Bristol-Myers Squibb Company (BMY) Earnings Call Transcript & Summary

My name is Trung Huynh, I am the pharma analyst here at UBS. It's my pleasure to welcome Dr. Robert Plenge, who is the Head of Research at Bristol-Myers Squibb. Robert, thank you so much for joining us today.

Yes. Thanks for having me.

Before I start, I do have a quick disclosure to read out. I am a research analyst. I am required to provide certain disclosures relating to the nature of my own relationship and that of UBS with any of the companies which we express a view on the call today. These disclosures are available at ubs.com/disclosure. Alternatively, please reach out to myself, and I can provide you them after the call. [Operator Instructions]

With that said, let's get into it. So we are delighted to have Bristol to talk on this subject. You are one of the leading companies in the protein degradation space. I think the best place to start is, Robert, if you can give us a quick background into yourself, your role at Bristol, how you got into that role, and then perhaps summarize yours and Bristol's enthusiasm for the protein degradation space.

Yes, certainly. So I've been at Celgene/BMS for years. I joined Celgene in 2017. And then BMS by way of the acquisition. So I've been involved in targeted protein degradation during that duration. I lead the research organization. We work very closely with the development organization and other parts of the company to deliver on our pipeline. And that piece is going to become very important as we talk about targeted protein degradation because I think a competitive advantage for us is how all of these pieces really fit together, knowledge of targets, knowledge of molecules and how to do clinical development, how to manufacture and ultimately how to get drugs to patients. One other just kind of disclaimer on my side, I will use we a lot in this discussion, but needless to say, there are many, many people who contribute to our knowledge and excitement around targeted protein degradation. So it's really a collective team effort. So to your question, I think why are we excited about the targeted protein degradation and why do we believe we're one of the leading companies, I think this is a field which has really matured a lot over the last several decades, and we're really proud that many of us, including our scientists at BMS have contributed to seminal discovery. So how thalidomide works, for example, binding the cereblon, the mechanisms of action, 2 approved medicines, Revlimid and Pomalyst but I think what really makes us excited and really speaks to our leadership is simply the number of clinical programs that we have ongoing. So we have 11 programs that are in clinical development, including 4 that are either in registrational trials today or will be in registrational trials in the next year. These include 3 distinct modalities, which we can actually talk more about. So molecular glues, CELMoDs, for example, as well as ligand-directed degraders, LDD, some call these PROTACs and then finally, degrader antibody conjugates or DACs. And then finally, I think just our commitment to the broader space of targeted protein degradation with regards to next-generation mechanisms. So we can talk about all of these in more detail, and I'm sure that we'll get to each of them.

Excellent. So yes, let's talk about perhaps a bit more generally, your protein degradation platform. As you said, you and Celgene, you are certainly considered one of the pioneers of the space. So perhaps can you give us a brief journey about how you guys have built out these platforms? And specifically, how Bristol's platform may differentiate from others that are in the space today.

So let me start with just the evolution from Revlimid and Pomalyst our images to what we now call our are CELMoDs. And so initially, the image were actually discovered more empirically. And since that time, we've continued to learn about how to make these molecules. And so now they're far more rationally and intentionally discovered in some cases, we use phenotypic screens. In other cases, we use binding to individual targets. So this has been a very long journey, and we've learned a lot along the way. Let me just give one -- a couple of specific examples around our platform. The first is how we've actually expanded our CELMoD library over time. So initially, we had several thousand CELMoD molecules in our library. And based upon all of our understanding, we've really been able to expand that library many fold. We know that these molecules bind to cereblon, and then they recruit neo substrates, so transcription factors, Aiolos and Ikaros for example, that get ubiquitinated and tagged for degradation. With our library expansion, we've been able to profile representative molecules across the entire human proteome and what we begin to see are novel proteins that did get degraded. And with these novel we call these neo substrates. With these novel neo substrates, we're beginning to learn kind of new rules about how these ternary complexes are formed, how cereblon recruits these neo substrates in the presence of these CELMoDs. We're beginning to discover entirely novel targets and novel motives, and these are now entering clinical development. So I think the first point to remember is just how we've expanded our CELMoD library based upon knowledge of the molecular mechanism of action. The second component of this is how we extended our knowledge of CELMoDs into 2 other approaches to target approaching degradation. Ligand-directed degraders, again, we call these LDDs. Others will refer to these as PROTAC's as well as degrader antibody conjugates and specifically for us CELMoD degrader antibody conjugates. And the reason that this is part of our platform, and I think that we believe that we're differentiating is that we can really understand aspects of cereblon molecular glues and how to hijack this ternary complex mechanism to design these LDDs or heterobifunctional molecules. We know how to think about optimal linker length, chemical flexibility of those linkers, for example, different features of neo substrate degradation, the kinetics of neo substrate degradation. So there's really a lot that goes in to designing these LDDs. A third component, and I think this is probably underappreciated is just our extensive collaboration network, not just within academics, but also within industry. And this allows us to think about novel targets, think about novel molecular blues, we have partnerships to use artificial intelligence and machine learning to really help with our capabilities. And so we're able to put all of this together, our knowledge of the clinical programs, manufacturing, knowledge of CELMoDs, LDDs, degraders, antibody conjugates and then our partner network to really, I think, be I think leaders in the field of targeted protein degradation.

Awesome. That's a great summary, and that leads me nicely on to the next question. So you've just talked about your work with the molecular glues. The heterobifunctional degraders, all the LDD, the ADCs. Perhaps, can you talk about some of the programs under each of those platforms, which ones are you most excited for? And where should we have the next set of updates in the next sort of 12 to 18 months?

Yes. So why don't I -- I'll start with the CELMoD program. So we have 2 myeloma programs that are in registrational studies today, iberdomide, and mezigdomide and then a third program, a semi program in registrational studies for lymphoma, and that's called golcadomide. Just to touch briefly on iberdomide and mezigdomide. We're really thinking about how to position these in the broader landscape of multiple myeloma. And by the way, I think this is another, I think, competitive advantage for us because we know not just about the biology of these individual molecules, but we understand the broader landscape of many of these diseases, including multiple myeloma for mechanisms beyond protein degradation. But for iberdomide and mezigdomide, iberdomide we're positioning in earlier lines of therapy in multiple myeloma as well as in the maintenance setting. And this is important because tolerability in the subset patients is very important. Mezigdomide is really interesting because it's our most potent CELMoD, and it was very intentionally designed to selectively and potently degrade 2 transcription factors Ikaros and Aiolos and this degradation was optimized even in cell lines that are resistant to our IMiDs, so Revlimid and Pomalyst. Mezigdomide also combines very well with other proteosome inhibitors and other mechanisms. And so we're positioning mezigdomide in more advanced and harder to treat patient segments. Just quickly on mezigdomide, just to say a few words about it, and then I'll pause and happy to kind of take your direction, Trung on where to go from here. But mezigdomide was very interesting because one of the things that we learned from our IMiDs is about how cereblon actually targets and then degrades these target proteins like Ikaros and Aiolos And what we learned from mezigdomide is that mezigdomide will actually lock cereblon in the closed state, which is the active state and this does this much more effectively than the IMiDs. And it's one of the features that allows us to have far more potent and selective degradation of Aiolos and Ikaros and I think the Phase I/II data that we published last year in the New England Journal of Medicine, both for the doublets and the triplets look very promising in terms of overall response rates and duration of disease and progression-free survival. And we expect data on both iberdomide and mezigdomide in 2026. So in the next couple of years for both of those registrational studies.

Excellent. And then within that talk of the other types of protein degradation that you have on board? Just do you think that people need to have a broad portfolio. So do you need to have a full toolkit here to see the greatest potential for each of these platforms?

I mean we believe it helps tremendously. I mean there are so many examples where we learn across our various programs. This includes knowledge around kind of translational data sets, knowledge about how to manage some of the side effects of these drugs, neutropenia is one example of that, how to combine them, and I think also about how to manufacture and make them. How to have the right formulation and then how all of this actually feeds back onto our preclinical programs to design the next generation of molecules. So we believe that having this full clinical development portfolio in a very, I think, robust toolkit is a very, very big competitive advantage for us.

Okay. Excellent. And then finally, just more on more broader questions before we dig into some of the CELMoD stuff and some of your other areas. If there was a novel target that you thought would be a great -- it would be greater suited to degrader target or drug how do you go about making a decision on how would you use this target, whether it's a CELMoD and LDD and ADC degrader, like what goes into that decision making?

Yes. So maybe just provide a very broad framework for how we think about programs even beyond targeted protein degradation. So we start with a deep understanding of causal human biology around the target of interest so in the case of targeted protein degradation, they're very high-value targets like the antigen receptor, BCL6, a number of others as well, and we can talk about those. But it's really more than just identifying a target. It's about how we will design a molecule to therapeutically perturb that target. So we call this matching modality to a molecular mechanism of action or matching modality to mechanism for short. And then finally, about how to actually bridge from research into development to actually show a clinical proof of concept because in early development there are obviously key inflection points, which tell you your drug is working and behaving the way that you think that it should. So that's a broad framework for how we think about all of our programs. And then in the case of a target that's suitable for targeted protein degradation, in some cases, there are functions of proteins that are -- go beyond enzymatic activity. So some proteins may have scaffolding function, for example, and you want to degrade both the enzymatic activity or get rid of the enzymatic activity in addition to the scaffolding function. There are other targets that just you can't modulate with traditional enzymatic inhibitors. So for example, transcription factors are great class because these are proteins that bind off into DNA and big complexes. And that is a very difficult process to interrupt. But if you can degrade those targets, we believe that, that will be a beneficial approach for patients. So BCL6 LDD is an example of that. And then finally, there are certain targets where there maybe enzymatic inhibitors but resistance occurs over time and we can actually think about how to make molecules against different parts of the protein to overcome those patterns of resistance. So the broad framework is causing a biology, matching modality to mechanism, path to clinical proof of concept and in particular, for the matching modality to mechanism segment of that framework, we think about ways in which targeted protein degradation is the ideal method of perturbing a target of interest.

Okay. Excellent. So let's touch upon some of the leading assets you have in development in the CELMoD. So iberdomide and mezigdomide. You touched on the mechanism of binding at cereblon and the degradation of E3 ubiquitin ligase. Revlimid also acts on the same sort of pathway, but it modulates this activity. These 2 drugs degrade the protein versus this modulation. So could you talk to how this differentiation could improve the efficacy beyond Revlimid here or overcome that resistance which you just touched upon?