Bristol-Myers Squibb Co at UBS Virtual Targeted Protein Degradation Day Transcript

The following is excerpted from the question-and-answer section of the transcript.

Question: Trung Huynh - UBS Group AG - Analyst : 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 probably 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? Robert Plenge - Bristol-Myers Squibb Co - Executive Vice President, Chief Research Officer, Head of Research, Member of the Leadership Team Yeah, certainly. So I've been at Celgene/BMS for seven years. So 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. without the prior written consent of Thomson Reuters. 'Thomson Reuters' and the Thomson Reuters logo are registered trademarks of Thomson Reuters and its affiliated companies.

Question: Trung Huynh - UBS Group AG - Analyst : Excellent. And so yeah, let's talk about -- and perhaps, a bit more generally, your protein degradation platform. As you say, you and Celgene, you certainly consider one of the pioneers of this 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? Robert Plenge - Bristol-Myers Squibb Co - Executive Vice President, Chief Research Officer, Head of Research, Member of the Leadership Team So let me start with just the evolution from REVLIMID and POMALYST, our IMiDs, to what we can now call our CELMoDs. And so initially, the IMiDs 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 manyfold. We know that these molecules bind to cereblon and they recruit neo-substrates. So transcription factors, Ikaros and Aiolos, 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 get degraded. And with these novel -- and 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 the CELMoDs. We're beginning to discover entirely novel targets and novel motifs, 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. without the prior written consent of Thomson Reuters. 'Thomson Reuters' and the Thomson Reuters logo are registered trademarks of Thomson Reuters and its affiliated companies.

Question: Trung Huynh - UBS Group AG - Analyst : Awesome. That's a great summary and that leads me nicely onto the next question. So you've just talked about your work with the molecular glues, the hetero bifunctional degraders, or the LDDs, 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? Robert Plenge - Bristol-Myers Squibb Co - Executive Vice President, Chief Research Officer, Head of Research, Member of the Leadership Team Yeah. So why don't I -- I'll start with the CELMoD program. So we have two of myeloma programs that are in registrational studies today, iberdomide and mezigdomide, and then a third program -- CELMoD program in registrational studies for lymphoma, and that's golcadomide. Just to touch briefly on iberdomide and mezigdomide, we're really thinking about how to position these in a 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. This is important because tolerability in this subset of 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 two transcription factors, Ikaros and Aiolos. And this degradation was optimized even in cell lines that are resistant to our IMiDs, to REVLIMID and POMALYST. Mezigdomide also combines very well with other proteasome 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 from -- on where to go from here. But mezigdomide was very interesting because one of the things that we learned from our IMiDs about how cereblon actually targets and then degrades these target proteins like a Ikaros and Aiolos. And what we learned from mezigdomide is mezigdomide will actually lock cereblon in the closed state, which is the active state. And this does this much more effectively than IMiDs. And it's one of the features that allows us to have far more potent and selective degradation of Aiolos and Ikaros. without the prior written consent of Thomson Reuters. 'Thomson Reuters' and the Thomson Reuters logo are registered trademarks of Thomson Reuters and its affiliated companies.

Question: Trung Huynh - UBS Group AG - Analyst : Excellent. And then within that toolkit 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 greatest potential for each of these platforms? Robert Plenge - Bristol-Myers Squibb Co - Executive Vice President, Chief Research Officer, Head of Research, Member of the Leadership Team I mean we believe it helps tremendously. There's 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 all of this actually feeds back on to our preclinical programs to design the next generation of molecules. So we believe that having this full clinical development portfolio and a very, I think, robust toolkit is a very, very big competitive advantage for us.

Question: Trung Huynh - UBS Group AG - Analyst : Okay. Excellent. So let's touch upon some of the leading assets you have in development in the CELMoDs. So iberdomide and mezigdomide, you touched on the mechanism of binding in cereblon and the degradation of E3 ubiquitin ligase. REVLIMID also acts on the same sort of pathway, but it modulates this activity. These two 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? Robert Plenge - Bristol-Myers Squibb Co - Executive Vice President, Chief Research Officer, Head of Research, Member of the Leadership Team So maybe just to clarify. So the way that all of these CELMoDs work is they're molecular glues, they bind to cereblon, they then recruit neo-substrates. The specificity and efficiency and depth of the degradation of those neo-substrates is really what delivers clinical activity. So REVLIMID, POMALYST, iberdomide, mezigdomide, golcadomide, all work in that same broad kind of molecular glue fashion. But the differentiation really comes from a few different features. In the case of iberdomide and mezigdomide, it's the ability to lock cereblon into this closed confirmation, and that's the active confirmation. And so REVLIMID, for example, locks cereblon in this active confirmation in about 20% of molecules. And in contrast to mezigdomide, golcadomide are closer to 100%. And that allows much deeper and more efficient degradation of neo-substrates like Ikaros and Aiolos. I think there are other features that go beyond kind of the IMiD class for CELMoDs and that include other features around how a drug can actually stay and penetrate, how it can penetrate into a tumor, how it can stand to a tumor and it can have a prolonged PD effect. And I think golcadomide is a good example of that in lymphoma. And then I think a third feature is how we can actually dial up or down selectivity. So there are some molecules which we think could actually add to clinical benefit -- sorry, some neo-substrates that are the targets of degradation that can actually add to clinical benefit and then others can actually add to the toxicity. And we can empirically dial these up or down based upon our knowledge of the mechanism of action. And again, this kind of comes back to this broader theme of -- because we have so many programs in clinical development and we can learn not only from our translational studies, but also in research across a variety of animal models, I think we have a pretty good handle on how to dial up and down some of the target degradation against these neo-substrates in a way that again creates a real competitive advantage for us.

Question: Trung Huynh - UBS Group AG - Analyst : And you touched perhaps on this a bit earlier when you were talking about combinations, but how do you think about adding DEXs to these compounds? Is DEXs enhancing of the benefit and tolerability of these studies because you've done some studies with mezi without DEXs, if that's right, and we haven't seen that data yet. Robert Plenge - Bristol-Myers Squibb Co - Executive Vice President, Chief Research Officer, Head of Research, Member of the Leadership Team So in general, I think the addition of dexamethasone, a steroid, to IMiDs and CELMoDs is seen as clinically beneficial and this includes not just on the efficacy side, but also on the tolerability side. So in terms of efficacy, there is improved cell autonomous killing. When you add dexamethasone to CELMoDs, we have preclinical data that we've actually published on that shows upregulation of various apoptotic mediators of cell killing. So it adds to the efficacy of CELMoDs. From a tolerability perspective, we think that dexamethasone can also help with one particular aspect, neutropenia. Although we don't fully know all the details of the mechanism of action, there is probably a component of it which has to do with the de-margination, but there are other features as well. We have done some exploratory studies on the neutropenia side with some of our reagents, including the human cereblon mouse model and we're working through some of the specifics in terms of the mechanism. But in general, dexamethasone has thought to be beneficial for both killing and for tolerability of these agents.

Question: Trung Huynh - UBS Group AG - Analyst : Okay, awesome. And just into the last five minutes here, I'd love to talk about your ligand directed degraders or the LDDs and also CELMoD ADCs. If we could start with the LDDs, can you compare and contrast how those -- how CELMoDs work versus LDDs and then your excitement for the BCL6 LDD program in lymphoma? Robert Plenge - Bristol-Myers Squibb Co - Executive Vice President, Chief Research Officer, Head of Research, Member of the Leadership Team So CELMoDs work as molecular glue. So it's a single molecule, tends to be smaller, binds to cereblon and then that recruits neo-substrates like Ikaros and Aiolos to this ternary complex. LDDs, again, people refer to these as PROTACs, they're hetero bifunctional molecule. So one end will bind to cereblon or another E3 ligase. There's a short linker. And then another part of the molecule, this is the hetero bifunctional piece of it, will bind to a target of interest. And so we can actually bind targets like BCL6, I'll talk briefly about that, but also targets such as the antigen receptor. And I do want to make sure I emphasize that we have, I think, very encouraging data for our antigen receptor LDD that we expect to advance into Phase 3 registrational trials within the next year. But specifically for BCL6, this is a target which is an incredibly high value target in lymphoma. It regulates germinal center dynamics in B-cells both for activation and maturation. But as a transcription factor, as I mentioned earlier, it's really, really hard to drug. So what we've done is we made this hetero bifunctional molecule, one end binds to cereblon, the other end binds to BCL6. And we can actually show in our preclinical models that we can actually degrade BCL6 and also have clinical benefit in these preclinical models. But what's really exciting is that we now have an IND that has cleared. We are now in human dose escalation studies and we should have data to report on this in the very near future to establish this relationship between BCL6 degradation and the impact on clinical activity.

Question: Trung Huynh - UBS Group AG - Analyst : Excellent. So we're heading up to the half hour mark here. Ellie has TRIANA Biomedicines on at 11:30. Dr. Plenge, that was timed to perfection. Thank you very much for your time and taken us through Bristol's developments here in the space. For those that listened in, we hope that was interesting to you and we hope you enjoy the rest of the day. Have a wonderful day, everyone. Robert Plenge - Bristol-Myers Squibb Co - Executive Vice President, Chief Research Officer, Head of Research, Member of the Leadership Team Thank you.