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

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. 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. 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. PRELIMINARY

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. The second component of this is how we've extended our knowledge of CELMoDs into two other approaches, two targeted protein degradation, ligand directed degraders. Again, we call these LDDs, others will refer to these as PROTACs; as well as the degrader antibody conjugates and specifically for us, CELMoD degrader antibody conjugates. 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. PRELIMINARY

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. PRELIMINARY

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. 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. PRELIMINARY

Question: Trung Huynh - UBS Group AG - Analyst : And can you perhaps talk about some of the data that we've seen so far, some of this early data in efficacy and also safety for both of these products? And then how translatable do you think that can be in more registrational trial? Robert Plenge - Bristol-Myers Squibb Co - Executive Vice President, Chief Research Officer, Head of Research, Member of the Leadership Team So I think for iberdomide and mezigdomide, again, for positioning these for earlier lines in multiple myeloma. Iberdomide, we're positioning for earlier lines and in the maintenance setting and then mezigdomide for later lines and more resistant refractory patient populations. And one of the things that we can actually see from our own translational data is not just the effect on degradation, but the other component of these drugs, which is not just direct tumor -- cytotoxic antitumor activity, but also the immunomodulatory features of these medicines. So the effect on T cell exhaustion, for example, or the effect on NK cell mediated killing. So those are a few examples about how, from a translational perspective, we see differential profiles. In terms of the clinical activity, and I think the real key for us is our ongoing registrational studies where we'll see more information. But the earlier data that we have from phase 1 and phase 2 in terms of both efficacy and toxicity profile is very favorable for multiple myeloma for both iberdomide and mezigdomide.

Question: Trung Huynh - UBS Group AG - Analyst : Yeah, it does seem that neutropenia is on-target tox for these agents. If we can move on to your other CELMoD, golcadomide. You presented some data at ASH last year, just how differentiated is this CELMoD? What's interesting to us here is it's in the treatment of Non-Hodgkin's lymphoma. So perhaps what's your thesis in developing it for something like BCL, specifically? Robert Plenge - Bristol-Myers Squibb Co - Executive Vice President, Chief Research Officer, Head of Research, Member of the Leadership Team So you asked in the beginning what are some of the favorite programs and I always get in trouble if I picked just one because depending upon who you ask, everyone has their favorite program. And I know there are some members of our team where golcadomide is absolutely the favorite. One interesting feature of this is how it was optimized specifically for Non-Hodgkin's lymphoma. So again, kind of building on this intentional and rational design on the next-generation of molecules. And here, what was a little bit different about golcadomide was to focus on other properties beyond just the degradation of Ikaros and Aiolos and specifically, how these medicines penetrate into bulky tumors such as lymphoma and how they get distributed, how they stay in the tumor and are active for a long period of time. And that's one of the features of golcadomide that I think is particularly unique, and we're beginning to see that play out in clinical development. And we did present some data at EHA just a few weeks ago that provide some updated information on the program. And this includes a rationalization for golcadomide from our preclinical models. But I think more importantly, how we're beginning to see this drug work in high-risk segments of DLBCL and follicular lymphoma. And this is really a target for us, is to go after first-line DLBCL in high-risk patients and it's about -- 30% to 40% of patients fall into this high-risk category. What we presented was evidence that showed a dose response between the two doses of golcadomide in this patient population. We showed data that demonstrates improvement across cell of origin in DLBCL. And also, we've provided -- we show data around the persistence and durability of MRD negativity. So I think multiple lines of evidence are making us very excited about golcadomide in first-line DLBCL and particularly, in high-risk patients. And as I mentioned, our Phase 3 study is ongoing and we expect to see data in the next few years.

Question: Trung Huynh - UBS Group AG - Analyst : Okay. That's useful to know. And then finally, just the last question on the CELMoD ADCs or DACs. We are a few ways away from the clinic here. I think you summarized the concepts at the start? But can you perhaps talk about your excitement here and then how difficult is this manufacturing process of the CELMoD ADCs versus normally ADCs? Is this difficult to manufacture? Robert Plenge - Bristol-Myers Squibb Co - Executive Vice President, Chief Research Officer, Head of Research, Member of the Leadership Team Yeah. So just clarification. We are actually in the clinic today with our lead program, which is a CD33 GSPT1 antibody drug conjugate or degrader antibody conjugate. And I think what makes us really excited about this particular molecule is that we know that each component of this is clinically active in patients with AML, but each individual component has limitations when given systemically. So GSPT1 -- sorry, there's a CELMoD that degrades GSPT1, it's clinically active. We know that there's benefit, but there are side effects such as hypercalcemia when it goes throughout the body. Similarly, CD33, the other component of this, clinically active. There's a drug called Mylotarg that was approved way back in 2000, but they're also side effects including veno-occlusive disease, which was thought to be caused by the drug that was conjugated to it. So we then asked ourselves can we combine both of these together to actually have the clinical benefit of each while limiting some of the adverse side effects? And that's the concept of a degrader antibody conjugate and as I mentioned, we are in clinical development with this program and Phase 1 dose escalation now. So we're really excited about showing data on that in the coming year or two.

Question: Trung Huynh - UBS Group AG - Analyst : Thanks, Dr. Plenge.