, biomarkers within that, we always keep in mind that it should be comparable to any approved therapy for that particular population. So that's how we have framed ourselves, that the most important one over here, because it is most commonly used, is pembro chemo.
But as we discussed with the regulators, if they say, you know, "You need to allow for investigator's choice," then we'll have to think about that as well, in terms of if there are multiple therapies approved for those patients, then we'll have to think about that as well.
Okay. As a third agent in the control, you mean?
Yes.
Okay. Got it. Okay, very helpful. Why don't we pivot? Let's see here. So, could you talk about the MYK-224, which is gonna generate the phase 2 MERCUTIO data in the first half of this year? Could you speak to that? I think that's a near-term readout as well.
Yes. So MERCUTIO is a study of MYK-224, which is a myosin inhibitor, a cardiac myosin inhibitor. So the optionality that we have, one is Camzyos. Camzyos is already approved for patients who are symptomatic with obstructive hypertrophic cardiomyopathy through the two phase 3 studies that led to the labels that we have. MYK-224 is the next generation, and because we know so much about obstructive hypertrophic cardiomyopathy through Camzyos data, we first wanted to test MYK-224 in obstructive hypertrophic cardiomyopathy, so we can easily look at the data and say: "What are the attributes of MYK-224, which are differentiated from Camzyos?" The second part, which we also are looking at, we have just initiated a study, a phase 2a study of MYK-224 in heart failure with preserved ejection fraction.
That gives us an optionality for MYK-224 to actually branch out and get into the heart failure data. So this year, we'll see the data for obstructive hypertrophic cardiomyopathy, and what we really want to see is how that data compares to what we've already known from Camzyos perspective. And next year, we'll get the data for the phase IIa study in HFpEF, which will then pave the way for future development in the late phases of heart failure as well.
Excellent. Okay. Perfect. And then, just continuing on, so KarXT is obviously a very, very compelling asset. And it appears set to be a multi-billion dollar blockbuster. Could you frame how you see it as a pipeline and a product? I mean, you know, discussed that, but...
Yeah.
Also include, you know, the potential timeline for additional indications.
Sure. So you're absolutely right. KarXT is a very important product, for if you think about, schizophrenia, no new drugs have been approved for decades now. And if you think about, KarXT, which has an efficacy, if not better, at least equivalent to Zyprexa. But if you look at the safety profile, it certainly differentiates itself through its muscarinic effects because it doesn't seem to have tardive dyskinesia or akathisia or prolactin increases, so on and so forth. So from that perspective, an efficacious drug with a safety profile that looks pretty good is what we are hoping to bring forward once the approval happens for KarXT. Following that is the adjunctive schizophrenia indication that is currently in enrollment, that clinical trial. I think what we've said is 2026 for that readout.
And then, beyond that, the study that is ongoing is also Alzheimer's disease psychosis, and that one is 2027 readout. Beyond that, our anticipation is that we should be able to initiate trials in AD agitation as well, and then looking to see what other indications we can add, such as bipolar disorder, et cetera. So much to come and more to explore. Now, beyond that, there is the element of simplifying the dosing, because as you know, in AD right now, the dosing is three times a day, and certainly, Karuna is already working on some of the formulation work, as well as defining the specific ratio between xanomeline and trospium to address the issue and then come with BID dosing.
So we'll see how we can incorporate that either in the ongoing program or new programs and bridging of that. And then once our scientists can sit together and discuss further, the idea would be to then also get into the long-acting injectable for ease of administration and bringing that forward as well.
Great. And then just in terms of the BID, what are, you know, some of the clarity points ahead when we have a better sense for BID, you know, and potential timing for BID?
Yeah. Right now, I know that Karuna has already started to work on that part.
Mm-hmm.
We'll need the phase I data to understand the PK and PD effects. More PK to see what the C trough and C mins are going to look like, and then we can take it forward into the next phases of development. The simplest way to think about it would be that we could easily implement that as we initiate the Alzheimer's disease agitation trial. We have the psychosis trial that is already ongoing, but how we bridge that is yet to be defined, so I can't get into that yet.
I see. Sorry, I'm just taking notes.
No, it's fine.
Okay. So, you know, obviously it has a great profile, but how did you get comfortable with the peripheral side effects, which could impact real-world persistence? And then if you could just touch on, you know, cardiovascular risk.
Oh, absolutely. So I think it's brilliant what, what Karuna did. So certainly, xanomeline is a muscarinic inhibitor, and if you just give xanomeline, what was observed almost 20 years ago now, is the peripheral side effects, which almost stopped the development of the drug. And that's where the combination of the two drugs, xanomeline plus trospium, trospium, which is a peripheral muscarinic inhibitor, helped the profile overall. And that's why it has come as far as it has come, and you don't see those peripheral side effects. Now, the other question that you asked is the cardiovascular effect, and that's where the blood pressure monitoring study, the ambulatory blood pressure monitoring study that, that Karuna has already done and submitted as part of the 120-day safety update, and FDA is reviewing it. So... And, and the results from there are pretty benign.
We don't see any major impact from that perspective. So looking forward to those discussions as we continue on. Karuna is going to be discussing, obviously, on a continuous basis as the review goes on, on the safety profile of the drug. But from our perspective, when we look at the data for the three studies that have been submitted, as with the longer-term follow-up, the four and five, we don't see the safety profile on a peripheral muscarinic inhibition as, as a problematic issue.
Okay, very good. And then from a commercial standpoint, I know that you're not in charge of commercial, but obviously, you engage closely with your teammates. What is the way to think about, you know, a product like this being introduced, which is clearly offering a better benefit risk ratio than Zyprexa, but is also going to be, you know, heavily reimbursed by Medicaid? So any high-level thoughts on how to bridge that with a you know, costly new brand, which has a great profile, but also, you know, competing with those super cheap generics?
Yeah. So, I think in this seat should have been Adam, who can give you obviously a, a much more cogent answer to that. My, my takeaway from what I've learned and heard and understand, because of the profile of this drug, because of the efficacy that has been seen, it is going to be an important option from a physician's perspective and prescription perspective for patients. From even a Medicaid perspective, the coverage is there. I think we talk about 34 states where it is going to be covered right away, and then, of course, much more work needs to be done to get it on the coverage for the rest of the states. But the teams are very well set.
Adam and team are all working towards making this one of the most important and effective launches later this year, with the ready force available to be able to launch as soon as the approval comes through. Certainly, there will be no stone left unturned to make sure that most patients benefit with a therapy like this.
Got it. And then obviously, Cerevel has plans to compete. Any, you know, things you would highlight as we look ahead to seeing their future data?
... Yeah, I think way to think about it is, one is the difference in mechanism of a M1, M4 muscarinic inhibitor, where we've talked about the importance of having the M1 inhibition, because that's what is important, at least from a biologic perspective, from a cognitive function improvement perspective. And you've seen the impact of that and trends of that in the schizophrenia program. The second element is going to be very important because of its direct muscarinic inhibition. You don't need the presence of acetylcholine, which will become very important in acetylcholine-deprived states such as Alzheimer's disease. And the issue with M4 PAMs is going to be that, one, no M1 inhibition, and number two, the need for acetylcholine to really be able to have an impact on AD psychosis, potentially, and maybe other indications as well.
So those are the two takeaways, but of course, we'll have to see what the data that Karuna or now the new company generates to be able to demonstrate the impact. We know xanomeline itself has demonstrated the positive outcomes for patients with AD, 1997 publication, in fact. So we know that the drug works. The issue was the toxicity, and trospium hopefully helps the toxicity, so we're looking forward to that readout now.
Excellent. Why don't we pivot to the tau program, which is advancing to phase 2? Could you just talk about the, you know, earlier data that gives you confidence, how it may be differentiated from other tau programs, such as Biogen's tau ASO program, and then potential timing of readout?
Yeah. So, remember the prior tau program that have gone in generally targeted the N-terminus or the kinase terminus of tau. We are differentiated. We are targeting the mid part of the MTBR region. Even there, there are 4 different receptors, R1 to R4. And so we are targeting 3 of them primarily, and the competitor drug is targeting the other 3, R1, R2, R3 versus R2, R3, R4. So of course, we don't have the randomized phase data, which is what we're doing now, the phase 2 that is starting now. What we do know is the PK profile of the drug. What we do know, concentrations achieved in the CSF. What we do know is the inhibition that we do see. So initial biomarkers give us the confidence that we can get into the phase 2 study.
But of course, now as we do the phase 2 study, we look at the overall safety in AD population and then impact on cognition and some of the functions, and through imaging, what the impact on the tau protein is in the brain itself. As you might have seen, the guidance just came out for amyloid protein just yesterday or day before yesterday from the FDA perspective, where a decrease in the amyloid protein in the brain could potentially be a surrogate for, for patients', outcomes, from a cognition and functional perspective that is currently being used as a regulatory endpoint. So if that trend continues, then we'll see how we discuss with the regulators as to what the impact of decreasing the tau protein would be as we go forward. From a timing perspective, we are just initiating the trial.
Let's see how the enrollment goes, and we'll be able to give a better guidance on the timing.
The primary endpoint?
Don't quote me on this yet, but primarily, we're looking at safety and then, of course, looking at some of the cognition and functional scales.
Got it. Okay. Very helpful. Why don't we pivot to, I guess, with respect to milvexian, you know, as you look ahead to the asundexian readout next year from Bayer, you know, that'll be, I think, the next event for the factor XIa class, and that is in, I guess, that's secondary stroke for that trial.
Mm-hmm.
Any observations there? You know, I know that you've said that their prior failure didn't change or impact your confidence in milvexian, but sort of interested in, you know, what you're hoping to learn from that program.
Mm.
Obviously, maybe, you know, different risk reward, obviously, since, you know, there is no apixaban in the control arm, given the disease-
Yeah
... state that it's being studied in.
Several takeaways, with one caveat that they've not presented the data, so we don't necessarily know the number of patients enrolled at the time when the DMC recommended to stop the study.
Okay
... or the number of events that happened that led to the stoppage of the study. What we do know that there was a huge difference seen between the two arms from a safety perspective, and therefore, the trial stopped. With that said, what we know about milvexian, and compare that to what was done in the clinical program for AF, for asundexian, is we do believe there is a differential dose that is required in atrial fibrillation as compared to what we are doing in combination with antiplatelet agents in SSP, as well as acute coronary syndrome studies. And the dose for atrial fibrillation for milvexian was based on prior studies that we conducted in TKR, or total knee replacement, patients undergoing total knee replacement.
That is what led us to that single agent given at a dose of 100 mg BID, rather than limiting it to a lower dose. That was not the case in case of asundexian. We are also aware now investigators conducting their own independent preclinical work, where they're beginning to show a differentiation dependent on the dose used, the concentrations achieved, and what they translate to on a therapeutic levels perspective. And they are showing, and hopefully, these data will be published sometime soon, what they're showing is there is a difference. If you don't use an appropriate dose, you don't achieve the therapeutic concentrations, and if you don't achieve the therapeutic concentrations, you don't deploy the mechanisms for avoiding the thrombus formation.
And that's why milvexian differentiates itself from asundexian from that perspective and looks similar to apixaban, and that's why the non-infusion priority makes sense in the AF trial. For SSP, again, both Bayer as well as ourselves, we are enrolling the studies, as well as we are enrolling in ACS. As the trials read out, we'll continue to keep a watch on it. I can't predict what the outcome is going to be, but what I can say is in the phase 2 study, the data looked pretty promising, and we did see an impact directly on the efficacy, and there was a small but important dose response from that perspective. And safety with the background of antiplatelet agents looked very promising and very tolerable.
Excellent. Well, we are out of time. Thank you so much for being here with us.
Thank you, Dave. Always a pleasure.
Appreciate it. Thank you.